Standards for Clinical Care of Adults

with Sickle Cell Disease in the UK

2nd Edition, 2018

Copyright © 2018, 2008 Sickle Cell Society. All rights reserved.
Although every precaution has been taken to verify the accuracy of the information contained
herein, the authors and publisher assume no responsibility for any errors or omissions. No
liability is assumed for damages that may result from the use of information contained within.

Sickle Cell Society

54 Station Road
London NW10 4UA
United Kingdom
Tel.: +44 (0)20 8961 7795
Fax: +44 (0)20 8961 8346
[email protected]
www.sicklecellsociety.org

Cover image by michaeljung/Shutterstock.com

Reproduced under license from Shutterstock.com

Figure 1: A suggested model of transition, from Musumadi, L., Westerdale, N., & Appleby, H. (2012).
An overview of the effects of sickle cell disease in adolescents. Nursing Standard, 26(26), 35-40
[Nursing Standard by Royal College of Nursing (Great Britain)]
Reproduced with permission of RCN Publishing Co. in the format ‘Other Published Product’ via
Copyright Clearance Center.

Figure 6: Percentage of women experiencing an unintended pregnancy within the first year of use
with typical use and perfect use (UKMEC 2016. https://www.fsrh.org/ukmec/)
Reproduced under licence from FSRH. Copyright © Faculty of Sexual and Reproductive
Healthcare 2006 to 2016. [This figure is modified from an original version in (Trussell, 2011).]

ISBN 978-1-5272-2070-6

Printed in the United Kingdom

First published 2008
Revised 2018

This and the previous edition of the standards are also available online at:
www.sicklecellsociety.org

The costs associated with the development of these standards were supported by an
unrestricted educational grant from Novartis Pharmaceuticals

Standards for Clinical Care of Adults with Sickle Cell Disease in the UK, 2nd Edition
 Contents
Tables and figures .......................................................................................................................................... 1
Editorial/writing group ............................................................................................................................... 3
Acknowledgements........................................................................................................................................ 7
Additional acknowledgements.................................................................................................................. 9
Production ........................................................................................................................................................ 9
Clinical disclaimer.......................................................................................................................................... 9
Foreword .........................................................................................................................................................11
Statements of support.................................................................................................................................13
Chair’s introduction.....................................................................................................................................19
Note on Methodology ..................................................................................................................................21
Standards................................................................................................................................................................ 21
Recommendations.............................................................................................................................................. 21
Overarching standards...............................................................................................................................23
General principles ..............................................................................................................................................................23
Transition ..............................................................................................................................................................................23
Primary care.........................................................................................................................................................................23
Acute pain..............................................................................................................................................................................24
Acute complications..........................................................................................................................................................24
Chronic complications......................................................................................................................................................24
Prevention of infection.....................................................................................................................................................24
Annual review ......................................................................................................................................................................25
Pregnancy ..............................................................................................................................................................................25
Hydroxycarbamide (HC) .................................................................................................................................................25
Transfusion ...........................................................................................................................................................................25
Emerging therapies...........................................................................................................................................................26
Section A: General principles ...................................................................................................................27
Chapter 1: Overview ....................................................................................................................................29
Introduction..........................................................................................................................................................................29

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Haemoglobin S and other significant variants.....................................................................................................29

Sickle cell carriers ..............................................................................................................................................................29
Epidemiology........................................................................................................................................................................30
Pathophysiology..................................................................................................................................................................30
Clinical presentation.........................................................................................................................................................30
Clinical course and survival...........................................................................................................................................31
Diagnosis................................................................................................................................................................................31
Screening for sickle cell ...................................................................................................................................................32
National screening programme .................................................................................................................... 32
Neonatal screening............................................................................................................................................. 32
Antenatal screening ........................................................................................................................................... 33
Emergency and opportunistic screening .................................................................................................. 33
Predictive factors and variability in phenotype...................................................................................................33
Rationale for therapies....................................................................................................................................................34
Chapter 2: Organisation of care...............................................................................................................35
General principles ..............................................................................................................................................................35
Introduction .......................................................................................................................................................... 35
Standards................................................................................................................................................................ 35
Background evidence ........................................................................................................................................ 36
Recommendations.............................................................................................................................................. 39
Transition services.............................................................................................................................................................40
Introduction .......................................................................................................................................................... 40
Standard.................................................................................................................................................................. 40
Background evidence ........................................................................................................................................ 40
Recommendations.............................................................................................................................................. 42
Quality improvement........................................................................................................................................................43
Introduction .......................................................................................................................................................... 43
Standards................................................................................................................................................................ 43
Specialised commissioning ............................................................................................................................................44
Background evidence ........................................................................................................................................ 44
Peer review............................................................................................................................................................................45
Background evidence ........................................................................................................................................ 45
National Haemoglobinopathy Registry (NHR) ....................................................................................................46
Background evidence ........................................................................................................................................ 46
Clinical audit ........................................................................................................................................................................48
Background evidence ........................................................................................................................................ 48

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Recommendations.............................................................................................................................................. 49
Chapter 2: Conclusion ......................................................................................................................................................50
Chapter 3: Primary care .............................................................................................................................51
Introduction..........................................................................................................................................................................51
Role of the primary care team......................................................................................................................................51
Introduction .......................................................................................................................................................... 51
Standards................................................................................................................................................................ 52
Background evidence ........................................................................................................................................ 52
Recommendations.............................................................................................................................................. 53
Community nursing...........................................................................................................................................................54
Introduction .......................................................................................................................................................... 54
Standards................................................................................................................................................................ 55
Background evidence ........................................................................................................................................ 55
Recommendations.............................................................................................................................................. 58
Prevention of infection: immunisations and prophylactic antibiotics ......................................................58
Introduction .......................................................................................................................................................... 58
Standards................................................................................................................................................................ 59
Vaccinations .......................................................................................................................................................... 59
Summary of vaccination advice .................................................................................................................... 62
Antibiotic prophylaxis....................................................................................................................................... 63
Travel vaccinations and antibiotics............................................................................................................. 64
Recommendations:............................................................................................................................................. 64
Blood pressure monitoring ............................................................................................................................................64
Introduction .......................................................................................................................................................... 64
Standard.................................................................................................................................................................. 64
Background evidence ........................................................................................................................................ 65
Recommendations.............................................................................................................................................. 65
Folic acid ................................................................................................................................................................................65
Introduction .......................................................................................................................................................... 65
Standards................................................................................................................................................................ 65
Background evidence ........................................................................................................................................ 66
Recommendation ................................................................................................................................................ 66
Bone health and vitamin D ............................................................................................................................................67
Introduction .......................................................................................................................................................... 67
Standards................................................................................................................................................................ 67
Background evidence ........................................................................................................................................ 67
Recommendation ................................................................................................................................................ 68
Dental management of SCD...........................................................................................................................................68

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Introduction .......................................................................................................................................................... 68
Standards................................................................................................................................................................ 69
Background evidence ........................................................................................................................................ 69
Recommendations.............................................................................................................................................. 70
Chapter 3: Conclusion ......................................................................................................................................................70
Chapter 4: Health and well-being ...........................................................................................................71
Public health.........................................................................................................................................................................71
Introduction .......................................................................................................................................................... 71
Standard.................................................................................................................................................................. 71
Background evidence ........................................................................................................................................ 71
Recommendations.............................................................................................................................................. 72
Psychological interventions...........................................................................................................................................73
Introduction .......................................................................................................................................................... 73
Standards................................................................................................................................................................ 73
Background evidence ........................................................................................................................................ 74
Recommendations.............................................................................................................................................. 74
Nutrition and lifestyle ......................................................................................................................................................75
Introduction .......................................................................................................................................................... 75
Standards................................................................................................................................................................ 75
Background evidence ........................................................................................................................................ 76
Recommendations.............................................................................................................................................. 77
Health education ................................................................................................................................................................77
Introduction .......................................................................................................................................................... 77
Standard.................................................................................................................................................................. 78
Background evidence ........................................................................................................................................ 78
Recommendations.............................................................................................................................................. 79
Support in education and training.............................................................................................................................80
Introduction .......................................................................................................................................................... 80
Standards................................................................................................................................................................ 80
Background evidence ........................................................................................................................................ 80
Recommendation ................................................................................................................................................ 81
Welfare and social security benefits..........................................................................................................................81
Introduction .......................................................................................................................................................... 81
Standard.................................................................................................................................................................. 82
Background evidence ........................................................................................................................................ 82
Recommendations.............................................................................................................................................. 83
Patient voice, support groups and peer support..................................................................................................83
Introduction .......................................................................................................................................................... 83
Standard.................................................................................................................................................................. 84

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Background evidence ........................................................................................................................................ 84

Recommendations.............................................................................................................................................. 86
Chapter 4: Conclusion ......................................................................................................................................................87
Section B: Management of acute and chronic complications........................................................89
Chapter 5: Acute and chronic pain .........................................................................................................91
Acute pain..............................................................................................................................................................................91
Standards................................................................................................................................................................ 91
Background evidence ........................................................................................................................................ 92
Reassessment and ongoing management ................................................................................................. 93
Monitoring ............................................................................................................................................................. 94
Discharge................................................................................................................................................................ 94
Recommendations.............................................................................................................................................. 95
Chronic pain..........................................................................................................................................................................95
Introduction .......................................................................................................................................................... 95
Standards................................................................................................................................................................ 96
Background evidence ........................................................................................................................................ 96
Management.......................................................................................................................................................... 97
Recommendations.............................................................................................................................................. 98
Chapter 6: Neurological complications ................................................................................................99
Introduction..........................................................................................................................................................................99
Acute stroke ..........................................................................................................................................................................99
Standards................................................................................................................................................................ 99
Incidence and aetiology..................................................................................................................................100
Investigation of patient presenting with symptoms of stroke .......................................................100
Management of acute ischaemic stroke...................................................................................................101
Management of acute haemorrhagic stroke ..........................................................................................102
Recommendation ..............................................................................................................................................102
Stroke prevention............................................................................................................................................................ 102
Standards..............................................................................................................................................................102
Primary stroke prevention............................................................................................................................103
Secondary stroke prevention.......................................................................................................................103
Recommendations............................................................................................................................................105
Other neurological complications ........................................................................................................................... 105
Standard................................................................................................................................................................105
Neurocognitive impairment .........................................................................................................................105
Headaches ............................................................................................................................................................105
Recommendations............................................................................................................................................106
Chapter 7: Cardiorespiratory complications................................................................................... 107

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Acute chest syndrome.................................................................................................................................................... 107

Introduction ........................................................................................................................................................107
Standards..............................................................................................................................................................107
Background evidence ......................................................................................................................................108
Recommendations............................................................................................................................................109
Chronic respiratory complications.......................................................................................................................... 110
Standards..............................................................................................................................................................110
Background evidence ......................................................................................................................................110
Respiratory investigations ............................................................................................................................111
Treatment.............................................................................................................................................................112
Recommendation ..............................................................................................................................................112
Cardiac complications................................................................................................................................................... 112
Standards..............................................................................................................................................................112
Background evidence ......................................................................................................................................113
Other cardiac abnormalities.........................................................................................................................116
Recommendations............................................................................................................................................116
Chapter 8: Renal and urological complications.............................................................................. 117
Introduction....................................................................................................................................................................... 117
Renal disease ..................................................................................................................................................................... 117
Standards..............................................................................................................................................................117
Background evidence ......................................................................................................................................118
Recommendations............................................................................................................................................121
Chapter 9: Priapism.................................................................................................................................. 123
Standards..............................................................................................................................................................123
Background information................................................................................................................................123
Acute priapism ...................................................................................................................................................124
Stuttering priapism ..........................................................................................................................................125
Recommendations............................................................................................................................................127
Chapter 10: Fever and sepsis ................................................................................................................ 129
Introduction ........................................................................................................................................................129
Standards..............................................................................................................................................................129
Background evidence ......................................................................................................................................129
Recommendations............................................................................................................................................131
Chapter 11: Orthopaedic complications ........................................................................................... 133
Osteomyelitis ..................................................................................................................................................................... 133
Introduction ........................................................................................................................................................133
Standards..............................................................................................................................................................133
Background evidence ......................................................................................................................................133

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Imaging..................................................................................................................................................................134
Treatment.............................................................................................................................................................134
Avascular necrosis .......................................................................................................................................................... 134
Standards..............................................................................................................................................................134
Background evidence ......................................................................................................................................135
Treatment.............................................................................................................................................................136
Recommendations............................................................................................................................................138
Chapter 12: Gastroenterological and hepatobiliary complications........................................ 139
Introduction ........................................................................................................................................................139
Standards..............................................................................................................................................................139
Background evidence ......................................................................................................................................140
Monitoring liver function and investigating liver disease ...............................................................140
Recommendations............................................................................................................................................144
Chapter 13: Ophthalmological complications................................................................................. 145
Introduction ........................................................................................................................................................145
Standards..............................................................................................................................................................145
Background evidence ......................................................................................................................................145
Recommendations............................................................................................................................................147
Chapter 14: Anaemia................................................................................................................................ 149
Introduction ........................................................................................................................................................149
Standards..............................................................................................................................................................149
Background evidence ......................................................................................................................................150
Other causes of acute anaemia ....................................................................................................................150
Recommendation ..............................................................................................................................................151
Chapter 15: Leg ulceration ..................................................................................................................... 153
Introduction ........................................................................................................................................................153
Standards..............................................................................................................................................................153
Background information................................................................................................................................153
Treatment.............................................................................................................................................................154
Prevention............................................................................................................................................................156
Recommendations............................................................................................................................................156
Chapter 16: Other complications......................................................................................................... 157
Acute multisystem organ failure.............................................................................................................................. 157
Standards..............................................................................................................................................................157
Background evidence ......................................................................................................................................157
Section C: Treatment and additional management issues.......................................................... 159
Chapter 17: Out-patient management ............................................................................................... 161

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Introduction ........................................................................................................................................................161
Standards..............................................................................................................................................................161
Background information................................................................................................................................161
Chapter 18: Reproductive health......................................................................................................... 165
Contraception ................................................................................................................................................................... 165
Introduction ........................................................................................................................................................165
Standards..............................................................................................................................................................165
Background evidence ......................................................................................................................................165
Contraception choices and effectiveness of contraceptive methods...........................................166
Recommendations............................................................................................................................................170
Pre-conceptual advice................................................................................................................................................... 170
Introduction ........................................................................................................................................................170
Standards..............................................................................................................................................................171
Background evidence ......................................................................................................................................171
Pregnancy ........................................................................................................................................................................... 172
Introduction ........................................................................................................................................................172
Standards..............................................................................................................................................................172
Background evidence ......................................................................................................................................173
Antenatal period................................................................................................................................................173
Delivery.................................................................................................................................................................175
Post-partum ........................................................................................................................................................175
Chapter 19: Surgery.................................................................................................................................. 177
Introduction ........................................................................................................................................................177
Standards..............................................................................................................................................................177
Background evidence ......................................................................................................................................177
Role of transfusion............................................................................................................................................178
Recommendations............................................................................................................................................180
Chapter 20: Hydroxycarbamide ........................................................................................................... 181
Introduction ........................................................................................................................................................181
Standards..............................................................................................................................................................181
Background evidence ......................................................................................................................................182
Patient selection ................................................................................................................................................183
HC administration.............................................................................................................................................184
Use of a treatment protocol ..........................................................................................................................185
Toxicity..................................................................................................................................................................185
HC and abnormal spermatogenesis...........................................................................................................185
Evidence of effectiveness in adults with genotypes other than sickle cell anaemia or
haemoglobin S/β0 thalassaemia. ................................................................................................................186
Recommendations............................................................................................................................................186

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Chapter 21: Blood transfusion.............................................................................................................. 187

Introduction ........................................................................................................................................................187
Standards..............................................................................................................................................................187
Aim of transfusion therapy and choice of modalities ........................................................................188
Selection of blood and communication with transfusion laboratory..........................................191
Compatibility testing .......................................................................................................................................191
Extended red cell phenotype/genotype ..................................................................................................191
Blood product selection .................................................................................................................................191
Adverse transfusion reactions.....................................................................................................................192
Indications for transfusion............................................................................................................................193
Indications for chronic transfusion ...........................................................................................................194
Recommendations............................................................................................................................................194
Chapter 22: Iron chelation ..................................................................................................................... 195
Introduction ........................................................................................................................................................195
Standards..............................................................................................................................................................195
Background evidence ......................................................................................................................................196
Iron chelation......................................................................................................................................................197
Chapter 23: Haematopoietic stem cell transplantation............................................................... 201
Introduction ........................................................................................................................................................201
Standards..............................................................................................................................................................201
Background evidence ......................................................................................................................................201
Recommendation ..............................................................................................................................................203
Chapter 24: Emerging therapies .......................................................................................................... 205
Introduction ........................................................................................................................................................205
Standard................................................................................................................................................................205
Drugs currently under evaluation..............................................................................................................205
Reducing vascular endothelial adhesion and cell-cell interactions .............................................205
Modifying nitric oxide signalling ................................................................................................................206
Reducing inflammation/oxidative stress................................................................................................207
Allosteric effectors of haemoglobin...........................................................................................................208
Reducing red blood cell dehydration........................................................................................................208
Reactivating foetal haemoglobin ................................................................................................................208
Gene therapy.......................................................................................................................................................208
Chapter 24: Conclusion...................................................................................................................................209
Chapter 25: Overall conclusion ............................................................................................................ 211
Appendices................................................................................................................................................... 213
Appendix 1: Medical staffing recommendations............................................................................................... 215
Appendix 2: Psychological therapies...................................................................................................................... 217

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Psychological Therapies.................................................................................................................................217
Other Psychological Therapies....................................................................................................................217
Appendix 3: Benefits advice........................................................................................................................................ 219
Personal Independence Payment (PIP)...................................................................................................219
Employment and Support Allowance (ESA) ..........................................................................................219
Statutory Sick Pay (SSP).................................................................................................................................220
Attendance Allowance (AA)..........................................................................................................................220
Direct Payment (DP)........................................................................................................................................220
Universal credit (UC).......................................................................................................................................220
Free NHS Prescription or prepayment prescription certificate ....................................................220
Local Welfare Assistance Scheme (LWAS) .............................................................................................221
Benefits Cap.........................................................................................................................................................221
Local Housing Allowance...............................................................................................................................221
Council Tax Reduction ....................................................................................................................................221
Additional benefits ...........................................................................................................................................221
Sources of further information....................................................................................................................222
Appendix 4: Annual review pro-forma .................................................................................................................. 223
Appendix 5: GP outpatient letter.............................................................................................................................. 229
Appendix 6: Indications for haematopoietic stem cell transplantation (HSCT) in adults with
sickle cell disease ............................................................................................................................................................. 237
Appendix 7: Frequently asked questions .............................................................................................................. 239
General questions .............................................................................................................................................239
Primary care........................................................................................................................................................240
Health and well-being .....................................................................................................................................241
Pain management .............................................................................................................................................246
Disease complications.....................................................................................................................................247
Surgery ..................................................................................................................................................................249
Treatment.............................................................................................................................................................249
References.................................................................................................................................................... 253

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 Tables and figures
Figure 1: A suggested model of transition .........................................................................................................41

Figure 2: The main issues about which the Sickle Cell Society are contacted.....................................85

Figure 3: Acute Pain Quick Reference..................................................................................................................92

Figure 4: Algorithm for pulmonary hypertension screening ..................................................................115

Figure 5: Ficat and Steinberg classification systems ..................................................................................136

Figure 6: Percentage of women experiencing an unintended pregnancy..........................................167

Figure 7: Comparison of different transfusion modalities .......................................................................190

Figure 8: Indicators where primary goal is to correct acute anaemia.................................................193

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 Editorial/writing group

Editorial Board
 Dr Jo Howard, Consultant Haematologist/Honorary Reader, Guy’s and St Thomas’ NHS
Foundation Trust, London/King’s College London and Chair of the UK Forum on
Haemoglobin Disorders (Chair of Editorial/Writing Group)
 Dr Kofi Anie MBE, Consultant Clinical Psychologist/Honorary Clinical Senior Lecturer,
Brent Sickle Cell and Thalassaemia Centre, London North West Healthcare NHS
Trust/Imperial College London
 Professor Karl Atkin, Head of Department, Department of Health Sciences, University of
York
 Dr Wale Atoyebi, Consultant Haematologist, Oxford University Hospitals NHS
Foundation Trust
 Dr Moji Awogbade, Consultant Haematologist, King’s College Hospital NHS Foundation
Trust
 Dr Gavin Cho, Consultant in Donor Medicine, NHS Blood and Transplant and Honorary
Consultant Haematologist, University College London Hospital Foundation Trust
 Ms Verna Davis, Service Manager and Lead Haemoglobinopathy Specialist Nurse,
Manchester Sickle Cell and Thalassaemia Service
 Mr John James, Chief Executive Officer, Sickle Cell Society
 Ms Natasha Lewis, Lead Nurse Sickle Cell & Thalassaemia, Homerton University Hospital
NHS Foundation Trust
 Ms June Okochi, Lead Mentor, Patient representative, Sickle Cell Society
 Dr Shivan Pancham, Consultant Haematologist, Sandwell and West Birmingham
Hospitals NHS Trust
 Dr Kate Ryan, Consultant Haematologist, Manchester Royal Infirmary and Chair of the
NHS England Clinical Reference Group for Haemoglobinopathies
 Ms Michele Salter, Vice Chair and Treasurer, Sickle Cell Society
 Dr Paul Telfer, Senior Lecturer in Haematology, Queen Mary University of London,
Consultant Haematologist Bart’s Health NHS Trust
 Dr Anne Yardumian, Consultant Haematologist, North Middlesex University Hospital,
London

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 Editorial/writing group

Contributing Authors
Grateful thanks to the following, who authored or co-authored individual chapters:

 Dr Shubha Allard, Consultant Haematologist/Honorary Clinical Senior Lecturer, NHS

Blood and Transplant and Barts Health NHS Trust/ Queen Mary University of London
 Dr Jeremy Anderson, Sickle Cell Team Psychologist, Imperial College Healthcare NHS
Trust
 Professor Selim Aractingi, Faculty of Medicine, University of Paris Descartes; Head of
Dermatology, Cochin Hospital, Paris
 Dr Glenda Augustine, Consultant in Public Health, City of Wolverhampton Council
 Mr Marcus Bankes, Consultant Orthopaedic Surgeon, Guy’s and St Thomas’ NHS
Foundation Trust
 Dr Martin Besser, Consultant Haematologist, Cambridge University Hospitals NHS
Foundation Trust
 Dr Gerry Coghlan, Consultant Cardiologist, Director of Pulmonary Hypertension service,
Royal Free London NHS Foundation Trust
 Dr Bernard Davis, Consultant Haematologist, The Whittington Hospital NHS Trust/
University College Hospital London
 Dr Emma Drasar, Consultant Haematologist, The Whittington Hospital, London
 Professor Simon Dyson, Professor of Applied Sociology, De Monfort University
 Professor James Elander, Head of Centre for Psychological Research, University of Derby
 Dr Perla Eleftheriou, Consultant Haematologist, University College London Hospital
Foundation Trust
 Dr Kate Gardner, Clinical Research Fellow/Specialist Registrar Haematology, King’s
College London/King’s College Hospital
 Dr Deborah Hay, Consultant Haematologist, Oxford University Hospitals NHS
Foundation Trust
 Dr Baba Inusa, Consultant Paediatrician/Honorary Reader, Evelina Hospital
London/Guy’s and St Thomas’ NHS Foundation Trust, London/King’s College London
 Dr Banu Kaya, Consultant Haematologist, Bart’s Health NHS Trust, London
 Dr Rachel Kesse-Adu, Consultant Haematologist, Guy’s and St Thomas’ NHS Foundation
Trust
 Professor Fenella Kirkham, Professor of Paediatric Neurology, University Hospital
Southampton NHS Foundation Trust/University College London/Great Ormond Street
Institute of Child Health
 Dr Pavel Kotoucek, Consultant Haematologist, Dartford and Gravesham NHS Trust
 Dr Stella Kotsiopoulou, Consultant Haematologist, Croydon Health Services NHS Trust

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 Editorial/writing group

 Dr Navdeep Kumar, Consultant in Special Care Dentistry/Honorary Lecturer University

College London, Clinical Lead for Oral Medicine, Facial Pain and Special Care Dentistry,
Eastman Dental Hospital for Oral Healthcare Sciences
 Dr Usha Kumar, Lead consultant for Reproductive and Sexual Health, Camberwell Sexual
Health Centre, King’s College Hospital NHS Foundation Trust
 Dr Jane Logan, General Practitioner, FRCGP.
 Dr Jenna Love, Clinical Psychologist, Red Cell Pain Management and Psychology Service,
St George’s University Hospitals NHS Foundation Trust
 Dr Asad Luqmani, Consultant Haematologist, Imperial College Healthcare NHS Trust
 Ms Claudine Matthews, Social Liaison Officer, Sickle cell and thalassaemia service,
Homerton University Hospital NHS Foundation Trust
 Dr Patrick Murphy, Consultant Respiratory Physician/Honorary Senior Lecturer, Guy’s
and St Thomas’ NHS Foundation Trust/King’s College London
 Mr Luhanga Musumadi, Advanced Nurse Practitioner Haemoglobinopathies and Lead
nurse for Adolescent Transition, Guy’s and St Thomas’ NHS Foundation Trust
 Dr Douglas Newman, Consultant Ophthalmologist, Cambridge University Hospitals NHS
Foundation Trust
 Mr Daniel Nyakutsey, Welfare Support Advisor, Sickle Cell & Thalassaemia Community
Services, South East London Sickle and Thalassaemia Centre
 Dr Ruben Nzouakou, Homerton University Hospital NHS Foundation Trust
 Mr Eugene Oteng-Ntim, Consultant Obstetrician, Honorary Reader in Women’s Health,
Guy’s and St Thomas’ NHS Foundation Trust/King’s College London
 Soorbhi Parekh, Sickle Cell Society
 Dr Elizabeth Rhodes, Consultant Haematologist, St George’s University Hospitals NHS
Foundation Trust
 Professor Vanderson Rocha, Principal Investigator of Stem Cell Therapies, NHS Blood
and Transplant, Oxford University Hospitals NHS Foundation Trust and Professor of
Haematology, Transfusion and Cell Therapy, University of Sao Paulo, Brazil
 Nasser Roheemun, Specialist Nurse/Centre Manager, The George Marsh Sickle Cell and
Thalassaemia Centre, North Middlesex University Hospital NHS Trust
 Dr Clare Samuelson, Specialist Registrar Haematology, Sheffield Teaching Hospitals NHS
Foundation Trust
 Dr Claire Sharpe, Reader in Renal Medicine, King’s College London and Honorary
Consultant Nephrologist, King’s College Hospital NHS Foundation Trust
 Dr Abid Suddle, Consultant Hepatologist, Institute of Liver Studies, King’s College
Hospital NHS Foundation Trust
 Dr Sara Trompeter, Consultant Haematologist and Paediatric Haematologist, University
College Hospital London and Consultant in Transfusion for Haemoglobinopathies, NHS
Blood and Transplant

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 Editorial/writing group

 Mr Nick Watkins, Consultant Haematologist, St George’s University Hospitals NHS

Foundation Trust
 Dr Josh Wright, Consultant Haematologist, Sheffield Teaching Hospitals NHS Foundation
Trust

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 Acknowledgements
We are grateful to the following parties, who gave helpful comments on chapters in the draft
document as part of our sounding board:

 British Psychological Society, Special Interest Group for Psychologists working in Sickle
Cell and Thalassaemia (Dr Heather Rawle, Dr Nicky Thomas, Dr Jeremy Anderson, Dr
Jenna Love, Dr Helen de Marco, Dr Gary Bridges, Dr Penelope Cream.)
 Ms Nkechi Anyanwu, Clinical Nurse Manager, Sickle Cell & Thalassaemia Community
Services, South East London Sickle and Thalassaemia Centre
 Professor Barbara Bain, Professor of Diagnostic Haematology, St Mary’s Hospital
 Dr Cormac Breen, Consultant Nephrologist, Guy’s and St Thomas’ NHS Foundation Trust
 Dr Annabel Crowe, General Practitioner, Mental Health Clinical Lead, Governing Body
Member for Hounslow CCG
 Dr Yvonne Daniel, Viapath, Specialist Lead Scientist, Haematological Sciences, Special
Haematology Lead, Blood Sciences, Guy’s Hospital
 Dr Lorna Fraser, Senior Lecturer, Department of Health Sciences, University of York
 Dr Helen Haynes, Research Group Administrator, Department of Health Sciences,
University of York
 Dr Quentin Hill, Consultant Haematologist, Leeds Teaching Hospitals NHS Trust
 Dr Paul Holmes, Consultant Neurologist, Guy’s and St Thomas’ NHS Foundation Trust
 Dr Moin Mohamed, Consultant Ophthalmologist, Guy’s and St Thomas’ NHS Foundation
Trust
 Ms Chengetai Muzah, Specialist Nurse, Sickle Cell and Thalassaemia Centre, East Ham,
London
 Dr Lola Oni OBE, Specialist Nurse Consultant/Service Director/Lecturer, Brent Sickle
Cell and Thalassaemia Centre, London North West Healthcare NHS Trust
 Dr Sue Robinson, Consultant Haematologist, Guy’s and St Thomas’ NHS Foundation
Trust
 Mr Majed Shabbir, Consultant Urologist, Guy’s and St Thomas’ NHS Foundation Trust
 Dr Farrukh Shah, Consultant Haematologist, The Whittington Hospital NHS Trust/
University College Hospital London
 Ms Sekayi Tangayi, Service Manager and Specialist Nurse, Sickle Cell and Thalassaemia
Centre, East Ham, London
 Mr Neill Westerdale, Advanced Nurse Practitioner Sickle Cell Disease, Guy’s and St
Thomas’ NHS Foundation Trust
 The Haematology team at North Middlesex University Hospital NHS Trust

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 Additional acknowledgements
In addition to all those mentioned above, these standards have benefitted from the
contributions and support of countless others, far too many to name here. Whether health care
professionals, patron or members of sickle cell support groups and sickle cell and thalassaemia
centres, the value of their collaboration is immeasurable and greatly appreciated. Thank you to
Jo Whitcombe for your assistance with literature searches and to Anne Oddotte with your help
in organising the meetings and secretarial support. Many thanks to Barbara Bain, for her time
spent reviewing the document and provision of numerous helpful comments and corrections.
Thank you also to Gavin Macmillan who provided excellent and painstaking editorial support.
Apologies to those we have not mentioned by name.

Thank you to the board of the Sickle Cell Society for your ongoing support.

Production
The publication of these standards is an initiative of the Sickle Cell Society and the UK Forum for
Haemoglobin Disorders. All the writers and editors donated their time and expertise and
received no remuneration or benefits in kind for their contributions.

An unrestricted educational grant was received from Novartis which supported costs of
production and publication. They have had no academic or editorial input into this document.

Clinical disclaimer
The content of the document is evidence based, as far as available evidence allows, and reflects
the experience and opinions of its authors. However they, the Sickle Cell Society, and the UK
Forum on Haemoglobin Disorders can take no responsibility for clinical problems arising in
individual patients managed in line with the contents. New evidence made available since
publication should be taken into account when using this document.

The Sickle Cell Society, UK Registered Charity No. 1046631

The Sickle Cell Society can be contacted at:

Registered address: Telephone: 020 8961 7795

54 Station Road 020 8961 8346
London, NW10 4UA email: [email protected]

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 Foreword
As Chair and Chief Executive of the Sickle Cell Society we are honoured to serve patients, and
their families, and work with the caring professionals in the National Health Service and
beyond. Patient Reported Experience Measures by Collaboration for Leadership in Applied
Health Research and Care (CLAHRC), National Institute of Health Research (NIHR), Picker
Institute and the Sickle Cell Society have revealed significant concerns over the treatment, care,
and the quality of service patients receive, which varies according to postcode and provider
(Picker Institute Europe, 2015). Research into this condition is increasing however and clinical
trials are providing real hope for improving treatments and cures.

If you are reading this foreword we would like to thank you for making a great start, but from
this outset, we encourage you to read the ‘Standards for Clinical Care of Adults with Sickle Cell
Disease’ to the end. Learn it, share it, and practice it, until its use is embedded at the heart of
treatment and care for people suffering the chronic lifelong medical condition of sickle cell
disorder.

These conditions generate enduring effects disproportionately exposing patients to adverse

economic and social factors that contribute to health inequalities, (World Health Organization
(WHO), 2011). The aim of the Standards is to reduce levels of morbidity and mortality and
improve the experience of all haemoglobinopathy patients by reducing these inequities and
improving timely access to high quality expert care.

The Standards comprise the components that characterise sickle cell disorder, and the various
practices and people, needed to care for patients. All stakeholders of the condition should make
the Standards a key reference document; patients, carers, haematologists, commissioners,
general practitioners, consultants, junior doctors, nurses, specialist nurses, accident and
emergency staff, ambulance staff and paramedics, pathologists, pathophysiologists,
psychologists, nutritionists, counsellors, support groups, academics, senior NHS and public
health policy makers, researchers and pharmaceutical companies involved in sickle cell
research and trials. It is essential they provide consistent best practice services through
integrated multidisciplinary teams with systematic approaches and pathways led by the public
patient voice. The Standards is clear on what to deliver, how to apply and manage delivery, who
delivers, and where change and transformation is needed and why.

We commend the Standards to all medical professionals especially those working with sickle
cell patients. I encourage the NHS and others to take it up and widely disseminate it, supporting
training and education around the standard as a requirement for changing the performance of
our professionals working in primary, clinical, and social care.

Kye Gbangbola MBA John James

Chair, Sickle Cell Society Chief Executive Officer, Sickle Cell Society

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 Statements of support

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 Statements of support

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 Statements of support

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 Statements of support

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 Statements of support

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 Chair’s introduction
The first edition of the ‘Standards for Clinical Care of Adults with Sickle Cell Disease in the UK’
(Sickle Cell Society, 2008) has certainly been instrumental in improving care for patients with
sickle cell disease (SCD). Haemoglobinopathies have been commissioned as a specialist service
by NHS England leading to the development of a service specification and there is an on-going
service review at the current time. The services for adults in England underwent peer review
against the standards in 2012/13 and this was repeated across the entire UK in 2014/16. The
peer review not only defined our baseline of care but the second review saw improvements in
many aspects of care across the country and have acted as a catalyst for further service
developments. The majority of these standards are applicable for the entire United Kingdom,
although commissioning arrangements may differ in the devolved nations so some of the
standards around organisation of care may be less relevant.

We have seen a huge amount of clinical and academic research into SCD globally including
several key publications on clinical research trials and new insights into pathophysiology. This
research continues, with many new drug therapies and potentially curative treatments now on
the horizon. It feels as if we are on the cusp of a new era of clinical care for adults with SCD.

Unfortunately these new developments have not always translated into an improvement of care
in quality of life or outcomes. Overwhelming feedback from patient surveys shows that many of
the issues patients raised in 2008, including timeliness of pain relief, inadequate education of
health professionals and inequity of care still exist.

The updating of the Standards document therefore seems timely, if not overdue. Our aims in the
production of this document were to engage a broad multi-disciplinary group of health
providers, patients and support groups. Whilst these are evidence based, as far as possible
where evidence exists, this is not intended to be an academic text and tries to focus on practical
management issues. By outlining a minimum expected level of care it aims to reduce inequities
in health provision.

We have aimed to retain the key standards from the first edition that are still needed, update
those where evidence has changed and add new standards where they are needed. There have
been several changes in the document including the development of recommendations and
additional appendices to support health care staff. We hope this document will continue to
support improvements and excellence in care across the UK.

This document was led and supported by members of the Sickle Cell Society who are working
for improvements in clinical care for all those with SCD in this country and worldwide. I would
like to thank them for their ceaseless effort and their continued support. They were integrally

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 Chair’s introduction

involved in the development of these standards at all stages. I would also like to thank the other
members of the Editorial Board who have put in many hours of their own time into reviewing
evidence and into writing and editing this document. In addition many of the health
professionals practicing in the UK have given up their time to author, co-author or review
chapters. This is truly a collaborative piece of work.

Finally I would like to acknowledge the work and memory of Ade Olujohungbe, the Chair of the
first edition of these standards. He was instrumental in the conception, development and
production of the standards and was a valued friend and colleague. Without him these
standards would not have been possible.

Dr Jo Howard

Chair of Editorial/Writing group

January 2018

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 Note on Methodology
The Sickle Cell Society instigated the update of these standards in 2015. The previous editorial
board and members of the UK Forum on Haemoglobin Disorders were invited to apply to join
the editorial board or to take part as contributing authors or as part of the sounding board. The
editorial/writing group met regularly, each oversaw a section of the Standards and were
responsible for co-ordinating co-authors, editing their chapters and reviewing the entire
document.

The document has been divided into three sections, Section A (General Principles) which
includes organisation of care and health and well-being, Section B on the management of acute
and chronic complications and Section C which includes other management issues and
treatments. In many of the areas discussed, particularly Section A, the guidance is largely
practical and organisational with no formal trial or other clear evidence. Even in the clinical
chapters there is often a lack of clinical trial evidence and we have relied largely on published
retrospective analyses, observational data, expert opinion and the views of patients and
families. If a recent systematic review was available its findings were incorporated into the
document. If this was not available a literature review was performed and its outcomes
summarised.

We have adopted two grades of practical interventions:

Standards
Being that which providers must do to ensure safe and adequate care or where omission could lead
to poor clinical outcomes. These include key requirements of any service. Where possible we have
tried to ensure these are auditable.

Recommendations
Being those that would be beneficial and that providers should try to follow, but for which there is
less evidence or that are less likely to have a direct impact on clinical outcomes.

We note however that there is a lack of research studies for many of these recommendations,
especially the non-clinical ones. Practice has evolved over time so we have tried to document
what most people do and what is a consensus view of good practice.

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 Note on Methodology

The entire document and in particular the standards and recommendations were debated by
the editorial panel. A draft document was sent to the Sounding Board in July 2017 and their
comments were incorporated into the final draft. Where evidence was lacking a consensus
decision was reached by the editorial board.

The patient quotes were collated by the Sickle Cell Society from surveys undertaken with the
Picker Institute (Europe); the National Institute for Health Research (NIHR); and Collaboration
for Leadership in Applied Health Research and Care (CLAHRC) – North West London. In
addition, some quotes were also developed by the Sickle Cell Society’s patient lead as part of the
peer review process.

Over 700 sickle patients and carers across the U.K participated in the survey and the key themes
emerging from the surveys were:

 The poor quality of emergency vs planned care

 Clinical awareness of dealing with SCD across primary and acute care
 Significant variation in care
 The poor management of SCD including coping with pain.

The survey was carried out anonymously and the main objectives of carrying out the survey at
this scale were to support the development of this document, to improve the overall quality of
sickle cell services across the country by supporting hospitals through the clinical peer reviews
and to represent the voices of the patients. The Sickle Cell Society ensured patients were
involved in these peer group evaluations engaging with other sickle patients across the country
by providing consistent support.

Following from this, the development of this document has also involved patients, carers and
the Sickle Cell Society. The objective is to ensure that the voices of sickle cell adult patients are
directly represented.

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 Overarching standards

General principles

OS 1. Adults with sickle cell disease (SCD) should be offered care close to home where
possible, but should also have access to highly specialist multidisciplinary care
including specialist nursing support.
OS 2. All local hospitals should be linked with a named specialist centre with agreed
pathways and protocols for advice and referral for acute and chronic complications.
OS 3. Specialist haemoglobinopathy teams should participate in a quality review
programme of haemoglobinopathy services against nationally agreed standards.
OS 4. All consenting patients should be registered on the National Haemoglobinopathy
Registry (NHR) and annual review data and adverse events should be reported to
the NHR.
OS 5. All patients should have access to specialist psychology support.
OS 6. Core staffing of Specialist Centres for SCD should include a psychologist with a
special interest and experience in SCD.

Transition

OS 7. Specialist teams should have a policy and dedicated team for transition, which
should include a named transition-lead.
OS 8. Further and higher education institutions, universities and colleges should develop
and monitor policies for supporting students with SCD with respect to their
education, their health and their careers.

Primary care

OS 9. All adults with SCD should be registered with a general practitioner (GP).
OS 10. Each SCD patient should be offered routine primary health care services at their GP
surgery.
OS 11. All adults with SCD should have access to community nursing support.

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 Overarching standards

Acute pain

OS 12. Patients presenting as a medical emergency with an acute painful episode should be
offered appropriate analgesia within 30 minutes of presentation to the emergency
department.
OS 13. All hospitals with emergency departments should have protocols to guide
management of uncomplicated acute presentations of SCD.

Acute complications

OS 14. All hospitals with emergency departments should have protocols to guide
management of uncomplicated acute presentations of SCD including when to seek
specialist advice.

Chronic complications

OS 15. All patients should be offered regular outpatient review to ensure screening for
chronic disease complications and early instigation of treatment according to local
protocols and national guidance.
OS 16. All patients with evidence of chronic organ dysfunction should have access to
review in multidisciplinary or specialist clinics.
OS 17. Patients with complex pain needs should be referred to a multidisciplinary chronic
pain team with experience of SCD, offering both pharmacological and non-
pharmacological interventions.

Prevention of infection

OS 18. Specialist and local haemoglobinopathy teams and GPs should ensure that adults
with SCD are adequately vaccinated against the following infections according to
advice in the Green Book:

 Invasive pneumococcal disease

 Haemophilus influenza type B
 Neisseria meningitis ACWY and B
 Hepatitis B

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 Overarching standards

OS 19. Patients should be periodically warned about the increased risk of invasive
pneumococcal disease (IPD) and other forms of sepsis. They should also be
educated about symptoms which might indicate infection and to attend for medical
assessment if temperature ≥380C.

Annual review

OS 20. All adults with SCD should be offered comprehensive review from a specialist
centre at least annually.
OS 21. A pro forma should be used for the annual review visit to ensure thorough and
consistent care and to facilitate data collection.

Pregnancy

OS 22. Pregnant women with SCD should be managed by a multidisciplinary team of

obstetricians, midwives and haematologists with an interest in SCD in a unit that
manages high risk pregnancy.
OS 23. Units which manage SCD pregnancy should have a clear protocol for patient
management.

Hydroxycarbamide (HC)

OS 24. All hospitals looking after adults with SCD should have a prescribing and
monitoring protocol for hydroxycarbamide (HC) (also known as hydroxyurea) to
maximise benefits and safety.
OS 25. Specialist centres should audit their use of HC to ensure it is discussed with all
patients who may benefit from its use.

Transfusion

OS 26. All hospitals that admit SCD patients should have protocols and training in
transfusion for SCD including manual exchange procedures.
OS 27. Automated exchange transfusion should be available to all patients with SCD and
should be provided by specialist centres.
OS 28. Specialist centres should audit their use of blood transfusion in the acute and
chronic setting to ensure its use is consistent with national guidance.

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 Overarching standards

Emerging therapies

OS 29. National Health Service (NHS) England should ensure that all patients have
equitable access to high cost interventions.
OS 30. Trials for haematopoietic stem cell transplantation (HSCT) in adults with SCD
should be available in the UK.
OS 31. All patients with SCD should have access to information regarding current clinical
trials, to enable participation if the patient so chooses.

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 Section A: General principles

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 Chapter 1: Overview

Introduction

This chapter is a brief description of sickle cell disease (SCD). It is not a comprehensive review
and readers are referred to standard texts for more detailed information.

Haemoglobin is the oxygen carrying protein found in the red blood cells. It comprises four
‘globin’ protein chains, each wrapped around an iron-containing ‘haem’ molecule. Newborn
babies have a form of haemoglobin called foetal haemoglobin (haemoglobin F). This is largely
replaced by adult haemoglobin (haemoglobin A) in the first year of life. Haemoglobin A consists
of two alpha (α) globin chains and two beta (β) globin chains.

The sickle mutation is a substitution of C for A at codon 6 of the β globin gene (βS). The resulting
exchange of valine for glutamic acid leads to the production of a sickle haemoglobin molecule
(haemoglobin SS). This has a tendency to form aggregates or to polymerise in the deoxygenated
state resulting in red cell breakdown and aggregation of red cells in the blood vessels thereby
causing blockage.

Haemoglobin S and other significant variants

SCD comprises a group of genetic conditions associated with βS, which give rise to significant
clinical complications. Individuals who inherit βS from both parents are homozygous and have
sickle cell anaemia. Individuals inheriting βS from one parent, and certain haemoglobin variants
(haemoglobin C, haemoglobin DPunjab, haemoglobin OArab, haemoglobin E, haemoglobin
Lepore)or a β thalassaemia gene, from the other parent will also have a variant (compound
heterozygote) form of SCD. There are many other variants detected on screening that are of no
clinical significance when found in combination with haemoglobin S.

Sickle cell carriers

Individuals who inherit βS from one parent and the normal β globin gene from the other are
referred to as carriers of sickle cell, or as having sickle cell trait. Their red blood cells contain
haemoglobin A and haemoglobin S. Sickle cell carriers usually have no clinical symptoms and
often do not know they are carrying βS unless they have a specific blood test.

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 Chapter 1: Overview

Epidemiology

Although SCD occurs predominantly in individuals of African descent, these disorders are also
prevalent in the Eastern Mediterranean, Middle East, India, the Caribbean and South and Central
America. The common factor is a high prevalence of malaria in the area, or migration from a
malarial area, because sickle carriers have partial protection from malaria and therefore a
survival advantage. In sub-Saharan Africa the gene frequency of βS ranges from 10% to 30%.

In England, SCD affects about 1 in 2000 live births and there are currently estimated to be
around 12,500 – 15,000 individuals living with SCD. It is one of the most common single gene
disorders in the UK.

Pathophysiology

Haemoglobin S polymerises when deoxygenated. The accumulation of intracellular

haemoglobin polymers results in damage to the red cell membrane causing changes in
permeability to cations. The red cell becomes dehydrated, more rigid and less able to negotiate
the capillary circulation. The survival of red cells in SCD is significantly reduced resulting in a
haemolysis (shortening of red cell life span). However, haemoglobin S releases oxygen to tissues
more readily than haemoglobin A, and this may reduce the drive to erythropoiesis. Red and
white cells and platelets adhere to the lining (endothelium) of the small vessels of the
circulatory system resulting in vascular damage, organ infarcts and progressive ischaemic
damage. This complex process of red cell adhesion and aggregation leads to blockage of the
blood vessels, known as vaso-occlusion, which impairs blood flow and prevents effective
delivery of oxygen to the tissues. This is thought to be the underlying cause of acute episodes
such as painful crisis as well as chronic damage such as avascular necrosis of hips and renal
failure.

Narrowing and occlusion of larger vessels is thought to be caused by chronic sheer-damage and
adhesion of blood cells to the vessel endothelium, complicated by vasoconstriction and nitric
oxide deficiency. This mechanism is likely to be responsible for complications such as
pulmonary hypertension and stroke.

Clinical presentation

SCD is an inherited condition, which can be diagnosed at birth. The UK has a universal newborn
screening programme. Clinical complications do not occur at birth – or in the first few months of
life - because the high proportion of intracellular foetal haemoglobin (haemoglobin F) inhibits
haemoglobin S polymerisation. During the first year of life, the proportion of haemoglobin F
decreases and the proportion of haemoglobin S increases within the red cells. Consequently,
pathological effects of sickling start to occur.

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 Chapter 1: Overview

The most common clinical manifestations are chronic anaemia and recurrent acute pain
episodes, which in adults typically affect the limbs and trunk. Other common clinical conditions
include acute complications such as splenic sequestration, overwhelming sepsis, acute chest
syndrome, priapism and stroke, and chronic complications such as lung disease, sickle
nephropathy, pulmonary hypertension, avascular necrosis of the hips or shoulder joints,
recurrent chronic leg ulceration and retinopathy. These are described in more detail in chapters
below.

Clinical course and survival

In its most severe form, SCD causes significant morbidity and mortality. However, SCD is
variable in severity and the onset of acute and chronic complications is unpredictable. This
uncertainty can add to the psychological consequences of living with a life threatening chronic
disease. It may also cause severe social disruption throughout the life course.

As recently as the 1970s, a patient was not expected to survive to adulthood. Nowadays,
childhood mortality is relatively rare, at least in developed countries, with 99% of children in
the UK surviving to adulthood. This is a result of introducing a variety of health care
interventions including neonatal screening and enrolment of affected babies in a
comprehensive care programme, pneumococcal prophylaxis, and early recognition and better
treatment of acute complications in children. Unfortunately, the current outlook for adults is not
so encouraging, with estimates of median survival for sickle cell anaemia in the 40s. Single
centre data from the UK have shown estimated median survival of 67 years in patients with
sickle cell anaemia and higher in patients with sickle cell/haemoglobin C disease (Gardner et al.,
2016). Certainly life expectancy is improving but older patients with SCD have an increasing
burden of chronic complications and often have complex health needs. A National Confidential
Enquiry into Patient Outcome and Death (National Confidential Enquiry into Patient Outcome
and Death (NCEPOD), 2008) study in England reported that the most common causes of death
in adults with SCD were cerebrovascular accidents, multi-organ failure and acute chest
syndrome. The enquiry also called for better evaluation and improved reporting of cause of
death in SCD patients.

Diagnosis

SCD may be suspected clinically if a patient from an at-risk ethnic group presents with clinical
features suggestive of a painful crisis or an acute complication of SCD. Ethnicity, however, is not
always a marker of who might be at risk of SCD. The large majority of new cases are now
diagnosed as a result of the neonatal bloodspot screening programme in England.

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 Chapter 1: Overview

Laboratory tests used to diagnose SCD:

a) Indirect methods which detect haemoglobin S on the basis of its physical/chemical

properties.

 Sickle solubility test (e.g. Sickledex). This test will identify the presence of haemoglobin
S if more than 15% of total haemoglobin. It does not differentiate between sickle cell
trait, sickle cell anaemia and compound heterozygous states and cannot be used for
newborn screening or diagnosis.
 Haemoglobin electrophoresis: cellulose acetate membrane at alkaline pH, acid agarose
gel, isoelectric focusing (IEF), capillary electrophoresis.
 High performance liquid chromatography (HPLC).

b) Methods that directly identify haemoglobin S or the underlying mutation:

 Tandem mass spectroscopy

 Direct detection of the βS mutation. Various methods of DNA analysis may be used.

The NHS Screening Programme for Sickle Cell and Thalassaemia publishes antenatal and
neonatal laboratory handbooks (Public Health England, 2017b) which provide detailed
guidance on laboratory standards, testing algorithms, standardised reporting formats and
indications for referral for DNA analysis. All laboratories testing for SCD should adhere to these
standards.

Screening for sickle cell

National screening programme

The plan to establish a linked antenatal and neonatal screening programme for Sickle cell and
thalassaemia in the NHS was agreed in 2001 and implemented over the next ten years. It has the
following aims:

 To support people to make informed choices before conception and during pregnancy
 To improve infant health through prompt identification of affected babies
 To provide high quality and accessible care throughout the UK
 To promote greater understanding and awareness of the disorders and the value of
screening

Neonatal screening
Screening of newborns for SCD is part of the National Newborn Screening Programme in the UK.
Testing is done on all babies using a heel prick bloodspot sample taken at 5-7 days of age. The

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 Chapter 1: Overview

aim is to identify babies prior to their first clinical presentation. There is compelling evidence
from programmes in Jamaica, UK and the United States that early diagnosis can improve clinical
outcomes and reduce mortality during childhood. Key interventions include parental education,
early initiation of oral penicillin, administration of pneumococcal vaccination and transcranial
Doppler risk screening.

Antenatal screening
Antenatal haemoglobinopathy screening is offered to all women in the UK as part of routine
antenatal care. In England, testing for sickle cell carrier status is universal in high prevalence
areas (more than 1.5 babies per 10,000 births with SCD) and targeted in low prevalence areas,
with risk assessed by determining the family origins of baby’s mother and father using a
validated questionnaire (Public Health England, 2012). Carrier mothers should be offered
counselling and fathers invited for testing.

When both parents are carriers, the pregnancy is regarded as ‘at risk’ (1 in 4 chance of an
affected child), and prenatal diagnosis (PND) is offered. Couples found to have an affected foetus
require further counselling and are given the option to terminate the affected pregnancy.

Emergency and opportunistic screening

Preoperative screening may need to be carried out in an emergency, sometimes outside normal
laboratory hours. In these cases the first test may be the sickle solubility test. However, this will
only detect the presence of haemoglobin S and further investigation is needed to distinguish
sickle trait from significant SCD. HPLC will give a quantitative level of haemoglobin S and
haemoglobin F, as well as demonstrating the presence of haemoglobin A to clarify the diagnosis.
Opportunistic screening requests may come from GP practices, dentists and Family Planning
Clinics, and siblings of babies identified through the newborn screening programme should be
tested.

Laboratories and clinical services need to ensure that a procedure is in place to allow affected
individuals to be counselled about their condition and to receive prompt appropriate medical
care. Laboratories should have a failsafe mechanism in place when issuing results, to ensure all
appropriate parties are informed of the result.

Predictive factors and variability in phenotype

SCD, although the result of a single genetic defect, is variable in clinical severity. Sickle cell
anaemia and haemoglobin S/β0 thalassaemia are regarded as most severe, but there is
remarkable variation in clinical phenotype between individuals with these genotypes. We are
yet to fully understand the reasons for this. Further, life threatening events can arise in ‘less
severe’ SCD. Genetic and environmental elements have a significant influence on disease
severity.

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 Chapter 1: Overview

The best characterised genetic factors are:

 Genetic determinants of increased haemoglobin F production

 Coexisting alpha thalassaemia
 Beta globin haplotype
 Linked genetic polymorphisms associated with specific acute and chronic complications
 Environmental factors include infection, climate, nutrition, psychosocial factors, socio-
economic status and access to medical care

Rationale for therapies

The goals of management are to improve survival, reduce acute and chronic complications, and
improve quality of life. Patients require ongoing continuity of care, starting in early infancy and
continuing throughout the life course. This document will describe the appropriate levels of
care required to achieve these goals.

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 Chapter 2: Organisation of care
"We require respect, care, dignity and candour. We require mandated standards that can be
challenged by patients when failures occur. Commissioning that reflects need that has parity with
other specialised illnesses given SCD is the world’s most common genetic condition."

General principles

“We need more nurses, more community services, more adult care support services and a dedicated
team to support us with the phases of change we experience as sickle patients.”

Introduction
Sickle cell disease (SCD) is a lifelong chronic disease causing complex multi-system medical
problems, which can be associated with variable clinical presentations and significant social and
psychological challenges. This leads to variable care pathways and the need to work with large
numbers of different practitioners. Care therefore needs to be provided by a multi-disciplinary
team, working across sector and agency boundaries. This will include health and social care
provision, community nursing care, primary health care and secondary/tertiary care in
specialist centres as well as third sector organisations.

Services need to take account of the chronic nature of the condition and its impact on further
education, work and family life, as well as the variable and unpredictable need for acute hospital
care. Service users with a clear understanding of their condition can manage their disease
optimally. An emphasis on patient education and independent self-care is fundamental to
successful outcomes, particularly given the uncertainties associated with the condition.
Partnership between ‘expert patients’ and professionals, which enhances care and patient
choice, is central to management decisions.

Health professionals need to be aware of the challenges of navigating these complex care
pathways and of the importance of consistent and clear communication.

Standards
 Adults with SCD should be offered care as close to home where possible, but should also
have access to highly specialist multidisciplinary care including specialist nursing
support.
 All patients should have a named key contact and a number to phone if needing advice.
 All hospitals with emergency departments should have protocols to guide management
of uncomplicated acute presentations of SCD.

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 Chapter 2: Organisation of care

 All local hospitals should be linked with a named specialist centre with agreed pathways
and protocols for advice and referral for acute and chronic complications including
when to seek specialist advice.
 All adults with SCD should be offered comprehensive review from a specialist centre at
least annually. All patients should be offered regular outpatient review to ensure
screening for chronic disease complication and early instigation of treatment according
to local protocols and national guidance.
 All patients with evidence of chronic organ dysfunction should have access to review in
multidisciplinary or specialist clinics.
 All patients should have access to specialist psychology support.

Background evidence
The appropriate model offers care for the patient as close to home as possible whilst offering
access to highly specialist health care when needed for expert assessment or management.
These requirements are thought to be best addressed by care networks but different models of
care have been developed, based on local availability and patient preference, with little evidence
about which is best.

Much care can be offered in the home or community setting, with clinical support from the local
hospital, which will provide routine health checks and acute and on-going care for less complex
complications. Primary and community services are commissioned by Clinical Commissioning
Groups (CCGs) and there should be dialogue and seamless service provision between them and
the specialist services commissioned by NHS England.

All local hospitals should be linked to a specialist haemoglobinopathy team (SHT). Care should
be overseen by the SHT and delivered at linked hospitals. SHTs will generally be linked to
hospitals on a geographical basis but arrangements will take into account the prevalence of the
conditions and expertise available. The roles and responsibilities for the SHT and their
interactions with the linked hospitals should be clearly defined and all patients should be
reviewed by the specialist team at diagnosis, for annual review and for major, severe or complex
presentations. Clinical management guidelines in local hospitals should be agreed with, and
overseen by, the SHT. NHS England is undertaking a service review of specialist
haemoglobinopathy services (2017/18) and there may be changes in specialist service
provision following completion of this review. It has been suggested that SHTs should work
collaboratively to provide a national service providing clinical advice on complex cases and
ensuring all patients have access to approved new treatments.

Communication between teams is crucial and may include multidisciplinary meetings and/or
patient-held shared care records. Clear arrangements should be in place for shared care. Service
users should have a named key contact(s) and be clear about whom to contact for emergency
and routine advice.

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Key participants in care provision are outlined below.

Family/carers and social network

Friends and family provide essential patient support, including valuable emotional and physical
support. They can also act as advocates, particularly when the person with SCD is not well.

Voluntary sector

The Sickle Cell Society (www.sicklecellsociety.org/) is a national organisation supporting

patients with SCD and their families. In some areas they offer home visiting services, support
groups and other patient/family support. Local voluntary organisations provide similar services
in some areas. Other local voluntary organisations also exist, including several regional OSCARs
(Organisations for Sickle Cell Relief & Thalassaemia Support).

Education and Employment support

Patients with chronic disease and disability may benefit from additional support within the
educational system or in the workplace. These may include student disability services and
occupational health services.

Community care

Community support is fundamental to provision of high quality care close to home and all
service users should be able to access appropriate community support. Access to dedicated
community services will vary between areas. In high prevalence areas there are often Sickle Cell
and Thalassaemia (SCaT) community centres run by specialist nurse counsellors offering
education, advice and support in the patient home or in the centre. In low prevalence areas,
community support may be provided by a community matron or district nursing teams.

Psychological support

Psychological interventions are very important for some people in managing their condition.
Psychology staff may offer cognitive behavioural therapy, annual review, one to one
intervention or neuropsychological assessment and management. Psychology staff may be
based in community centres, in the local hospital or within the specialist centre. All patients
with SCD should have access to specialist psychology services.

Primary care

The primary care team has an important role in co-ordinating care for service users with SCD
and ensuring that they receive general health care screening and advice. The primary care team
will have the responsibility for repeat prescriptions, vaccinations and reproductive care
(contraceptive and pre-conceptual care), along with general healthcare unrelated to SCD, but is
also important in ensuring the well-being of the patient (e.g. hypertension and cancer
screening).

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Linked or Local Hospitals

Local hospitals provide services typically for a small to moderate number of SCD services users
living locally. The majority of hospitals in the UK will be linked hospitals.

Their role includes:

 Delivery of care, close to a patient’s home, in conjunction with SHT according to an agreed
care plan
 Having responsibility for care which is delivered locally
 Working with SHT and providing input into multidisciplinary team and governance
arrangements

The responsibilities of linked hospitals should be agreed by the SHT and the linked hospital and
will depend on local expertise and facilities. However, all hospitals should be able to provide
emergency care for painful episodes and other acute complications. They should also be able to
undertake simple transfusions and blood monitoring of patients on hydroxycarbamide and iron
chelation drugs.

Specialist Haemoglobinopathy Team (SHT)

These are multidisciplinary teams including consultants, trainees, specialist nursing staff
(acute), community staff and psychologists with expertise in the management of SCD.

The roles of the SHTs is being re-defined as part of the NHS England service review but the SHT
will need to show compliance against the agreed new service specification. The SHT will:

 Be based at a specialist haemoglobinopathy centre (SHC) and will work with named and
linked hospital teams (LHT). The SHT may work across several sites, e.g. through
outreach clinics or shared posts, in order to ensure they achieve the required standards
and oversight of care for each patient whether they attend for his or her care at the SHT
or the LHT
 Need to have expertise in the care of people with SCD. For areas of low prevalence the
SHT may form partnerships to ensure sufficient patient numbers to develop expertise
 Develop and review each individuals care plan. This should start at birth and be updated
as required and at annual review
 Be responsible for governance e.g. audit, mortality reviews, guidelines and protocols
 Provide clinical advice for its linked centres either alone or in collaboration with other
SHTs with an agreed rota for cover
 Have access to range of co-dependent services which should include the provision of
multi-specialist clinics
 Offer a specialised acute and chronic pain service for sickle cell
 Provide patient information and education

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 Provide education and training for staff

 Work with local hospitals to ensure care close to home as possible by offering outreach
clinics or by employing new technologies
 Ensure there are mechanisms for ensuring patient participation in service development
and quality reviews
 Ensure adequate and comprehensive data sharing flows between LHT and SHT and data
entry to the National Haemoglobinopathy Registry

Networks

There is wide geographical variation in the prevalence of SCD across the UK. In order to provide
uniform standards of care to all service users, care networks for haemoglobin disorders (SCD
and thalassaemia) are recommended so that every patient in the UK can have equitable care,
irrespective of where they live, close to home, but with access to a specialist team for
management of more severe and complex complications. The effectiveness of such service
arrangements have already been demonstrated for other chronic conditions such as cystic
fibrosis, asthma, diabetes and haemophilia, although these conditions all have a more consistent
distribution around the country.

The model of a network may vary according to prevalence of SCD in the local population,
expertise of health professionals and proximity to other services. In high prevalence areas
several large hospital centres may work together to provide specialist services across the
network. In low prevalence areas a ‘hub and spoke’ clinical care model with a SCD specialist
clinical centre supervising and sharing care with local hospital units and primary and
community care teams across a wide area may prove more effective. In very low prevalence
areas, it may prove difficult to develop sufficient expertise to provide a specialist service and
these networks should link with a larger specialist centre in another network to support them
in the management of complex cases and for the development of guidelines, training and audit.
This will be defined further in the revised service specification following the service review
taking place in 2017/18.

Recommendations
 Service users should be offered information about local patient support groups and
voluntary organisations.
 Good communication between community, local and specialist teams is essential and
should involve multidisciplinary team meetings. This should include clear instructions
for the GP and a care plan. Patient held records may also be helpful.
 Adults with SCD should have access to multi-specialist clinics for management of chronic
disease complications.
 The specialist haemoglobinopathy team should have adequate clinical and
administrative resources to support all SCD patients in their network.

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 The specialist haemoglobinopathy team should supervise a programme for education

and training, research and audit and data collection within their network.
 Out of hours facilities for blood tests, outpatient clinics and day facilities should be made
available where appropriate for the local population.

Transition services

“As a parent and carer, I know the transition process from child to adult is not effective and non-
existent in some areas. We need to crack this issue better.”

Introduction
Transition is the process of moving from children's to adults' services. It includes initial
planning and offering ongoing support during and after a young person makes this move. The
purpose is to help young people and their carers have a positive experience, and to encourage
them to adhere to treatment at this time when they can readily default. The process should take
into account the broad developmental changes associated with the teenage years and not focus
solely on meeting clinical needs. It is important that young people are involved in service
design, delivery, and evaluation, and that their experiences are valued.

Standard
 Specialist teams should have a policy and dedicated team for transition, which should
include a named transition-lead.

Background evidence
There is a lack of research evaluating the efficacy of transition programmes for young people
with haemoglobin disorders in the UK. Most of the evidence is low quality and based on expert
opinion, but there are some examples of excellent models of transition programmes for patients
with SCD across National Health Service (NHS) institutions (Howard et al., 2010; Inusa et al.,
2015; Musumadi et al., 2012). In view of the lack of specific evidence about SCD, many of the
recommendations in this chapter are based on the generic Department of Health (DoH) and
National Institute for Health and Care Excellence (NICE) recommendations (Department of
Health, 2003, 2011; Department of Health Partnerships for Children Families and Maternity /
CNO Directorate, 2008; National Institute for Health and Care Excellence, 2016b).

The transition process should take into account the mental and physical developmental stage of
the young person and the prevailing circumstances (personal crises, social context and health
care service provision). This seamless process should actively begin several years before
transfer from paediatric to adult clinic and include assessment of an individual’s understanding

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of his or her condition, commitment to self-management and the ability of service provision to
support the needs of the young person. A jointly created profile or ‘passport’ document can be
developed from discussions between the transition team and the young person. This can then
be shared with adults' services. It should be produced early enough to form part of discussions
with the young person about planning his or her transition and include information about his or
her health condition, education and social care needs, his or her preferences about parent and
carer involvement, emergency care plans, history of unplanned admissions, his or her strengths,
achievements and future aspirations (Musumadi et al., 2012).

Ideally, there should be a single practitioner acting as the 'named worker’ to coordinate
transition care, working with the young person to complete the transition planning. Having a
single transition lead who works with young people throughout transition until early adulthood
has proved effective in ensuring consistent care and has improved the development of
relationships with the adult team. It is generally agreed that transfer of patients from paediatric
to adult services should be completed by 18 years but transfer can occur earlier in those
individuals who are ready for transfer (see Figure 1).

Figure 1: A suggested model of transition (Musumadi et al., 2012)

From: Nursing Standard by Royal College of Nursing (Great Britain). Reproduced with permission of RCN
Publishing Co. in the format ‘Other Published Product’ via Copyright Clearance Center.

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Provision of specialist transition teams can be associated with improved concordance, in

addition to reduced hospitalisation and emergency care utilisation. This team should identify
and utilise the broader psychosocial support available to the young person, which might include
family/carers, social services, primary care and colleagues in education (Labore et al., 2017;
Williams et al., 2015). Service managers in both adults' and children's services -and across
health, social care and education - should proactively identify and plan for young people with
sickle cell disease in their locality with transition support needs (Treadwell et al., 2016). Some
units have teenage and young adult (TYA) units for inpatient care which can be accessed by
patients with SCD and are valued highly where they exist.

It is essential that the young people are treated as equal partners in the transition process and
that their views are taken into account. This will support them in making informed decisions
and build their confidence to express their preferences for their own care (Noronha et al., 2016;
Sobota et al., 2015). The views of young people should also be integral in service planning and
development.

The Department of Health quality criteria provides ten generic benchmarks against which all
NHS Institutions must measure the quality of their services provision (Department of Health,
2011). These are relevant to SCD and include accessibility, a dedicated transition team,
confidentiality and safeguarding, ensuring the environment is young people friendly and staff
are appropriately trained. Young people should be involved in monitoring and evaluating
patient experience and transition services should include health issues relevant for young
people, sexual and reproductive health services and specialist child and adolescent mental
health services. It may also be helpful to provide access to peer support during, and in the
immediate period after, transition. Transition events or open days where the young people are
invited for an introduction to adult service provide a good opportunity for networking and the
development of peer support.

Recommendations
 Adult and paediatric sickle services should work together with their local teenage and
young person population to ensure they offer accessible and flexible care appropriate to
patient need.
 A joint profile or ‘passport’ document can be used to enable the Transition Lead to work
with the young person and to assess when they are ready for transition.
 Young people should be offered the opportunity to meet a practitioner from the relevant
adult services before they transfer from children's services.
 If a young person does not engage with adult services, health and social care
practitioners, working within safeguarding protocols, should try to contact the young
person and his or her family and involve other relevant professionals, including the GP.
 Services should work with young people to support them in planning for leaving home
to study or work.

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 Services should support and encourage access to peer support networks.

Quality improvement

Introduction
Following the production of the first edition of the Standards for Clinical Care of Adults with
Sickle Cell Disease in the UK (Sickle Cell Society, 2008) and similar documents on the care of
children with SCD and patients with thalassaemia, the haemoglobinopathy community has
worked together to meet these standards. The aim is to reduce levels of morbidity and mortality
and improve the experience of all haemoglobinopathy patients by reducing inequities and
improving timely access to high quality expert care. Haemoglobinopathies have been designated
as a specialist service for commissioning by NHS England leading to the development of a
service specification. Other initiatives include a rolling programme of peer reviews against
quality standards and a national haemoglobinopathy registry.

Suggested medical staffing levels have been given in a review of haemoglobin disorders work
force and are summarised in Appendix 2. Similar work on recommended nursing and
psychology staffing levels is underway.

Standards
 NHS England (Specialised Commissioning Teams) should ensure that all adults with SCD
have access to care from a Specialist Haemoglobinopathy Team.
 NHS England (Specialised Commissioning Teams) should work with Clinical
Commissioning Groups in their area to ensure that all adults with SCD have access to
community care, local hospital care, social work support and benefits advice.
 NHS England should ensure that all patients have equitable access to high cost
interventions.
 SHT should participate in a quality review programme of haemoglobinopathy services
against nationally agreed standards.
 All consenting patients should be registered on the National Haemoglobinopathy
Registry and annual review data and adverse events should be reported to the National
Haemoglobinopathy Registry.
 All centres providing acute care for adults with SCD should participate in an audit of
acute pain relief, using the NICE recommendations, at least annually.
 SHT should submit data as required by NHS England for the quality dashboard.

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Specialised commissioning

Background evidence
Commissioning is a process by which health needs are identified and services bought to meet
those needs. Where possible, an evidence-based approach is used in procuring services and in
monitoring their delivery. Specialist services are low volume and high cost or are very complex
to deliver.

Services for children and adults with haemoglobinopathies (sickle cell and thalassaemia) and
other inherited anaemias were designated as a specialist service for commissioning by NHS
England in April 2014 (NHS Specialised Services, 2010). The service specification B-08 (NHS
England, 2013) describes the aims and objectives of the service and pathways of care. This
recommends care should be delivered by a specialist haemoglobinopathy team (SHT) which by
working with linked providers, is expected to deliver a network of care for all patients in the
geographical region.

Specialist services are commissioned by Specialised Commissioning Hubs, which are

responsible for the Trusts within their geographical region. At the time of this report, network
configurations and pathways have not been fully clarified and are the subject of an NHS England
service review. This will define the roles and responsibilities of the specialist and linked teams
and the commissioning arrangements of the Specialised Commissioning Hubs and the Clinical
Commissioning Groups. This must involve consideration of patients’ needs and convenience.

Specialised commissioners are supported by Clinical Reference Groups (CRGs) which bring
together groups of clinicians, commissioners, public health experts, patients and carers to
advise NHS England on the best ways that specialist services should be provided (NHS England,
2016). CRGs lead on the development of clinical commissioning policies, service specifications
and quality dashboards. They also provide advice on innovation, conduct horizon scanning,
offer advice on service reviews, identify areas of unexplained clinical variation and guide work
to reduce variation and deliver value. CRGs, through their Patient and Public Voice (PPV)
members, also help ensure that any changes to the commissioning of specialised services are co-
produced with and involve patients and the public.

Commissioning of haemoglobinopathy services for patients in Wales and Scotland are devolved
locally.

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Peer review

Background evidence
Aiming to improve services for patients with haemoglobinopathies, the UK Forum on
Haemoglobin Disorders, the Sickle Cell Society, the UK Thalassaemia Society and the NHS Sickle
Cell and Thalassaemia Screening Programme have worked with the West Midlands Quality
Review Service (WMQRS) to produce Quality Standards and set up a peer review programme of
haemoglobinopathy services in the UK.

The first programme of peer review was of services for Children and Young People with
Haemoglobin Disorders. This ran between 2010 and 2011. Nineteen centres were reviewed. A
review of Adult Services between 2012 and 2013 looked at 32 teams providing
haemoglobinopathy services. This was succeeded by programme of joint reviews of children
and adult services which ran between 2014 and 2016 and its findings are presented in more
detail below. An overview of all of these programmes of peer review and the report from each
participating centre are available at www.wmqrs.nhs.uk/publications.

The peer reviews were based on assessment against quality standards, revised before each new
programme, and which are consistent with the service specification for haemoglobinopathies.
The most recent peer review programme defined standards looking at the following areas:

 Information and support for patients and their families

 Staffing
 Support services
 Facilities and equipment
 Guidelines and protocols
 Service organisation and liaison with other services
 Governance
 Network
 Commissioning

Peer reviewer training was provided for health professionals (doctors, nurses and
psychologists), managers, commissioners and patient representatives who were to be part of
review teams, before each programme began. All specialist centres and non-specialist centres
with a large population of haemoglobinopathy patients were offered the opportunity to take
part in the programme and although participation in the programmes was voluntary, all invited
centres agreed to be visited. Centres in Wales, Scotland and Republic of Ireland, who requested
to be visited, were also included in the most recent programme.

Prior to the visit, centres were asked to complete a self-assessment against the quality
standards and also to provide some background information about their service. During the
visit the multidisciplinary review team reviewed the evidence provided by the centre, toured

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the facilities and interviewed staff members and service users before producing a visit report
demonstrating compliance with the quality standards. The programme was overseen by a
steering group consisting of multidisciplinary health professionals, members of the WMQRS and
patient representatives who met regularly. The steering group reviewed all reports and wrote
an overview report. This overview discussed several themes which had become apparent
during the visits, and made recommendations.

The peer review report showed marked geographical variation in SCD provision across the UK.
Over 80% of service users attended haemoglobinopathy centres in London, with lower
attendance reported in other areas particularly the North-East and South West of England.
There were unknown numbers of adults with SCD who were cared for by hospital or community
teams that did not link to a Specialist centre. Whilst at most of the centres visited, the reviewers
identified key staff members who were providing high quality care, they were often working
‘singlehanded’ and the workload of clinical staff was frequently deemed unreasonably high. This
had not improved between successive peer reviews and in several centres there had been
problems reappointing into key staff positions following retirement. Doctors in training were
often not involved in the routine care of patients with SCD. This exacerbated workforce
planning problems. Deficiencies in multidisciplinary care were highlighted and included a lack
of psychology support and a shortage of social workers and benefits advisors. Other concerns
raised by the peer reviewers included delays in the administration of analgesia for adults
presenting with painful sickle cell crisis in emergency departments and the perception that
their needs were not being taken into consideration. Many service users requested the
provision of routine care, including transfusion and outpatient appointments, outside usual
working hours. This, however, was only provided in a minority of centres.

National Haemoglobinopathy Registry (NHR)

Background evidence
The National Haemoglobinopathy Registry (NHR, www.nhr.nhs.uk) was set up in 2009 and is
run by an independent group Medical Data Solutions and Services (MDSAS, www.mdsas.com).
The NHR aims to improve the quality of data available for patients with haemoglobin disorders
in the UK. Initially the registry included numbers of people with SCD, age, geographical location
and basic demographic and clinical details. Centres were encouraged to join the NHR and to
register their patients using a simple on-line pro forma. The NHR provided a patient
information sheet and clinicians were asked to obtain verbal or written consent from patients
before entering their details on the registry.

Registrations onto the NHR have gradually increased since it began and over 10,000 patients
with SCD from 55 centres registered at the time of publication.

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The functions of the NHR have expanded and include the capability to report adverse events
including anonymised data for patients who have not given consent for their identifiable details
to be registered. This is encouraged as a mechanism for collecting national data for shared
learning from these events. This adverse event reporting should be done in addition to usual
local mechanisms for reporting mortality and morbidity. A panel of three clinicians reviews
clinical events and can raise concerns with the Clinical Reference Group if there are persistent
events at a single centre or there are patterns of concerns nationally.

The annual review has been highlighted as a fundamental component of developing specialist
care for patients with SCD and all patients with SCD should have an annual review performed by
their specialist centre. The NHR has developed a minimum data set for collection at annual
review. Use of the NHR annual review template encourages a basic level of data collection on
each patient but also allows individual centres to collect more detailed annual information if
they wish. Details about the clinical information collected in the annual review are given in
Chapter 17: Out-patient management and Appendix 4: Annual review pro-forma.

The annual review can be printed out or transposed into a letter and given to the patient, with
copies to his or her GP and any local hospital they attend as an annual summary of care. The
annual review function of the NHR needs further work to become fully functional and the peer
review programmes highlighted that many centres lacked resources for data input. It is
envisaged that information required for the Quality Dashboard currently being developed by
the Clinical Reference Group (CRG) should be collected through the NHR annual review screens,
allowing centres to rapidly extricate data.

The use of the NHR as a tool for annual review allows collection of up-to-date patient figures at
each centre with the ability to track patient numbers over successive years. It has also allowed
local or national data to be collated into an annual report (available on the website). Data
presented in this report include registrations per centre, genotype, gender, age, ethnicity,
adverse events and some specific treatments: transfusion, hydroxycarbamide and iron
chelation. These data, plus the adverse events data are also presented at an annual conference.

Additional developments include a patient card and an information service which is available
via the website and allows real-time access to the clinical information. This allows filtering of
information on a national, regional or trust basis and whilst data are anonymised, it can be
exported locally for analysis. This facility ensures that the NHR is a useful resource for
stakeholders and it has also provided anonymous information to commissioners and political
‘think tanks’.

The NHR is overseen by a steering group of stakeholders from the third sector and community
organisations, clinical services and NHS England.

The NHR is a continually evolving resource. It has great potential. Future developments include
its use for quality assurance and for epidemiological studies. This is especially valuable given
the lack of evidence for the provision of some aspects of clinical care in SCD. The NHR steering

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board is also keen to promote greater user interaction, for example, by including patient
surveys or by linking to patient information and education websites.

Clinical audit

Background evidence
Clinical audit is a quality improvement activity that seeks to improve patient care and outcomes
through the systematic review of care against explicit criteria, and the implementation of
change according to available evidence. Defining expected standards of care, which can be used
to judge service quality, is fundamental to the process of audit. The editorial board has
attempted to ensure that the standards within this document are auditable and can be used as a
framework for the development of audit standards.

In addition, there are other areas of care for which audit standards already exist.

There are six quality statements in the NICE Quality standard [QS58], ‘Sickle cell disease’
(National Institute for Health and Care Excellence, 2014b). These were based on the NICE
clinical guideline, ‘Sickle cell disease: managing acute painful episodes in hospital’ (National
Institute for Health and Care Excellence, 2012b). We highlight the first four of the quality
statements:

 People who present at hospital with an acute painful sickle cell episode should have a
pain assessment, a clinical assessment and appropriate analgesia within 30 minutes of
presentation
 People with an acute painful sickle cell episode should have an assessment of pain relief
every 30 minutes until satisfactory pain relief has been achieved and then at least every
4 hours
 People with an acute painful sickle cell episode who are taking strong opioids should be
monitored for adverse events every hour for the first 6 hours after first administration
or step up of pain relief and then at least every 4 hours
 People with an acute painful sickle cell episode should be assessed for acute chest
syndrome if they have one or more of the following: abnormal respiratory signs or
symptoms, chest pain, fever or hypoxia.

Annual audit of the first of these quality standards is included in the data which specialist
haemoglobinopathy centres must collect for the Quality Dashboard.

The British Society of Haematology has produced national guidance on some aspects of sickle
cell care and audit templates have been produced for their guidelines. These are available on
their website (www.b-s-h.org.uk) and include the following:

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 Red Cell Transfusion in Sickle Cell Disease Part 1: Principles and Laboratory Aspects
 Red Cell Transfusion in Sickle Cell Disease Part 2: Indications for Transfusion
 Guideline on the management of acute chest syndrome in sickle cell disease

The quality standards for the recent peer review of haemoglobin disorders (2015-2016) (West
Midlands Quality Review Service, 2016a) included a standard on clinical audits. This required
that audits covering the following areas should have been undertaken within the last two years:

 Proportion of patients with recommended immunisations up to date

 Proportion of patients on regular penicillin or equivalent or who have a supply for
immediate use if required
 Compliance with NICE Clinical Guideline (National Institute for Health and Care
Excellence, 2012b) on the management of acute pain, including the proportion of
patients attending in acute pain who received first analgesia within 30 minutes of
arrival, and achieved adequate pain control within two hours of arrival; and
 Availability of extended red cell phenotype in all patients

It also recommended that services should have a rolling programme of audit including an audit
of implementation of clinical guidelines and participation in agreed network-wide audits.
Twenty-four per cent of adult centres met this quality standard overall and 30 per cent of adult
centres demonstrated evidence of participation in a rolling programme of audit.

In addition to the above audits, centres should be encouraged to develop and participate in
other audits relevant to their local populations and local issues.

Recommendations
 NHS England (Specialised Commissioning Teams) should work with Clinical
Commissioning Groups to designate Specialist Haemoglobinopathy Teams and the
geographical area and local teams for which they are responsible.
 NHS England, CCGs and Hospital Trusts should review the WMQRS peer review reports
and work towards implementation of their recommendations.
 Hospital Trusts providing specialist haemoglobinopathy services should review the
medical, nursing and psychology staffing levels to ensure they are sufficient to provide
an adequate level of care.
 NHS Health Education England should review the workforce plan for specialist medical
and nursing staff caring for service users with SCD to ensure there are adequate
numbers of trained staff and should ensure that all doctors in haematology training
posts gain adequate experience in the care of people with SCD.
 Centres should participate in a rolling programme of audit against their clinical
guidelines.

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 Lessons learnt from these audits should be incorporated into quality improvements and
services should be subsequently re-audited to document these improvements.

The full list of recommendations from the most recent peer review overview reports is available
(West Midlands Quality Review Service, 2016b).

Chapter 2: Conclusion

This chapter offered a broad introduction to the organisation of care. Sickle cell disease has
clinical, social, economic and psychological consequences for both the individual and his or her
family. This presents various challenges requiring a multi-disciplinary response and excellent
communication among various stake-holders, alongside a commitment to evidence-based
practice and clinical audit.

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"The hospital consultants are knowledgeable and always on hand to help or advise. I have minimal
contact with my GP with regards to my sickle cell."

“Improved knowledge on the management of sickle cell is required for GPs, specifically when we
require medical support.”

Introduction

This and the following chapter consider the broader context of care and in doing so introduce a
more holistic and discursive account of supporting those with sickle cell disease (SCD) and their
families. The scope is necessarily broad, particularly in the use of evidence, which at times is
general rather than specific to the experience of SCD. While reasonable to do this, since the
experience of those with SCD is likely to share similarities with other long standing chronic
conditions, it does identify potential gaps in the research evidence and highlights the need for
more research exploring the social experience of SCD. This chapter by focusing on primary care
and community nursing highlights their potential for supporting to those with SCD and their
families, before considering more specific examples of interventions that can be managed
through primary care. Consistent with the broad scope of primary care, this chapter also
considers dental care.

Role of the primary care team

Introduction
The family remains the primary caring place for people with acute and chronic ill health.
General Practitioners (GPs) and the primary care team have an integral role in supporting the
service user with SCD and have a holistic overview of his or her care. The primary care team
includes the core team of practice nurses and administrative staff and additional staff which
may include midwives, health visitors, district nurses, mental health nurses, social workers and
welfare benefits counsellors. Ideally primary care teams represent the first point of contact for
patients and families. They can provide continuity and help coordinate care. It is usual for GP
registration to take place on birth notification and the 'cradle to the grave' concept of
registration promotes a life journey approach.

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Standards
 All adults with SCD should be registered with a GP.
 Primary care teams should maintain good communication with the specialist and local
haemoglobinopathy teams, enabling two-way exchange of expertise to optimise the care
of their mutual patients.
 Each SCD patient should be offered routine primary health care services at their GP
surgery.
 Specialist haemoglobinopathy teams should develop locally agreed shared care
protocols with GPs defining the roles and responsibilities of each.

Background evidence
An effective primary health care team that includes information sharing, easy communication
and agreement on common goals, alongside an understanding of each team member’s
responsibilities, skills and knowledge, can be of great benefit to someone with SCD and their
families. The potential value of primary care, however, is not always realised.

Families are integral to providing health and social care and collaboration is essential in
delivering effective primary care. Direct involvement with the patients and their home support
and environment can be a particular strength of primary care. There is often a greater
awareness of social, economic, family and psychological context and this enables members of
the primary care team to become important advocates for the patient, providing valuable advice
on welfare, housing and educational issues. While being sensitive to the needs of the individual
patient, members of the primary care team can also be well placed to identify and support
family carers.

The primary care team also have a role in genetic screening, offering reproductive and health
advice, providing routine screening, patient follow-up after emergency admission and co-
ordination of care. This might include supporting patients with multiple co-morbidities and
managing SCD alongside other unrelated health issues. However, every effort must be made to
co-ordinate care between different specialties to avoid omission or unnecessary duplication.
This includes developing good working relationships with secondary and tertiary care
providers, along with the sharing of information. While not always easy to achieve in practice, it
is of great benefit to patients and their families. It also has the potential to reduce health care
costs, by ensuring the most appropriate care and treatment.

To facilitate this and ensure continuity of care, a primary care medical record could be problem
coded for all known identified patients with a significant haemoglobinopathy. This involves
having a system in place for updating patient records as part of the neonatal heel prick, the
receipt of new patient registrations and information from other sources, such as hospital
discharge summaries. Similarly, results of haemoglobinopathy screening tests, which show
'carrier' status, could be coded on the patient record to prompt the provision of preconception
information.

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In order to meet their roles and responsibilities, GPs and the primary care team need to have a
good understanding of SCD and be aware of patients within their practice. Qualitative studies of
patients with SCD and their carers indicate a general lack of ‘comprehensive knowledge of SCD’
(Al Juburi et al., 2012; Jacob et al., 2016). The outcome of one study was the development of a
GP education intervention (Al Juburi et al., 2012) to improve knowledge and management.
Whilst this intervention may not be universally available, continuing professional development
(CPD) has been available for management in of SCD in the community (Brousse et al., 2014).

Specific responsibilities of the primary care team include (Patel, 2016):

 Early treatment of infections to prevent sepsis

 Prescription of antibiotic prophylaxis
 Ensuring vaccinations are up to date
 Early referral of pregnant women
 Reproductive provision to include contraceptive advice, pre-conceptual counselling and
partner testing. They may also be involved in shared antenatal care with the specialist
centre
 Referral for psychological support and counselling (including neuropsychological
support)
 Encourage treatment compliance
 Patient education and self-management of mildly painful episodes
 Support during transition and the move onto further education

Access to primary care has been highlighted as a barrier to effective treatment; continuity of
care and follow-up after discharge from hospital (Al Juburi et al., 2012). Alternative models of
care within the community, for instance with specialist service involvement in providing home
or day case management have been described (Brousse et al., 2014; Lanzkron et al., 2015;
Raphael et al., 2008; Wright et al., 2004).

Recommendations
 SCD specialist teams should provide support and training for GPs and their primary care
colleagues.
 The primary care team should be responsible for infection prophylaxis including the
prescription of regular antibiotics and vaccination for the prevention of infection due to
functional asplenia. Good communication between primary and secondary care is
essential to share this information e.g. by using patient held records.
 The primary care team should let the hospital team know if the patient is not collecting
prescriptions (e.g. for antibiotics) regularly.

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 Hospitals should inform GPs and the primary care team of hospital discharge within
seven days and identify any patients who require post-discharge follow-up.
 The primary care team should be responsible for documenting and providing repeat
prescriptions for other regular medications including analgesics and there should be
clear communication between the GP and SCD specialist centre about the agreed
analgesia to be prescribed for management of uncomplicated painful crises in the
community.
 GPs should keep records of a person’s carrier status and offer timely reproductive
advice, when appropriate. They should also offer advice on the implications of being a
carrier for the individual and family members.

Community nursing

“More home visits should be encouraged by support workers and nurses”

“My community specialist nurse gave me a card which I carry in my wallet and shows I am on the
national haemoglobinopathy registry and has all my medical details at hand in case of an
emergency”

Introduction
The provision and easy access to good quality community health care and treatment, with its
emphasis on self-management and a family centred approach can support patients with SCD in
achieving their goals, including caring for their families and participation in education and the
workplace with less disruption than ensues from hospital attendance (see Chapter 4 - Health
and well-being). The models of community specialist nursing for sickle cell care vary across the
country and there is no nationally agreed model of nursing care. The community nursing role
may include social, psychological support and more practical nursing support (e.g. phlebotomy,
review of medications, pain management). Community nursing may be provided as a standalone
community service, often as part of a community Sickle Cell and Thalassaemia (SCaT) centre, as
part of a wider community NHS directive or may be integrated with the acute
haemoglobinopathy team. Such nurses often work across primary, community and secondary
care. In low prevalence areas community matrons may provide care for patients with SCD as
part of a wider brief for chronic disease management although this resource will not be
available in all communities. Community teams usually have the responsibility for follow up of
screen positive women identified on the national antenatal screening programme and screen
positive newborns identified on the national newborn screening programme, both of which are
outside the brief of these guidelines which will focus on community nursing for adults with SCD.

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Standards
 All adults with SCD should have access to community nursing support.
 The number and case mix of specialist nurses in the community should be regularly
evaluated to ensure that services have adequate staffing levels in line with the duties
they are undertaking.
 Specialist community nurses should receive appropriate training, supported by
certification and competencies to be evaluated as part of their annual professional
practice review.
 Clear arrangements for shared care between the community team and local hospital
should be in place. This should include multidisciplinary team meetings.

Background evidence
The community specialist nurse has an important role in encouraging self-management and
more general health promotion for people of all ages living with SCD (see Chapter 4 - Health and
well-being). This role may include:

 Raising community awareness of SCD

 Management of screen positive pregnant women (trait and disease) and their partners
including genetic counselling and discussing options for the management of an at risk
pregnancy including, where selected, referral for pre-natal genetic diagnosis
 Co-ordination and adoption of a multi-disciplinary team approach, informed by holistic
approaches to health care, which can be especially valuable in the management of pain,
aiming to avoid omission or unnecessary duplication (Coulter et al., 2013). A patient-
held shared care record may be helpful to aid communication between the different care
providers.
 Development of personalised care plans, working together with service users and health
professionals to agree goals, identify support needs, develop and implement action
plans and to monitor progress
 Offering education and enhancing self-management skills of patients and their families
to ensure effective self-management within the community setting. This may include
mechanisms to minimise risk of crises and other complications, and symptom
management, including how to manage uncomplicated pain at home with a range of
suitable analgesics and non-pharmaceutical methods (Edwards, 2014)
 Prompt management of painful crises in patients’ homes with the aim of avoiding
hospital admission and thereby reducing disruption to the patient’s life

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 Provide education to patients and their families about which symptoms can indicate
serious complications and require them to seek urgent medical assessment, including
significant fever, chest pain, breathing difficulties, dehydration, priapism, and any
unfamiliar pain or other unexpected symptom
 Supporting early discharge from hospital and offer continuing good quality care in a
home setting
 Offering advice on a range of subjects including activity and rest; nutrition; prevention
and early treatment of infection; general health and well-being; reproductive issues
(including pre-conception screening of partners, genetic counselling and prenatal
diagnosis if required); and access to benefit and welfare advice
 Facilitating local support groups and forums where patients/carers provide can share
their experiences
 Review of community care and specialist standards including collection of data, audit,
research and advice at local and national level for improvement of care.

According to local provision, community nursing support may be provided by specialist nurses,
specialist nurse counsellors, specialist nurses outreach nursing teams, or use of district nursing
services/community matrons working under the specialist guidance of a sickle and
thalassaemia community centre or a specialist haemoglobinopathy centre. In areas where
disease prevalence is high, community centres staffed by specialist nurses and a variety of other
health and social care providers have emerged. These Sickle Cell and Thalassaemia (SCaT)
centres are usually based within the local community, but may be within the hospital premises.

In addition to the nursing staff based in the SCaT centre, other specialist service providers may
include occupational therapists, dieticians, psychologists, social workers, welfare officers and
dentists. There should be access to other social services including housing and benefits advice.
Ideally, there should be a ‘one-stop shop’ available so that a service user can access services in a
single visit.

The larger Sickle Cell and Thalassaemia centres may also offer:

 Educational programmes for health and allied professionals who care people with or at
risk of SCD and Thalassaemia
 Nurse-led outpatient clinics, treatment adherence clinics and day care pain management
services
 Self-management support services in the patient’s home

It may be helpful for service users to have a key worker identified within the community
service. Certainly service users should have access to telephone contact with a sickle cell and
thalassaemia community centre for discussion and advice. Staff at sickle cell and thalassaemia
community centres should be prepared to offer guidance to colleagues in local community
services that the patient has contact with.

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The role of the community nurses in education is very important and this can be done with
different methodologies including individual education, supported by written documentation or
group education which can be supported by leaflets, posters, DVDs and minutes. The
community nurses should also engage in governance work to obtain evidence of service users’
views and this can be in the form of service users’ group engagement or patient reported
experience and outcome measures (PREMS and PROMs) (Department of Health Long-term
Conditions NSF Team, 2005).

The Department of Health chronic disease model (2007) suggest three levels of care. This has
successfully been employed by some Sickle Cell and Thalassaemia (SCaT) Community Teams.
Level one is self-care support. This includes organising regular community education for service
users and their families/carers, with the focus on living successfully with the condition. These
sessions may be topic driven and encourage self-management, whilst raising awareness of acute
complications which may need urgent hospital care. Level two is disease specific case
management and is aimed at those requiring additional community support. The community
nurses have a particularly important role in co-ordinating multidisciplinary care, which may
include district nurses, physiotherapists, social workers, community psychiatric teams and
psychological support. Initial assessment by the community nurse includes history taking and
full nursing assessment during home visits or within a community centre. Assessment can be
used to evaluate pertinent issues and develop a care plan.

Depending on local practice and available services, facets of the care plan may include:

 Pain management
 Work and Employment issues
 Psychological concerns
 Failure to attend clinics
 Compliance management
 Post-discharge follow up
 Drug monitoring
 Social issues e.g. housing, welfare, employment
 Leg ulcer care
 Chelation therapy monitoring
 Hydroxycarbamide monitoring
 Management of parenteral therapy at home
 Issues impacting on education
 Relationships, sexual health and family planning
 Self-management and advocacy

Level three is case management of complex sickle cell conditions. It is for those service users with
more complex or high intensity needs. This will usually involve the multidisciplinary team
across the community and within secondary services. Examples may include patients with
frequent admissions to hospital, with serious chronic complications (e.g. leg ulcers, chronic

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pain, and chronic lung disease) or with complex needs due to co-existence of other long term
conditions.

Recommendations
 Specialist community nursing guidelines and protocols with measurable outcomes
should be developed for the management of this client group.
 Where there is an acute pain service in the community, the nursing team should have
protocols for pain management in the community, including nursing assessment tools,
care plans and referral pathways (Royal College of Nursing, 2015).

Prevention of infection: immunisations and prophylactic

antibiotics

"The penicillin and folic acid helps me. The six monthly clinic at the hospital is usually for blood
tests and checks. I have not been in hospital with a crisis for nearly two years."

“I get my pneumococcal vaccines every five years and my flu jabs yearly. I don’t tend to have chest
infections lately”

Introduction
Patients with SCD are susceptible to a range of bacterial and other infections. Invasive
pneumococcal disease (IPD) has generally been considered the most significant cause of
infection-related morbidity and mortality, but other bacterial infections, including salmonella
and gram-negative urinary tract infections are also important causes of sepsis. The increased
susceptibility to IPD is related to a reduction in splenic function which is apparent from an early
age. Patients who have been splenectomised are probably at highest risk (Rankine-Mullings &
Owusu-Ofori, 2017). Infants and young children are especially vulnerable to infection, but older
children and adults are also at increased risk. People with sickle cell/haemoglobin C compound
heterozygosity and haemoglobin S/β+ thalassaemia have a lower incidence of life threatening
infection because their spleen function is less damaged. Nonetheless, they should also receive
appropriate vaccination.

The Public Health England publication ‘The Green Book’ (Public Health England, 2014) provides
advice on immunisation against infectious disease in the UK as well as additional antibiotic
prophylaxis and vaccines. (Frequently updated guidance is available through
www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-
book.) Recommendations for the treatment of suspected or proven infection should be based on
local protocols, with relevant antimicrobial resistance patterns taken into consideration.

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Standards
 Specialist and local haemoglobinopathy teams and GPs should ensure that adults with
SCD are adequately vaccinated against the following infections according to advice in the
Green Book:
o Invasive pneumococcal disease
o Haemophilus influenza type B
o Neisseria meningitis ACWY and B
o Hepatitis B
 Adults who have not previously been immunised with conjugate pneumococcal vaccine
should be given a single dose of the current recommended conjugate pneumococcal
conjugate vaccine (PCV13). In addition, the pneumococcal polysaccharide vaccine (PPV)
should be given at five yearly intervals.
 Influenza vaccine should be offered annually.
 Hepatitis B immunity (HBsAb) should be reviewed annually and a booster offered if
levels are <100 mIU/ml.
 Patients should be periodically warned about the increased risk of IPD and other forms
of sepsis. They should also be educated about symptoms which might indicate infection
and be advised to keep a thermometer at home to check for fever and to attend for
medical assessment if ≥ 38°C. Written confirmation of patient education should be
provided, either in a clinic letter or as an information sheet.
 Adults with SCD who have had a splenectomy or a history of IPD should continue on
lifelong penicillin prophylaxis.
 A discussion of oral antibiotic prophylaxis should be undertaken on transition to adult
care and at annual review. Adults with SCD who choose not to continue regular oral
prophylaxis should ensure they have received pneumococcal vaccination and should be
provided with a supply of appropriate antibiotics for emergency use.

Vaccinations
Vaccinations are usually administered in primary care, but it is useful for hospital teams to
remind the staff what is necessary, and check that it has been administered. Advice about
vaccinations for adults who are hyposplenic can be found in the Green Book (Public Health
England, 2014). Adults with SCD in the UK may not have received all the vaccinations currently
recommended for routine childhood immunisation or additional vaccination for hyposplenic
children. Therefore the primary care physician and SCD specialist should both ensure that
patients receive immunisations in line with the most up to date vaccination advice.

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Pneumococcal vaccine

There are two types of pneumococcal vaccine recommended for SCD.

Pneumococcal polysaccharide vaccine (PPV). This was the first vaccine in widespread clinical
use for prevention of IPD. The current version contains purified capsular polysaccharide
antigen from 23 serotypes of Streptococcus pneumoniae (PPV23, Pneumovax). It does not induce
a T-cell response, and is not immunogenic in infants. The overall efficacy of PPV in preventing
pneumococcal bacteraemia is probably around 50-70% and the 23 types included account for
about 96% of the pneumococcal serotypes that cause serious infection in the UK.

Most adult patients develop a good antibody response to PPV by the third week following
immunisation but the antibody response may be reduced in those with absent or dysfunctional
spleens. The length of protection offered by PPV is not known and may vary between capsular
types. Post-immunisation antibody levels usually begin to wane after five years but may decline
more rapidly in asplenic patients (Butler et al., 1993). Repeat vaccination of PPV is safe and is
usually recommended every five years in patients with SCD because of this declining response.
It has been suggested that non responders should perhaps be re-vaccinated more frequently
than this, with decisions on re-immunisation being based on antibody levels, but routine
laboratories do not measure antibody response to all serotypes and this does not form part of
routine practice at present (Cherif et al., 2006; Stanford et al., 2009).

Pneumococcal conjugate vaccines (PCV) have been introduced over the past two decades and
are now part of routine childhood immunisation in many countries in the developed and
developing world. They consist of a polysaccharide antigen conjugated to an immunogenic
protein carrier, and elicit a T cell-dependent immune response which generally produces a
durable protective antibody response. The current generation of PCV includes the serotypes
responsible for the majority, but not all cases of IPD. Epidemiological and surveillance data
suggest a recent serological shift in IPD to serotypes not represented in the current PCV
vaccines.

A recent trial of PCV booster doses in older children who had previously received PPV but not
PCV provided some evidence for enhanced protective antibody responses.

Recommendations for PCV have recently been revised (Public Health England, 2017a) so that
children and adults in a clinical risk group, such as those with asplenia or hypofunction of the
spleen, ‘including conditions such as homozygous sickle cell disease’ should be offered a single
dose of 0.5ml of PCV13, although the recommendation is qualified by ‘decision based on clinical
judgement’.

The majority of adults will not previously been immunised with conjugate pneumococcal
vaccine and they should be given a single dose of the current recommended conjugate
pneumococcal conjugate vaccine (PCV13) in addition to the previously recommended five
yearly PPV.

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Health professionals should ensure that adults with SCD should have been offered:

 Pneumococcal polysaccharide vaccination (PPV23) at five yearly intervals; and

 A single 0.5 ml dose of pneumococcal conjugate vaccine (PCV13) which should be given
at least six months after PPV.

Meningococcal vaccination

Meningitis B vaccine was added to the childhood vaccine programme in 2015 and is now
offered to all patients with an absent or dysfunctional spleen. For adults, two doses not less than
one month apart are recommended. It should not be given to pregnant women unless there has
been a clear risk of exposure to Meningococcal infection.

In August 2015 a MenACWY conjugate vaccine catch up programme began for all children aged
14-18 years and those <25 years of age and is now recommended for adults with SCD.

Health professionals should ensure that adults with SCD should have been offered:

 One dose of Hib/Men C; followed by,

 One dose of MenACWY conjugate vaccine one month later
 Two primary doses of MenB vaccine one month apart [this can be at the same visits as
the other vaccinations above].

Haemophilus influenzae type b (Hib) vaccination

There has been a dramatic decrease in the incidence of invasive Hib infections observed in the
post-vaccination era in people with sickle cell disease living in high-income countries.
Therefore, despite the absence of evidence from randomised controlled trials, it is expected that
Haemophilus influenzae type b conjugate vaccines will be useful in children affected with sickle
cell disease (Allali et al., 2016). It is included in the childhood vaccination programme in the UK.
There is a lack of data on effect of the Hib vaccine in adults but it should be offered to adults
with SCD who have not previously been vaccinated in childhood.

Health professionals should ensure that adults with SCD should have been offered:

 One dose of Hib/Men C

Influenza vaccination

Patients with SCD are at higher risk of complications associated with influenza. These can
include vaso-occlusive crisis, acute chest syndrome and invasive bacterial infections. Adults
with SCD should be offered annual influenza vaccination.

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Hepatitis B vaccination

Blood for transfusion is screened for hepatitis B in the UK but patients with SCD have a high
lifetime likelihood of receiving emergency blood transfusion and a number may require regular
routine blood transfusion.

Adults with SCD should be offered immunisation for hepatitis B if they do not have protective
antibody levels (HBsAb >100 mIU/ml). Antibody levels should be checked regularly and
vaccination booster offered if HBsAb <100 mIU/ml, unless there is evidence of a previous,
cleared infection as indicated by positive HBcAb (Hepatitis B Core Antibody).

Summary of vaccination advice

Please refer to the Green Book for most up to date advice (Public Health England, 2014)

The majority of adults in the UK will not have received primary vaccination according to the
current recommendations and specialist teams should communicate with primary care
providers to ensure all adults receive appropriate vaccination to prevent infection from
Streptococcus pneumoniae, Haemophilus influenza type B and Neisseria meningitis ACWY and B
according to the currently recommended vaccination schedule.

Adults with SCD who have not received primary vaccination as part of the national schedule in
the UK should be offered:

 One dose of Hib/Men C and one dose of pneumococcal polysaccharide vaccine (PPV23);
followed by,
 One dose of MenACWY conjugate vaccine one month later
 Two primary doses of MenB vaccine one month apart [this can be at the same visits as
the other vaccinations above]
 A single 0.5 ml dose of pneumococcal conjugate vaccine (PCV13) which should be given
at least six months after PPV

Adults with SCD should also be offered:

 Pneumococcal polysaccharide vaccination (PPV23) at five yearly intervals

 Annual influenza vaccination
 Hepatitis B vaccine if they have not previously received it and are non-immune (HBsAb
<100 mIU/ml)

Salmonella vaccine

Salmonella organisms are a common cause of infection in patients with SCD, and the infection
much more commonly becomes invasive, and can lead to sepsis and multi-organ failure.
Vaccines have been licensed for use but vaccination has not been implemented at a country-

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wide level, in part due to the poor immunogenicity in young children. There is promise of an
oral vaccine in the near future. First line antibiotics for sepsis must cover salmonella species.

Antibiotic prophylaxis
The highest risk of pneumococcal infection occurs in children under three years of age. This risk
persists despite inclusion of PCV in the routine infant vaccination schedule. The PROPS trial,
conducted over 30 years ago, before pneumococcal vaccines were available, showed that
regular oral prophylactic penicillin reduced the rate of pneumococcal infections in children with
SCD less than five years old and was associated with minimal adverse reactions (Gaston et al.,
1986; Rankine-Mullings & Owusu-Ofori, 2017). Evidence is lacking in children with genotypes
other than sickle cell anaemia.

National guidelines on prophylaxis for asplenic patients have previously recommended lifelong
prophylaxis with oral penicillin. This recommendation was based on expert opinion and case
series of IPD in asplenic and hyposplenic adults who mostly had not been advised on any
specific measures for prevention of infection. Current opinion on long-term oral penicillin
prophylaxis is divided. PROPS 2 attempted to compare the risk of IPD in children age >5 years
who continued or stopped oral penicillin, however, the study was not adequately powered and
there were insufficient cases of IPD in either group to draw definitive conclusions about lifetime
risk (Falletta et al., 1995). As risk of infection decreases with age, there might be a time when
preventative antibiotic treatment can be stopped in the fully immunised individual. Those who
have had a splenectomy or invasive pneumococcal infections should continue lifelong
pneumococcal prophylaxis.

Careful assessment of adherence to treatment will often reveal inconsistent usage. Therefore
the clinician should discuss oral antibiotic prophylaxis on transition to adult care and
periodically thereafter as part of the annual review. If adults would prefer to continue regular
prophylactic antibiotics these should be prescribed. Adults with SCD who are unlikely to adhere
to regular oral prophylaxis should consider stopping penicillin prophylaxis if they have received
adequate pneumococcal vaccination and are aware of the risk of invasive pneumococcal disease.
Those who stop regular antibiotic prophylaxis should be provided with a supply of appropriate
antibiotics for emergency use. They should be reminded to carry these when they travel abroad.
Suitable antibiotics include penicillin V 500mg qds, or amoxicillin 500mg tds or – if penicillin
allergic – erythromycin 500mg qds. Patients and their carers should regularly be reminded of
the ongoing risk of infection and encouraged to seek medical advice if the patients become
febrile (≥380C) and/or develop symptoms of infection. This can be reinforced with written
patient information, either via a clinic letter or a patient information leaflet. The risk of
pneumococcal infection increases with increasing age and it may be advisable to restart
penicillin prophylaxis over the age of 50 years.

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Travel vaccinations and antibiotics

Patients should be encouraged to seek travel advice and to accept all the offered immunisations
relevant to the area to which they are travelling; this includes live vaccines such as yellow fever.

There is a common misconception among patients – and some healthcare professionals – that
people with sickle cell disease do not get malaria infections; this is incorrect, and malaria
infection can be very serious and fatal. Patients with SCD should receive malaria prophylaxis
when travelling to malarial areas, in line with general guidance for the area of travel. All
chemoprophylactic agents are acceptable in patients with SCD although it should be noted that
there is an increase of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in this patient
group and in these patients certain agents should be avoided.

Recommendations:
 Patients should be given the relevant and appropriate information to alert health care
professionals to the risk of overwhelming infection.
 All patients should be educated regarding the potential risks of travel related infection
risks and how to avoid them (in particular malaria and unusual infections, e.g. animal
and insect bite infections).
 The patients’ primary care team should be responsible for keeping clear records of
vaccination and revaccination status for patients with SCD and the status documented at
annual review and included in hospital records.

Blood pressure monitoring

“My blood pressure is always monitored when I attend my outpatient appointments. However, this
is not very regular.”

Introduction
Hypertension is an independent risk factor for stroke, renal disease and pulmonary
hypertension. Patients with SCD generally have a lower mean blood pressure (BP) than age and
sex matched controls.

Standard
 Check blood pressure at every GP and hospital visit.

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Background evidence
In patients with SCD, blood pressure should be monitored at every routine visit to the GP and at
each hospital appointment.

In the absence of albuminuria (albumin creatinine ratio (ACR) <3.5mg/mmol), the target blood
pressure should be < 140/90. If BP is ≥140/90, treatment should be started in accordance with
the NICE / British Hypertension Society algorithm (National Institute for Health and Care
Excellence, 2011 updated 2016). This recommends that a calcium channel blocker, e.g.
amlodipine, is started as initial management if the patient is African/Caribbean of any age.
Diuretics should not be used as first-line treatment in isolated hypertension.

For patients with albuminuria (ACR ≥3.5mg/mmol) target blood pressure should be 130/80. If
BP is ≥ 130/80 in the presence of proteinuria initial treatment should be with an ACE inhibitor
or angiotensin receptor blocker (ARB) or a calcium channel blocker. Treatment of proteinuria is
considered in Chapter 8: Renal and urological complications.

Recommendations
 Hypertension in SCD should be monitored and treated in primary care.
 Patients with hypertension and ACR <3.5 mg/mmol should be treated with a BP target
of <140/90 mmHg. Patients with hypertension and ACR ≥3.5 mg/mmol should be
treated with a BP target of <130/80 mmHg.
 In the absence of proteinuria initial treatment should be with calcium channel blockers.

Folic acid

“I have been taking folic acid since I was a child, I am now in my 40s”

Introduction
In common with other chronic haemolytic conditions, patients with sickle cell disease are at risk
of developing folate deficiency due to increased erythropoiesis and folate turnover.

Standards
 Folate levels should be checked in any patient with worsening anaemia or macrocytosis.
 Co-existing cobalamin deficiency should be considered in any patient taking folic acid
supplementation who has neurological signs or symptoms or develops megaloblastic
anaemia.

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Background evidence
Studies have shown lower levels of folic acid in patients with SCD compared to healthy controls
(Liu, 1975) but there are no trials showing the benefit of routine folate supplementation. A
recent Cochrane review concluded that a lack of evidence-based research means that while it is
possible that folic acid supplementation may increase serum folate levels, the effect of
supplementation on anaemia and any symptoms of anaemia remains unclear (Dixit et al., 2016).
There are no trials in adults and one randomised double-blind control study of folic acid
supplementation in children showed no convincing improvement in anaemia or any other
clinical outcome (Rabb et al., 1983). A recent study of discontinuation of folic acid
supplementation in young people with SCD showed no differences in haemoglobin, reticulocyte
count or folate levels after discontinuation (Nguyen et al., 2016).

Historically many patients have been prescribed daily folic acid but in those who eat a good
mixed diet it is probably not necessary. Some patients have a preference to continue folic acid,
sometimes only intermittently or when they know their diet may be poor, and there is no
reason to discourage this. It may be helpful to take folic acid during periods of ill health and for
a short period subsequently. Folate levels should certainly be checked in any patients with
increasing mean cell volume or worsening anaemia. Folic acid at a dose of 5mg should be
started in women with SCD before conception if possible (see Chapter 18 - Reproductive
health.)

There is a small risk that routine folate supplementation may mask the megaloblastic anaemia
caused by cobalamin deficiency thereby permitting neurological dysfunction to develop.
Superimposed cobalamin deficiency must be considered whenever anaemia worsens or the
mean cell volume (MCV), lactate dehydrogenase (LDH) or bilirubin level rises or in the context
of any neurological signs or symptoms in a patient on folate supplementation.

Recommendation
 Folic acid supplementation is unlikely to be necessary on a regular basis in adults with
SCD with a good mixed diet but could be considered in adults with SCD with a diet which
does not contain adequate folic acid or in whom there is proven folate deficiency.

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Bone health and vitamin D

“I have been told recently that my Vitamin D is very low and due to lack of sunlight in the UK, it is
difficult to receive natural sunlight so my consultant has prescribed Vitamin D supplements and I
eat foods high in Vitamin D too”

Introduction
Vitamin D is essential for the normal absorption of calcium and to maintain normal calcium
homeostasis and bone mineralisation. Vitamin D deficiency (VDD) can lead to low blood calcium
levels and result in bone damage. In adults this can lead to osteomalacia. VDD has been
associated with increased fracture risk, musculoskeletal pains, chronic fatigue, cardiovascular
disease, asthma and nephropathy. Dietary sources of vitamin D include oily fish and fortified
foods but the principal source is biosynthesis from 7-dehydrocholesterol due to the action of
ultraviolet (UV) light in the skin. VDD has a high incidence in SCD patients. It has been suggested
that osteoporosis may be more common in people with SCD.

Standards
 Vitamin D levels should be measured at least annually in all patients with SCD.
 Patients who have vitamin D insufficiency or deficiency should be started on
appropriate vitamin D replacement.
 If there is any evidence of pathological fracture, bone mineral densitometry (BMD)
assessment should be carried out.

Background evidence
A systematic review of the prevalence of VDD in SCD identified 15 relevant articles and
concluded that suboptimal vitamin D levels were highly prevalent when compared with non-
SCD patients or control populations (Nolan et al., 2015). When VDD was defined as vitamin D
<20 ng/mL, prevalence estimates in SCD populations ranged from 56.4% to 96.4%. Prevalence
of VDD was similar in the general African American population and the SCD population. Rates of
VDD in African American patients with and without SCD were both substantially higher than
that of Caucasians. The African and African-Caribbean population in the UK is similarly at risk of
VDD due to decreased synthesis in pigmented skin, reduced exposure to sunlight due to
spending less time outdoors, inadequate dietary intake and compromised intestinal absorption.

VDD is associated with musculoskeletal pains and chronic fatigue in the non-SCD population.
These symptoms are common in patients with SCD and it has been suggested that VDD may be
contributory. It has also been suggested that VDD may contribute to acute painful episodes
(Adegoke et al., 2017; Lee et al., 2015). Many studies have demonstrated an improvement in
pain symptoms, bone density markers and overall quality of life in SCD patients treated with
high dose Vitamin D supplementation (up to 100,000 IU weekly). A recent Cochrane review

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identified only one randomised controlled trial of moderate to low quality (Soe et al., 2017). In
this trial 37 people (7-21 years) were treated with vitamin D supplementation or placebo for six
months (Osunkwo et al., 2012). Patients taking vitamin D had higher levels of vitamin D in their
blood after treatment and significantly fewer pain days, but worse health related quality of life.
The Cochrane review concluded that existing evidence was not sufficient to guide clinical
practice and that clinicians should consider relevant existing guidelines for vitamin D
supplementation and dietary reference intakes for calcium and Vitamin D (Holick et al., 2011;
Ross et al., 2011). These advise daily dietary Vitamin D intake of 1500-2000 IU.

Vitamin D is most commonly assessed by measuring 25-hydroxy vitamin D (25-OHD) levels. It

may be advisable to assess vitamin D levels regularly in patients with SCD perhaps as part of the
annual review. If levels are found to be inadequate or deficient, patients should be offered
Vitamin D supplementation according to local guidelines.

Some studies have suggested a raised incidence of osteopenia and osteoporosis in patients with
SCD (Almeida & Roberts, 2005; Sarrai et al., 2007). The risk of abnormal bone mineral density
may be increased in those with increased bone marrow expansion, decreased haemoglobin and
body mass index, suboptimal achievement of peak bone mass and poor calcium and Vitamin D
intake. Although it is not routine practice to assess bone mineral densitometry (BMD) in SCD
patients, if there is any clinical suspicion of osteoporosis (i.e. pathological fracture) this should
be assessed and referral for a specialist opinion for more detailed assessment should be
considered.

Recommendation
 Consider measuring bone mineral density in those with low body mass index and
haemoglobin.

Dental management of SCD

Introduction
Oral health is an integral and important part of general health and may impact on the general
well-being of those with SCD (Fernandes et al., 2016). SCD may be associated with dental
problems, including alterations in dental occlusion, which may influence the quality of life of
affected individuals. Further, dental infections can lead to an increased likelihood of triggering a
sickle cell crisis (Laurence et al., 2013).

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Standards
 All patients with SCD should access regular dental care to prevent oral infection and
manage the potential orofacial features associated with bone marrow expansion.
 Dentists should be aware of the increased risk of infection in patients with SCD and
ensure they prescribe appropriate antibiotics to treat acute infections or to cover dental
procedures.

Background evidence
Many orofacial features have been described in SCD but the extent of changes remains variable.
SCD may result in compensatory hyperplasia and expansion of the bone marrow including the
facial bones which may lead to depression of the nasal bridge, mid-facial overgrowth resulting
in maxillary protrusion, and an increase in the vertical dimension (Licciardello et al., 2007).
Hypoxia related to SCD has been associated with osteomyelitis of the jaws, particularly the
mandible (Javed et al., 2013). Osteomyelitis and/or vaso-occlusive changes may result in painful
episodes and/or neuropathies, including ‘numb chin syndrome’ where the mental nerve is
affected (Friedlander et al., 1980).

SCD is a risk factor for moderate to severe malocclusion. Anterior tooth loss, anterior spacing,
increased overjet, anterior cross-bite and open-bite have all been described (Costa et al., 2015).
Delayed eruption of teeth and dental hypoplasia/ hypo-mineralisation and hypercementosis
may also occur. The evidence on susceptibility to dental decay remains contradictory
(Fernandes et al., 2015). Data suggest that patients with SCD have increased susceptibility to
dental caries, with a higher prevalence of tooth decay and lower prevalence of filled teeth.
However, the severity of periodontal disease and inflammatory conditions in patients with SCD
is more likely associated with oral hygiene maintenance and other caries risk factors rather
than the haematological disorder itself (Al-Alawi et al., 2015; Arowojolu et al., 1996; Javed et al.,
2013). This is a reminder about the important of providing good general dental care,
irrespective of SCD. Dental pulp necrosis due to infarction/thrombosis of the dental pulp vessels
may result in toothache (Cox & Soni, 1984). Diagnosis may be challenging as the tooth may
appear otherwise healthy.

There are no randomised trials investigating dental care in patients with SCD and
recommendations are based on observational data and expert opinion (Mulimani et al., 2016).

Individuals with SCD may experience additional complications following routine dental
treatment and dental care may need to be adapted. In order to reduce the likelihood of
triggering a sickle cell crisis, measures should be implemented to reduce stress, such as anxiety
management, augmented with inhalational sedation where appropriate (Bryant & Boyle, 2011).
It is also important to ensure that the environment is not cold, that the patient is well hydrated
and dental infections are managed early. Inhalation sedation is preferable to intravenous
sedation but may not be sufficient to enable the delivery of a longer and more complex
treatment, particularly when the patient is very anxious.

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Recommendations
 Improve awareness of the potential dental and orofacial manifestations of sickle cell
disease among patients, their families and the practitioners involved in their care.
 Adults with SCD should receive regular dental care to facilitate preventive measure such
as oral hygiene instructions, diet control and fluoride prescription/applications (Smith
et al., 1987).
 Dental care should be delivered as a coordinated team approach, with close liaison with
the haematologist. If sedation or general anaesthesia is planned, treatment should not
be in a community setting, but in a hospital dental department with a sickle cell
haematology team on hand, and any pre-procedure interventions must be discussed
with them in advance.
 Dentists caring for patients with SCD presenting with acute dental infections/abscesses
should receive urgent dental care and antimicrobial therapy as required.

Chapter 3: Conclusion

This chapter considered the role of primary and community health care and although
sometimes neglected, such support – as we have seen – has an important role to play in
supporting those with SCD. The scope of primary and community health care is necessarily
broad. This highlights the importance of coordination, communication and team working
between the different stakeholders, including primary and secondary care. This helps ensure
patients and their families received seamless care, consistent with the principles of holistic
support. The next chapter explores this further, by exploring the role of social and psychological
support in the care of those with SCD.

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 Chapter 4: Health and well-being
Following on from the previous chapter, we now discuss the more general social and
psychological support of potential benefit to people with sickle cell disease (SCD) and their
families. Once again the focus is broad and at times more theoretical informed, particularly
given the lack of evidence specific to the experience of SCD. Nonetheless, the evidence of more
general benefit of many of the interventions introduced in this chapter is strong and there is no
reason to assume they are not of equal benefit for those with SCD. The chapter also offers a
timely reminder of the role of socially orientated provision, which can make an important
contribution to improving a person’s quality of life.

Public health

Introduction
While there is a strong evidence base for the role of various public health interventions in
improving general well-being, there is little if any research that connects it to SCD.
Consequently, this is not an especially well established area, although aspects of public health
such as nutrition and oral health are beginning to be debated. The general importance of
understanding a person’s social and economic context and its impact on health and well-being
has also been highlighted (Berghs et al., 2016). Public health has an important role to play in
advancing the well-being of people with long standing chronic conditions, such as SCD by
helping support behavioural change that is sensitive to context (Marmot & Bell, 2012).
Interventions that aim to tackle underlying causes of ill-health and reduce health inequalities
have the potential to transform lives (HM Government, 2010). To this extent, public health is a
natural ally of primary care.

Standard
 Advice on benefits, housing, education and other forms of social care provision should
be given when appropriate.

Background evidence
There are marked social gradients in long standing chronic conditions across the life-course;
and evidence of enduring effects associated with childhood circumstances (Marmot & Bell,
2012). Further, people with disabilities are disproportionately exposed to the social factors that
contribute to health inequalities, (World Health Organization (WHO), 2011) including risk

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factors such as lack of physical activity and social isolation alongside broader determinants
associated with educational and employment opportunities, poverty and poor housing, and
inequitable access to service support (Emerson et al., 2012). These environmental
disadvantages are, in turn, disabling and create the potential for social exclusion (World Health
Organization (WHO), 2011). There is no evidence to suggest the disabling experience of
someone with SCD is any different. It is, therefore, likely that generic public health interventions
will improve well-being among those with SCD. This is an important consideration, particularly
since such interventions can help maintain and improve quality of life for those with SCD. It
remains, however, a neglected area and the potential of public health has yet to be realised.

Previous perceptions of long standing illness are been challenged by a more encompassing
understanding of the relationship between ‘being ill’ and ‘being disabled’ (Atkin et al., 2010).
Disability, although socially patterned, can affect anyone, including those with pre-existing
chronic conditions (Marmot & Bell, 2012). Further, international understandings have moved
away from a strictly medical definition, where ‘disease’ and ‘disability’ are ‘caused’ by functional
deficits (such as physical disability), to one sensitive to environmental determinants and
connected to how people experience disability (and illness) as they go about their day-to-day
lives (Lollar & Crews, 2003; Oliver & Barnes, 2012). The United Nations Convention on the
Rights of Persons with Disabilities (CRPD) reflects these changes. Disability is understood to
result ‘from the interaction between persons with impairments and attitudinal and
environmental barriers that hinders their full and effective participation in society on an equal
basis with others’ (United Nations, 2007). Human rights and equality frameworks are also
increasingly employed to articulate the moral claims and service needs of people with long
standing chronic conditions, such as SCD. This has led to a focus on facilitating an enabling
environment and emphasising capability, which can support resilience and encourage people to
‘flourish’ with their condition (Berghs et al., 2016).

Recommendations
 Strategies to address social isolation and lack of social opportunities should be
considered, alongside an emphasis on how best to facilitate behavioural change,
resilience and empowerment among people with SCD.
 The relationship between socio-economic disadvantage and health needs to be taken
into account, when providing support to those with SCD and their families.
 The broader well-being of a person with SCD should be considered during his or her
contact with primary and more specialist secondary care provision.
 Appropriate advice should be provided and a person encouraged and supported to take
a proactive approach to his or her health.
 An assessment of general health and well-being should occur and advice provided on
how best to support a person’s quality of life, in a way that facilitates resilience, while
being sensitive to his or her socio-economic circumstances.

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Psychological interventions

“It is not death or pain that is to be dreaded, but the fear of pain or death.” – Epictetus

Introduction
Sickle cell disease (SCD) poses multiple and severe psychological challenges to patients,
families, health care professionals and the health care system. As it is present from birth it can
interfere with normal adjustment to developmental challenges and achievement of personal
goals. This occurs in the context of SCD being a stigmatising medical condition causing
considerable socio-economic challenges. On a more individual level, psychosocial issues for
people with SCD and their families can result from the impact and disruption due to pain and
other symptoms on their daily lives, affecting their quality of life. For example, stress,
depression, fear or anxiety may affect pain experience leading to frequent hospital admissions.
People with SCD have different levels of health, and variations in their ability to cope from day-
to-day. Studies suggest a person’s way of coping appears to be a significant predictor of
adjustment, independent of the severity of his or her disease.

Psychological interventions should be offered as standard care in the management of SCD

adjunctive to medical treatment and nursing care. The specialist multidisciplinary team should
include clinical/health or counselling psychologists. The overall goal is to help people build
resilience, enhance coping strategies, develop ways to manage symptoms such as anxiety,
depression and anger, be able to engage in valued activity and roles and improve their quality of
life. These interventions should be available in both hospital and community based settings.
Furthermore, cognitive impairment is well recognised as a complication of SCD, both in patients
who have had an overt or silent stroke, and in those without magnetic resonance imaging (MRI)
evidence of disease. Neuropsychological evaluation can establish the extent of cognitive
damage, map this over time and offer treatment strategies.

Standards
 All people with SCD should have access to specialist psychology support.
 Core staffing of Specialist Centres for SCD should include a psychologist with a special
interest and experience in SCD.
 Psychological assessments should be carried out when indicated or at least annually,
and include the following:
o Subjective estimates and objective measure of emotional well-being and pain
o Physical and social function i.e. participation/non-participation or reduction in
activities e.g. work, social – subjective estimates and objective measures
o Objective measures of coping strategies and sources of support.

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 Neuropsychological assessments should be carried out as appropriate when

neurological complications are indicated.
 Psychological therapies including Cognitive Behavioural Therapy (CBT) should be
offered as required, and could be offered in individual or group sessions.
 Psychological support should be offered to patient and carer support groups.

Background evidence
Reviews of psychological studies have shown that people with SCD have a severely
compromised health-related quality of life in comparison to the general population and other
medical conditions (Anie, 2005; McClish et al., 2005). Moreover, depression, anxiety, and
psychological difficulties are prevalent among people with SCD, and predictive of pain
experience (Levenson et al., 2008; Sogutlu et al., 2011). There is good evidence to suggest that
cognitive behavioural therapy in adults with SCD is beneficial to moderate chronic pain,
disability, depression and anxiety associated with SCD (Anie & Green, 2015; Chen et al., 2004;
Williams & Tanabe, 2016). This is supported by studies of chronic pain management (in non-
SCD samples) with psychological therapies delivered via the internet that were shown to be
effective in reducing pain, disability, depression and anxiety in adults, comparable to
effectiveness in face-to-face therapies (Eccleston et al., 2014a).

Furthermore, reviews of psychological therapies with children and young people show that
these have been effective in reducing pain and perceived disability amongst those with non-
headache pain (including sickle cell disease), but only soon after treatment (Eccleston et al.,
2014b); and group psychoeducation in families of children and adolescents with SCD has shown
improvements in knowledge (Anie & Green, 2015).

Cognitive impairments have been highlighted in adults with SCD who have normal MRIs,
suggesting the importance of neuropsychological assessments (Rawle et al., 2015; Vichinsky et
al., 2010). Further psychological therapies are outlined in Appendix 2

Recommendations
 Psychologists should be an integral part of multidisciplinary teams for the management
of SCD.
 Health professionals should routinely assess a patient’s desire for psychological
intervention/support by asking questions such as ‘How are you feeling/coping?’ and
should identify patients who would benefit from psychological intervention in order to
maximise health related behavioural changes e.g. improving adherence.
 Patients should be encouraged to practice CBT techniques such as relaxation on a
regular basis, or seek instruction if needed.

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 Patients and their families should be made aware of what psychological support is
available within hospital and community settings.
 Patients seeking to make health-related behavioural changes such as quit smoking,
should be referred for psychological support in order to maximise success.
 Where serious mental health difficulties or psychiatric problems are identified, referral
to a secondary mental health service should be considered and, if possible, discussed
with the team psychologist in a timely fashion.
 Specialist staff should be aware of the importance of psychosocial issues in providing
care for people with SCD and should have access to training, support, consultation or
supervision from a psychologist with a special interest in SCD.

Nutrition and lifestyle

"We could do with some help with food management and what not to eat e.g. foods with iron if you
are on an exchange programme."

"I have been fortunate enough to have a research background, so I have researched myself
treatments, management and why I need to eat certain foods etc."

Introduction
The importance of nutrition in patients with SCD is largely under-recognised in the UK. Sickle
cell patients are not readily referred to dieticians and dietetic involvement in the nutritional
care of sickle cell patients is mostly poor. Current nutritional support generally consists of
advice on healthy eating and possibly the prescription of a nutritional supplement. An improved
strategy for nutritional support should be part of the broader commitment to enhancing the
general well-being of people with SCD.

Standards
 Dieticians should be included in the multi-disciplinary team caring for patients with
SCD.
 Patients with SCD should be screened for malnutrition/risk of malnutrition by
healthcare professionals with appropriate skills and training (National Institute for
Health and Care Excellence, 2012a)
 Patients with SCD who have been identified as high risk for malnutrition should be
offered nutritional assessment by an appropriately trained dietician and should receive
a nutritional management care plan.

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Background evidence
Dieticians are qualified health professionals able to assess, diagnose, and treat diet and
nutrition problems at an individual and wider public health level and they have a responsibility
to comprehensively assess the nutritional needs of all patients and make an accurate nutritional
diagnosis. Undernutrition or poor nutrition has been described as a feature of SCD since the
1980s but the specific dietary requirements for this group of patients has not yet been
established despite the recommendation for inclusion of nutritional advice into routine care
(Hyacinth et al., 2010).

A national cross sectional survey exploring the involvement, knowledge and attitudes of
dieticians towards SCD in the UK concluded that dieticians did not understand the nutritional
implications of SCD, there were no sickle cell-specific nutritional guidelines, standards and
resources to help dieticians, and poor referral rates of sickle cell patients for dietetic input
occurred. Dieticians need to comprehensively assess the nutritional needs of sickle cell patient,
considering all the factors that affect his or her nutritional intake (European Society for Clinical
Nutrition and Metabolism (ESPEN) et al., 2006). These include the wider determinants of health
and psychosocial factors, nutritional factors (infection risk, dehydration, frailty and
gastrointestinal intolerances) and medical considerations (hydroxycarbamide, transfusion
treatment, iron overload) (Matthews, 2015).

NICE guidelines (National Institute for Health and Care Excellence, 2006) recommend that
nutrition support should be considered in people who are malnourished or at risk of
malnutrition, as defined by any of the following:

 Body mass index (BMI) of less than 18.5 kg/m2

 Unintentional weight loss greater than 10% within the previous 3–6 months
 BMI of less than 20 kg/m2 and unintentional weight loss greater than 5% within the
previous 3–6 months
 Having eaten little or nothing for more than 5 days and/or are likely to eat little or
nothing for the next 5 days or longer
 Have a poor absorptive capacity, and/or have high nutrient losses and/or have
increased nutritional needs from causes such as catabolism

Patients with SCD should be evaluated for these risk factors and referred to a dietician for
review if appropriate. Effective management of the nutritional needs of patients with SCD could
include the development of a ‘national nutrition strategy’, acknowledging all the key players
involved including primary and secondary care practitioners, the dietitian and the patients and
their families.

There is little published research in this area but elevated protein turnover and energy
expenditure have been reported in adults with SCD, suggesting increased protein and calorie
requirements (Badaloo et al., 1989; Hibbert et al., 1992; Jackson et al., 1988) and patients with

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SCD often experience anorexia due to general chronic malaise. There is a suggestion that routine
dietary supplementation may be of benefit. In a small study, supplementation with Omega (N3)
fatty acids resulted in significant reductions in inflammation, oxidative stress, red cell density
and pain episodes (Tomer et al., 2001) and several small studies have shown benefit with
supplementation of micronutrients (e.g. iron, zinc) but these need further study to establish
their efficacy. Prior to iron supplementation it should always be confirmed that the patient is
iron deficient.

Recommendations
 The British Dietetic Association should consider development of a sickle cell specific
nutritional risk assessment tool to allow consistent dietary assessment.
 Centres could consider offering an annual review with a dietitian to advise on optimal
nutrition.
 Health and social care practitioners should be aware of how diet can enhance healthy
living and general well-being among patients with SCD.
 Further research into the role of nutritional support for patients in patients with SCD is
needed.

Health education

‘… the competencies that ‘lay’ contributors can offer should not be permitted to draw attention
away from the need to change professional attitudes and practices, and the value of constructive,
‘grown up’, professional/patient relationships.’

(Taylor & Bury, 2007)

Introduction
This section covers several aspects of education for adults living with SCD in the community,
including how best to think about ongoing education of someone with SCD around his or her
illness (what has been called self-management of illness or the ‘expert patient’). In doing so, it
connects to ideas, such as resilience and empowerment. This section explains why such adult
patient education should be a mutual process rather than an issue to be ‘managed’; why
knowledge and confidence should be the aim rather than the containment of health care
utilisation or costs; the danger that some initiatives may be socially exclusive and inadvertently
increase disparities in ethnic health; and the importance of recognising the influence of social,
economic, political and environmental factors in how people understand and engage with their
SCD.

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Standard
 Goals for education of adults with SCD should include increased patient involvement,
knowledge and confidence.

Background evidence
Much of the literature on patient education for self-management in the UK deals with chronic
illnesses in general or chronic illnesses other than SCD specifically. While potentially useful,
lessons from studies of other chronic illnesses cannot always be assumed to transfer to a
condition such as SCD nor from one ethnic population group to another (Greenhalgh, 2009;
Kennedy et al., 2007; Kennedy & Rogers, 2009). Further, evaluation of generic patient education
programmes is mixed at best. Such programmes have severe methodological limitations (such
as comparing those select few who volunteer with those waiting to enrol on such programmes)
and tend to exclude less affluent or so-called lower ‘literacy’ groups (Greenhalgh, 2009). They
also exclude minority ethnic groups (Taylor & Bury, 2007). Available evidence suggests generic
education programmes for people with a chronic illness improve knowledge and confidence in
the short term, and people enjoy working in groups.

Most, however, do not show improved health outcomes (Greenhalgh, 2009). Nor is there any
evidence that such programmes reduce health care utilisation. They may increase it, as
knowledgeable people make greater demands of service provision overall (Greenhalgh, 2009).
Further, there is no evidence for reduction in long-term health costs (Greenhalgh, 2009;
Kennedy et al., 2007; Rogers et al., 2008). A review of four randomised trials of lay-led self-
management programmes in the UK showed improved self-efficacy, but three showed no
improvement in quality of life and none demonstrated changes in overall health care utilisation
(Griffiths et al., 2007). A review of fifteen complex interventions for groups of ‘lower literacy’
had mixed results, with no differences of the intervention being reported twice as frequently as
significant changes across a range of measures; including clinical outcomes, health knowledge,
health behaviours, quality of life, and utilisation of health care (Clement et al., 2009).

Patient education programmes have been criticised for three broad reasons. First, for their
failure to consider the social determinants of health (poverty, inequality, housing, social
security, environment and transport), thereby running the risk of blaming the person living
with a chronic illness if change is thought of as a matter for individual behaviour rather than a
response to social exclusion (Atkin et al., 2010; Rogers et al., 2008; Taylor & Bury, 2007;
Vicarelli & Bronzini, 2009). Second, for drawing attention away from the need to change some
professional attitudes and practices; just as people with SCD may not follow health management
advice for reasons to do with the context of their lives, so clinicians do not necessarily follow
guidelines, for reasons to do with the context of their practice (Ong et al., 2014). Third, the
manner in which more aggressively managed systems of care negatively affect people’s
freedoms and opportunities to cope with the challenges of chronic illness in the ways they find
most effective and appropriate (Taylor & Bury, 2007).

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Interventions have proved most effective when they (1) involve changes for the health
professional as well as the client; (2) look at how people manage and understand their illness in
the context of family and social relationships; (3) look at how people manage their illness in the
context of material and social resources available to them (Ong et al., 2014). Listening to the
stories of people with chronic illness in the context of activist events begins to expose how
broader issues of social justice and social inclusion impact on living with the chronic illness
(Greenhalgh, 2009).

Some studies have suggested expanding the notion of expert patient to expert family, but note
that this can only work if the work situation, home situation and socio-economic situations of
the family are taken into account (Vicarelli & Bronzini, 2009). Whilst self-management
programmes for African asylum seekers with a chronic illness did not work in improving self-
management, because they had other overwhelming social priorities for survival, the course
provided a surrogate family and a focus for subsequent campaigning around political and social
needs (Kennedy & Rogers, 2009).

Small scale descriptive studies of self-management of adults with SCD suggest that motivational
or strength based interviews (focussing on what adults with SCD enjoy doing) can identify the
expertise of the person with SCD, enabling them to be educators of health professionals
(Campbell et al., 2010); and that adults with SCD can identify key self-management practices
they feel work, including keeping journals, body awareness and various forms of lay and
professional support (Tanabe et al., 2010). However, social factors making people with SCD
vulnerable, including employment status and ability to earn income, are directly related to poor
health and were not improved by self-management resources such as communication skills or
self-care abilities (Jenerette & Murdaugh, 2008). This connects to the broader evidence, which
reminds us that people with disabilities and long term conditions are disproportionately
disadvantaged with respect to the social factors that contribute to health inequalities (see
above).

Recommendations
 Health education for an adult living with SCD should be regarded as a process that flows
in several directions: the person with SCD, his or her family members and professionals
can all educate one another.
 There is a need for robust evaluation of the long term effects of inclusive adult education
programmes specifically for people with SCD.
 Health and social care practitioners need to be aware of the broader impact of SCD on a
person’s life and how this impacts on his or her general health well-being.

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Support in education and training

Introduction
The section considers how to ensure that educational establishments fulfil their duty of care to
students with SCD. This is an especially important consideration as educational qualification can
protect against social-economic disadvantage, while also facilitating greater social inclusion.

Standards
 Further and higher education institutions, universities and colleges should develop and
monitor policies for supporting students with SCD with respect to their education, their
health and their careers.
 Secondary care providers should have a protocol for management of young adults who
move away from home to study. This should include transfer of information to their
term-time care provider.

Background evidence
There are few studies of adults with SCD in post-compulsory education, that is, in further or
higher education colleges or in universities. Most such studies are concerned with general
student population knowledge of, and/or attitudes to, reproductive risks of sickle cell carriers,
rather than the experiences of adults with SCD themselves. In the absence of specific evidence
for adults with SCD, we do know that young people up to age 25 years are not well supported in
schools and colleges in the UK, either in terms of catching up any education missed or in being
well supported in their health in school (Dyson et al., 2010a). Whether or not staff members
know that a person has SCD makes no significant difference to his or her being well-supported
or being poorly treated, and young people themselves are sharply divided as to whether or not
disclosure of their SCD is beneficial (Dyson et al., 2010b). Changing the social environment of
the school/college through the introduction of policy has therefore been proposed as a way
forward (Dyson, 2016), though the effectiveness of such policies have yet to be evaluated.

There is even less evidence when assessing the success or otherwise of interventions aimed at
supporting students in higher and further education. Some general observations, however, can
be made. Students might be unfamiliar or insecure about presenting themselves for treatment
at their local hospital, particularly if the student has concerns about the quality of treatment.
This could be a specific problem if a student were to move from an area with good experience of
managing SCD to another, with perhaps less experience. Anecdotal evidence suggests some
students have got on the train back to London whilst in crisis so as to access their known
provider. There are several reports of deaths too, where a local hospital has little experience of
managing a SCD crisis. Managing this move to further education, therefore, would seem an
important part of the process. Some universities have worked with the local sickle cell specialist

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nurses to introduce the students with sickle cell to the local team and to the ward where they
would be treated should they become ill whilst at university. In other localities, a formal hand-
over between health care teams might also be helpful. If the university entry forms ask a
question about medical conditions/needs, it might be useful to specify sickle cell as one of the
options, particularly since it is one of the most common monogenetic conditions in England.
Current questions tend to list asthma, epilepsy or diabetes as examples. This is unlikely to
prompt someone with sickle cell.

Finally, universities need to apply flexibility when supporting someone with a long term
condition, such as SCD. Does the ‘mitigating circumstances’ policy take into account the
fluctuating nature of the condition and the fact that symptoms can appear at short notice? Is the
leave of absence policy sensitive to the needs of someone with SCD? Reports by clinicians in
support of mitigation and leave of absence requests can assume particular importance. More
generally, are curricula designed in such a way so as a student can catch up weeks/months of
missed work? Anecdotal observations suggest that laboratory–based subjects are especially
problematic in this regard.

Recommendation
 There is a need for research on the specific challenges facing adults with SCD in
education or training, whether in colleges, universities or the workplace.

Welfare and social security benefits

Introduction
Historically, patients with SCD and their families have experienced challenges accessing
appropriate welfare support. The undue pressure and stress experience affects their quality of
life, health and well-being (as outlined above). Further, financial pressures resulting from
current socio-economic factors i.e. austerity and the increasing need to do ‘more with less’
continues to impact on service provision for sickle cell patients. Most people living with SCD are
in full-time employment and therefore may not need to claim welfare benefits support. It is,
however, recommended that they are well informed about benefits they could apply for and
what the application processes are, should they need to. It is important to note, however, that
the benefit system can be difficult to negotiate. This can be off putting and discourage people
from making claims. There also remains the long standing difficulty of ensuring that those who
administer claims understand the consequences of what it can be like to live with a fluctuating
condition, such as SCD, where impairment can be intermittent and often not immediately
obvious.

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Standard
 Patients raising concerns about social security and welfare entitlements should be
referred for specialist advice.

Background evidence
There have been significant changes in benefits and entitlement conditions since the
introduction of the Welfare Reform Act 2012 (HM Government, 2012). This Act introduced two
major benefits (from 2013): Universal Credit (UC) and Personal Independence Payment (PIP).

UC is the new means-tested benefit being introduced in stages to replace Job Seekers Allowance
(JSA); Housing Benefit (HB); Child Tax Credit (CTC); Working Tax Credit (WTC); Employment
and Support Allowance (ESA); and Income Support (IS). PIP replaced Disability Living
Allowance (DLA) for claimants aged from age 16 to 64 years. Unlike DLA, PIP is a point-based
system. The Act also introduced changes ranging from Benefit Capping, the ‘Bedroom Tax’, Local
Housing Allowance (LHA) and Local Welfare Assistance Schemes to the abolition of Council Tax
Benefits (CTB). (Additional information on the different benefits mentioned can be found in
Appendix 3.)

One of the aims of UC was to simplify the benefits system but claiming benefits remains
complex. Those with SCD and their families are not always aware of their entitlements, how
they can claim these entitlements and how to appeal. Financial support can be fundamental to
general health and well-being and benefits can play an important role in facilitating this. There
is a more general lack of coordination of welfare support, which can include housing and other
social care needs, in addition to benefits.

Greater joint-working (and to include those working in health care), support for the role of third
sector organisations, along with making accessible information and advice available to those
with SCD and their families, would be an important way forward. The fluctuating nature of SCD,
however, makes it difficult to assess. Moreover, assessors within the benefits and social care
agencies can seem poorly informed and lack insight into the consequences of SCD, which make
it difficult to make reasoned and evidence-based care assessments and may lead to conflict with
patients.

It has been suggested that the creation of a single multi-agency body in areas of high SCD
prevalence, consisting of all key stakeholders (including primary and secondary care agencies,
social services, housing departments, Department for Work and Pensions representatives,
welfare support advisors), similar to the current multi-disciplinary team (MDT), but including a
broader range of disciplines, could help solve current difficulties. Alternatively the employment
of specialist community benefit or welfare advisors may improve patient access and support.

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Recommendations
 Those assessing such claims should have sufficient knowledge of the consequences of
SCD and its impact on a person’s life. Specialist training should be considered to
facilitate this.
 The production of detailed welfare benefits application guides, specifically addressing
how sickle cell patients need to complete forms, by third sector (voluntary)
organisations in partnership with statutory providers would be useful in decreasing
benefit rejections.
 The provision of welfare support advisors or volunteers with the expertise to assist with
benefits applications should be considered.
 Benefits and welfare advice should be offered to patients during transition because of
specific changes in benefits at 16 years, whereby patients entitled to DLA must apply for
PIP.

Patient voice, support groups and peer support

‘Patient engagement can deliver more appropriate care and improved outcomes’

(The King's Fund, 2012)

Introduction
Voluntary and community organisations (non-government organisations), often in partnership
with National Health Service (NHS) practitioners, have played an instrumental role in ensuring
the visibility of sickle cell in UK (Anionwu & Atkin, 2001). Research reminds us how such
organisations not only have the trust of local communities, but act as mediators and guarantors
of good practice by operating as a bridge between local communities and health care providers
(Berghs et al., 2015). Funding, however, remains a problem and many voluntary and community
organisations have to continually bid for grants, which are often short-term, to ensure their
sustainability. This creates vulnerability and has the potential to threaten the important support
and advocacy role played by voluntary and community organisations.

The Sickle Cell Society is the national charity for SCD in the U.K. It provides a range of services to
individuals living with SCD and their families including provision of information and advice,
direct support services such as a helpline service, training and education and a peer mentoring
programme and activities for children and young people. There are also large numbers of small
geographical based sickle cell patient and families support groups across the country with
whom the Sickle Cell Society works in partnership, as part of its core objective to support
individuals to achieve their full potential.

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The Sickle Cell Society enables engagement and involvement of patients and their families in
peer reviews of all sickle cell services in England with clinicians and NHS England, as well as
involvement in research and clinical trials and the development and/or improvement of sickle
cell services at individual hospital and community sites. For example, the Society worked closely
with the Picker Institute (Europe) and the Collaboration for Leadership in Applied Health
Research and Care (CLAHRC) to carry out the biggest survey of SCD patients in England to
support service improvement and outcomes for patients and their families (Picker Institute
Europe, 2015).

Standard
 Statutory agencies should develop partnerships with voluntary and community
organisations aiming to improve access to patient and family voices, while delivering
more social orientated provision.

Background evidence
Experience of care, clinical effectiveness and patient safety are the key components of quality in
the NHS (NHS England, 2014). Care for patients with SCD can be inconsistent. Service provision
can also vary depending on where you live in the country. These factors together with the
varied prevalence of SCD pose a challenge for patients when accessing appropriate specialist
care, particularly in low prevalence areas (West Midlands Quality Review Service, 2016a).

In 2015, the National Institute for Health Research (NIHR) collaboration for Leadership in
Applied Health Research and Care for North West London, the Picker Institute Europe and the
Sickle Cell Society (SCS) collaborated on a project to better understand the experiences of
people living with SCD of the health care they receive for their conditions.

As a consequence of this collaboration, the SCS analysed the main issues they are contacted
about (see Figure 2). This monitoring data revealed that 23% of calls to the SCS helpline were
by individuals seeking information regarding their nearest support group, so that they may link
with other people with SCD and share relevant issues, ideas, information, and experiences.
Many individuals also required support and advice on benefits, as they were concerned about
how the recent changes had affected their entitlement and financial situation (see above). Ten
per cent of individuals with SCD were seeking advice and information about managing their
condition, often relating to temperature changes, employment, and recent stressors, and
another 10% enquired about sickle cell trait.

[Figure 2 shown overleaf]

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Figure 2: The main issues about which Sickle Cell Society are contacted

Welfare fund, 3%
Awareness, 7%
Vacancies, 3%

Benefits, 17%
Support groups,
23%

Employment , 4%

Events, 7%

Trait, 10% Fundraising, 7%

General
information, 3%
Screening, 3%
Managing sickle Housing, 3%
cell, 10%

NHS clinicians and care providers can form bridges with local communities by linking with
organisations involving patients, families, support groups and the SCS to shape and improve
local health and health care services. This can facilitate trust and confidence in formal health
and social care support.

The key principles of NHS/SCD working include:

 Voluntary and community organisations can provide a channel for the views of
patients/families directly and/or indirectly
 Such organisations can facilitate the involvement and support of patients in NHS matters
 They can ensure patients/families affected by service issues are supported and/or
consulted/involved in any decision making processes
 Voluntary and community organisations can facilitate and involve patients/families in
any appropriate training for clinical/non-clinical NHS staff
 Staff members from voluntary organisations often serve on advisory groups to input the
patient perspective as well as other expertise. This may include research steering
committees, review bodies (e.g. National Institute of Health and Care Excellence, NHS
Sickle Cell and Thalassemia Screening Programme) and guideline production.

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Patients with SCD and their families, often seek professional help, advice and support beyond
doctors and nurses. They also rely on support from family members, peers and charities. This
led to charities such as the SCS and the various branches of the Organisation for Sickle Cell
Relief & Thalassaemia Support (OSCAR) by parents, clinicians and people living with SCD in the
1970s. Over the years other local peer support groups have been established, most operating
under the national umbrella of the Sickle Cell Society or OSCAR usually covering small
geographical areas.

These support groups mainly offer information and advice to local people with SCD and their
families. They vary in size, leadership, capacity and resources, to the extent that some groups
have not been able to continue their operation over the years. The Sickle Cell Society has over
15 affiliated peer support groups across the country (www.sicklecellsociety.org).

There is good evidence to show that external help, advice and support beyond the clinical
treatment of patients by doctors, nurses and other health professionals can optimise health
outcomes (Berkman & Glass, 2000; Cohen et al., 2000). Voluntary and community organisations
are in an excellent position to offer this care and support as they work within the communities
they help, which helps engender trust and legitimacy. These organisations are especially helpful
in engaging with the social determinants of health and the disadvantages faced by those with
SCD and their families. They can also provide sickle cell patients with vital information
regarding their rights and entitlements, offer advocacy services and represent their
psychosocial and financial needs. Good partnerships with statutory health and social care
agencies remain fundamental in facilitating the role of voluntary and community organisations.
Adequate funding is required to ensure continuation of their work as funding for voluntary and
community organisations is often difficult to obtain and can be short-term. This creates
problems of continuity and sustainability.

Recommendations
 Central and local government should work with NHS commissioners and providers to
consider how best to fund the work of third sector organisations, especially given the
important role these organisations can have in facilitating patient voice and community
involvement.
 Health and social care agencies should explore ways of developing the capacity of
voluntary and community organisations as a means of ensuring the maximum
opportunities for offering accessible and appropriate provision for those with SCD and
their families.
 Ways of ensuring mutual respect and understanding between third sector organisations
and statutory provision should be negotiated and established. Good practice should be
disseminated as widely as possible.

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 Sustaining the support provided to the SCS as the national charity representing people
with sickle cell in the UK.
 Co-production and continued involvement with patients and their families in peer
reviews, research, clinical development and trials.

Chapter 4: Conclusion

The chapter connects to the previous chapter, by considering the broader aspects of care. In
doing so, it offers a reminder about the importance of understanding individual and family
context, alongside the need to support people to take responsibility for their health and well-
being. Sensitivity to the social and economic circumstances in which people and their families
experience SCD underpins this emphasis; as does a consideration of the broader determinants
of health when considering well-being and quality of life. This highlights the role of a diverse
range of provision, while also underlining the value of resilience and empowerment. This in
turn is consistent with broader debates about disability and human rights, which are
increasingly being employed to facilitate an enabling environment, in which people can flourish
and fulfil their full potential. Such debates have not had a great deal of impact on our current
understanding of SCD, but their influence could open up different ways of thinking about the
disabling consequences of the condition.

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Section B: Management of acute and chronic
complications

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 Chapter 5: Acute and chronic pain
The acute painful episode, or crisis, is the characteristic presentation of sickle cell disease (SCD).
These episodes can occur unpredictably, often without clear precipitating factors. Pain can
fluctuate in intensity and duration, ranging from mild to severe and debilitating. The acute
painful episode is the most frequent cause of hospitalisation, accounting for more than 90% of
hospital episodes but the majority of acute painful episodes are managed within the community.

Chronic pain is usually defined as persistent pain lasting for more than three months. In
patients with SCD, this needs to be distinguished from a long lasting or repetitive acute pain
crisis. The mechanisms of chronic pain are not fully understood and the incidence is almost
certainly underreported. There is little evidence about management strategies specific for
patients with SCD.

Acute pain

‘I insist upon compassionate care, adequate pain control and respectful communication’

"Some doctors at A&E are very prompt in responding to my pain crisis and some not."

“…At *** Hospital, no matter how serious the pain, you are not seen immediately you arrive. Even
though I have a care plan, it takes the nurses and doctors ages to get it and implement it. In the
meantime, you are just screaming in agony, and the staff will actually shut the "door" of your
cubicle/room and ignore you. There can be a delay of anything between 40 minutes, over an hour
or two, before you are given medication. To get adequate and timely treatment in A&E feels like a
struggle."

Standards
Based on: (National Institute for Health and Care Excellence, 2012b)

 Patients presenting as a medical emergency with an acute painful episode should be

offered appropriate analgesia within 30 minutes of presentation to the emergency
department.
 All hospitals should have a protocol for management of acute pain crisis which is
consistent with (National Institute for Health and Care and Excellence (NICE) standards
and compliance with this protocol should be audited at least annually (see Figure 3,
overleaf).

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Figure 3: Acute Pain Quick Reference

(PCA: Patient controlled analgesia)

Background evidence
The pathophysiological events driving the manifestation of the acute sickle painful episode
include vaso-occlusion by sickled red cells, tissue ischaemia and inflammation and nociception
(Ballas et al., 2012).

The patient presenting with acute sickle pain should be treated as an medical emergency and
offered analgesia within 30 minutes from time of booking (National Institute for Health and
Care Excellence, 2012b). Assessment of pain with a pain-scoring tool and history of analgesic
use can inform the choice of an appropriate initial analgesic. The choice of drug, dose and
administration route should be tailored to pain and severity using the WHO analgesic ladder for
pain relief (World Health Organization, 1986). Patients with moderate pain that have not had
any prior analgesia at home can initially receive a non-steroidal anti-inflammatory drug

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(NSAID) and weak opioids whereas patients presenting with severe pain or moderate pain
persisting after prior analgesia should be offered a strong opioid up front (National Institute for
Health and Care Excellence, 2012b). Either an oral or a parenteral route of administration of the
strong opioid may be appropriate, depending on clinical situation and patient choice. The
subcutaneous route is preferred to intra-muscular due to the risks of muscle scarring and poor
absorption with the latter.

Patients’ experiences of treatment in the Accident and Emergency Department (A&E) are
sometimes negative and underlined by a perceived lack of staff training and experience; lack of
understanding; and break down of trust (Elander et al., 2011; Telfer et al., 2014). Interventions
aiming at increasing patient-healthcare provider trust and respect may improve quality of care
(Elander et al., 2011).

Reassessment and ongoing management

The effectiveness of pain relief should be assessed every 30 minutes from initial analgesic
administration until satisfactory pain relief is achieved and four hourly thereafter (National
Institute for Health and Care Excellence, 2012b). If the patient has severe pain on reassessment
a second bolus dose of a strong opioid can be offered (or a first bolus dose if they have not yet
received a strong opioid).

If pain persists in spite of repeated doses of bolus strong analgesics, then patient controlled
analgesia (PCA) should be considered (National Institute for Health and Care Excellence,
2012b). PCA has been shown to be efficacious in achieving pain relief, with smaller total doses
of opioid analgesics compared to continuous infusion, thereby having the potential for fewer
adverse effects (van Beers et al., 2007). Further, repeated bolus opioid doses do not achieve
smooth and sustained analgesic effect (Telfer et al., 2014). PCA should, therefore, be considered
for analgesia in patients who are admitted to hospital with painful crises. PCA can be initiated
either in the A&E department or on the ward, following admission (National Heart Lung and
Blood Institute, 2014).

Pethidine, although offering effective pain relief, has significant neurological adverse effects
(convulsions) and therefore it is not recommended for use in the acute sickle painful episode
setting (National Heart Lung and Blood Institute, 2014; National Institute for Health and Care
Excellence, 2012b). Corticosteroids are also not recommended for treatment of the acute
painful episode.

Supportive treatment: As an adjunct to opioid treatment, patients should receive regular

paracetamol and NSAIDs, unless contra-indicated (National Institute for Health and Care
Excellence, 2012b). Moreover, opioid medication has frequent adverse effects, thus regular
laxatives – and if needed, anti-emetics and antipruritics – are recommended for patients who
are on opioid treatment (National Institute for Health and Care Excellence, 2012b). Intravenous

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hydration is recommended for patients who are unable to take fluids orally (National Heart
Lung and Blood Institute, 2014). Oxygen therapy should be offered to patients who have a
reduction in measured oxygen saturation 95% or below (National Institute for Health and Care
Excellence, 2012b). Some patients find supplementary oxygen helpful even if their saturations
are normal.

Prevention of complications: Incentive spirometry has been shown to reduce the incidence of
acute chest syndrome (ACS) in children and young adults (2-18 years) with acute sickle pain in
the chest and back. Incentive spirometry should be considered in adults admitted with chest or
back pain (National Heart Lung and Blood Institute, 2014).

Blood transfusion during the acute sickle painful episode: Red cell transfusions are not
recommended for the treatment of the uncomplicated sickle painful episode. They may be
needed if there are additional indications for blood transfusion (Davis et al., 2017a, 2017b) (see
Chapter 21 - Blood transfusion).

Non-pharmacological interventions: Although trials have not demonstrated a clear benefit from
the use of non-pharmacological interventions for the management of the acute sickle painful
episode, such interventions (including relaxation/behavioural techniques and local heat
application) could be used on a case-by-case basis to support pain management (National Heart
Lung and Blood Institute, 2014; National Institute for Health and Care Excellence, 2012b).

Monitoring
Close monitoring is essential to ensure optimal analgesic effect and to identify:

 the presence of adverse effects from analgesic treatment

 any indicators of underlying or additional complications such as infection, falling oxygen
saturations etc.

Detailed clinical assessment (pain score, sedation score, respiratory rate, oxygen saturations on
air) should be performed, especially in patients on strong opioids, every hour for the initial six
hours and after any dose escalation and four hourly thereafter (National Institute for Health and
Care Excellence, 2012b). This will help detect and manage any adverse effects from analgesia. If
the patient does not respond to standard treatment for an acute painful sickle cell episode, he or
she should be reassessed for the possibility of an alternative diagnosis.

Discharge
As the painful sickle episode resolves, there should be a gradual withdrawal of opioid analgesia
(National Heart Lung and Blood Institute, 2014). Prior to discharge, patients should be offered
adequate information on the management of their painful symptoms at home, access to
specialist advice and care, and how to obtain repeat prescriptions and adequate supplies of

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analgesics (National Institute for Health and Care Excellence, 2012b). This is necessary, as many
patients with sickle cell disease experience pain in between acute painful episodes (Ballas et al.,
2012). Good discharge planning enables smooth transfer of patient care to the community and
should aid in reducing readmissions.

Recommendations
Based on (National Institute for Health and Care Excellence, 2012b)

 All units should be able to offer patient controlled analgesia (PCA) for when pain does
not settle with initial intermittent opiate dosing.
 Trusts should consider treating patients presenting frequently with uncomplicated pain
in a day unit setting. However, for patients who present infrequently, overnight
admission should be preferred.
 Staff (nursing and medical) involved in the care of patients with acute painful sickle
episodes should have training in pain monitoring and management and should have
access to local management protocols and specialist support.

Chronic pain

"Can do with more appointments that aren't rushed. Further investigation into chronic pain in one
area of the body should be looked at. More information about NHS trials for treatments."

Introduction
The Pain in Sickle Cell Epidemiology Study (PiSCES) concluded that pain in SCD was far more
prevalent and severe than previously thought with most patients managing their pain at home.
Adult patients in this American single site study reported experiencing pain on 54.5% of the
surveyed days; with 29% of patients experiencing pain on more than 95% of the days (Smith et
al., 2015). Whilst this study did not distinguish between acute and chronic pain it does suggest
that a large number of patients experience pain on most days. Another American study of adult
patients with SCD reported 92% of patients experienced pain lasting from 6 months to 2 years
with 90% taking pain medication on a daily basis for a period of 6 months (Thompson & Eriator,
2014)

There is little robust evidence about the management of SCD chronic pain, so most of the
following is derived from general guidance on the management of chronic pain, and prescribing
in non-cancer chronic pain. Alongside medication-directed management, there is increasing
support and recommendation for working within a multidisciplinary team (MDT) in managing
chronic pain, including therapeutic interventions such as psychology and specialist pain

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physiotherapy, rather than depending on pharmacological therapy alone. Through engagement

with the MDT, people living with SCD can be supported in acquiring and developing skills in
pain management, including managing unhelpful or difficult thoughts, managing difficult
emotions including anxiety, stress and worry, pacing activities, moving and exercising in the
presence of SCD and mindfulness and relaxation strategies.

Standards
 Patients should be asked about whether they experience chronic pain as part of their
annual review.
 Use of opioids should be regularly reviewed at clinic visits, including at annual review.
 An underlying cause of chronic pain should be sought and treated if appropriate.
 Patients with complex pain needs should be referred to a multidisciplinary chronic pain
team, with experience of SCD, offering both pharmacological and non-pharmacological
interventions.

Background evidence
Chronic pain in patients with SCD may result from obvious tissue damage such as avascular
necrosis of a joint or an on-going leg ulcer. In these situations treatment of the underlying cause
is paramount. In other situations the pathological basis is less clear, but the pain may be due to
slow to resolve acute painful episodes or chronic pain syndromes associated with previous
tissue injury, central sensitisation and neuropathic pain.

Central sensitisation is the result of excessive nociceptive signals acting on the central nervous
system causing changes within the brain and spinal cord. The consequence is continuous and
increased pain sensations (Ballas et al., 2012). Central sensitisation has been described in many
chronic pain syndromes and in SCD there is some evidence that patients with higher levels of
central sensitisation have more pain and experience more vaso-occlusive crises. Hyperalgesia is
an exaggerated pain response to normally mild stimuli and is associated with central
sensitisation syndrome and excessive opioid usage.

Neuropathic pain (pain often described as numb, tingling, shooting or like pins and needles) is
increasingly recognised as an element of acute or chronic SCD pain (Brandow et al., 2014). It is a
result of nerve injury or dysfunction secondary to a blockage of blood supply or persistent
inflammation.

Patients with SCD may also describe pain transforming from acute to chronic. As patients get
older, pain patterns are seen to change and older patients with a history of highly painful
episodes do appear to transition into a chronic pain state (Hollins et al., 2012).

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Management
Management of chronic pain is aimed at improved function and quality of life and needs a
multidisciplinary approach (Niscola et al., 2009) including medical and psychological
interventions (Howard et al., 2009). Patients should be asked whether they suffer from chronic
pain (which they may describe as ‘every day’ pain, background pain or on-going pain they
experience at home) including frequency, site, duration and triggers, as a minimum, as part of
their annual review. Patients should be helped to understand the differences between acute and
chronic pain, that chronic pain is not necessarily an indication of tissue injury or damage, and
that different management approaches may be necessary and more helpful than those used for
acute crisis pain.

Pain syndromes have historically been managed pharmacologically, often using opiates.
Pharmacological management should be specific to the patient, and use of an individual care
plan with patient involvement will aid successful treatment (Ballas et al., 2012). Medication
choices need to take into account the risk of short and long-term side effects. There is no
specific guidance to management of chronic pain in SCD and so good practice guidelines can be
derived from evidence for prescribing in non-cancer chronic pain (Chou et al., 2009; Franklin,
2014). Atypical analgesics (e.g. gabapentin, amitriptyline, pregabalin, duloxetine) are useful for
the management of neuropathic pain.

There is increasing awareness and concern about prescription opioids in the management of
chronic pain. At doses of more than 120 mg oral morphine equivalent a day there is increased
risk of harm, with no increased benefit and the likelihood that opioid-based medication is not
working (BMA board of science, 2017). The prescriber must be aware of these cautions, while
also recognising the difference between physical dependence (which is to be expected and
should not automatically raise concerns) and addiction (which is more problematic) (Savage et
al., 2003). There have been reports of patients with SCD being vulnerable to pseudo-addiction
due to ongoing under-treatment of pain and subsequent stigmatisation as addicts (Elander et
al., 2004). Understanding the balance between giving sufficient pain relief and the risk of side
effects is important, particularly since for many patients the levels of pain experienced will be
difficult for them to manage.

Cognitive behavioural therapies (CBT) have been used alongside conventional medical
treatment for the management of sickle cell pain, with some preliminary positive results
(Thomas et al., 1999). CBT has also been incorporated into treatment manuals (Anie et al.,
2002). There has been relatively little exploration of the application of other psychological
treatments, such as acceptance-based approaches, in patients with SCD (Masuda et al., 2011). In
other conditions, pain management programmes (PMPs) based on CBT and more recently
acceptance-based principles are the treatment of choice for people with persistent pain. These
techniques are particularly useful when the pain adversely affects quality of life and where
there is significant impact on physical, psychological and social function (British Pain Society,

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2013). The aim is to help patients learn self-management strategies to reduce the impact pain
has on their mood, quality of life and daily activities. These approaches could be beneficial to
people living with chronic SCD pain but need further evaluation.

Recommendations
 Patients with neuropathic pain should be offered appropriate analgesic medication.
 Individual care plans should be considered for patients with complex care needs.
 Long-term opioid use should be regularly reviewed. A care plan should be devised to
avoid an escalating regime of opioids. Clear prescribing guidance should be developed in
conjunction with the chronic pain team and GPs to ensure a single prescriber.
 All health care professionals involved in caring for the patient, including primary care,
should be aware of prescribing plans for opioids and who the key prescriber is.
 Self-management techniques such as pain management programmes and
complementary therapies need further evaluation in patients with SCD.

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“I have had migraines for the last 10 years and get them twice a month. I haven’t been given any
pain killers that help them. My consultant sent me to have an MRI and found nothing and advised
that migraines are not curable and therefore I need to manage the triggers”.

Introduction

Central nervous system (CNS) complications in adults with sickle cell disease (SCD) cause
significant morbidity and mortality. Acute presentations can include headache, seizures, focal
neurological signs, visual impairment, altered consciousness and acute deterioration in
cognition; aetiologies include stroke and infection. Early recognition of acute neurological
complications is vital, alongside rapid diagnosis and appropriate management. Adults with SCD
are at risk of both acute ischaemic and haemorrhagic stroke with the risk of acute ischaemic
stroke increasing with older age (Ohene-Frempong et al., 1998; Strouse et al., 2009).

Strokes have long-term effects including neurocognitive and neuropsychological dysfunction.

There is very little evidence or commentary focused on the assessment and management of
these conditions in adults. Most guidance and treatment strategies are extrapolated from
paediatric data and expert consensus. Consequently, there are key questions that remain
unanswered.

Acute stroke

Standards
 Patients presenting with suspected transient ischaemic attack (TIA) or stroke should
have urgent neuroimaging.
 Adults presenting with TIA or stroke should be managed within a hyperacute stroke unit
with access to multidisciplinary support from a haemoglobinopathy specialist centre,
vascular interventional neuroradiology, neurology and neurosurgery.
 Urgent red cell exchange is recommended for patients with a sickle related acute
ischaemic stroke.
 Thrombolysis should be considered for patients with acute ischaemic stroke who meet
current UK national recommendations for stroke treatment if there are no contra-
indications.

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Incidence and aetiology

Observational studies have reported high rates of acute ischaemic stroke in adults with SCD of
11% by the age of 20 and 24% by the age of 45 years (Ohene-Frempong et al., 1998; Strouse et
al., 2006). There are many fewer data on de novo and recurrent stroke rates in adults following
the introduction of childhood stroke screening or with increasing use of hydroxycarbamide.

Cerebral vasculopathy is the most common cause of stroke in children with SCD but is found to
be a cause of stroke in only 41% of cases in adults (Calvet et al., 2015). Older patients may have
other co-morbidities including hypertension, diabetes, hyperlipidaemia, renal dysfunction,
impaired cardiac systolic function and atrial fibrillation which are all recognised cardiovascular
risk factors in adults without SCD. Other contributory factors are relative and acute anaemia,
and multi-organ dysfunction (Powars et al., 1978).

Acute haemorrhagic strokes are reported at increased rates in adults with SCD. Hypertension
and multi-organ failure are risk factors for cerebral haemorrhage. Aneurysms, which are
reported in 10.8 per cent of adults with SCD, (Nabavizadeh et al., 2016) can rupture, typically
leading to subarachnoid haemorrhage, most commonly in young adults. Low steady state
haemoglobin concentration, high steady state white cell count and transfusion within the
previous 14 days have been identified as risk factors for haemorrhagic stroke (Ohene-
Frempong et al., 1998; Strouse et al., 2006).

Extradural and subdural haemorrhage is also recognised and may occur in the absence of head
trauma.

Investigation of patient presenting with symptoms of stroke

All adult SCD patients presenting with acute stroke should be carefully assessed by a
multidisciplinary team which includes an experienced haematologist, neurologist and stroke
physician. Early liaison and transfer to specialist centres with access to appropriate services is
recommended.

Patients presenting with acute symptoms of TIA or stroke should have urgent neuroimaging. UK
stroke management standards dictate all patients presenting with stroke symptoms should
have neuroimaging within one hour of presentation. This must also apply to patients with sickle
cell disease. Whilst this is being organised, preparations for exchange transfusion including
provision of appropriately selected blood and line insertion if necessary should be planned.
Non-contrast computed tomography (CT) of the head can help to exclude acute haemorrhage.
Magnetic resonance imaging (MRI) of the head and magnetic resonance angiography (MRA) of
head and neck with diffusion weighted imaging will help to identify acute ischaemic events,
vasculopathy and other pathology. Magnetic resonance venography may be necessary in some
cases to exclude cerebral sinus venous thrombosis (CSVT).

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Management of acute ischaemic stroke

Exchange transfusion: retrospective review of children presenting with acute stroke showed
better outcomes after initial treatment with exchange transfusion compared to simple
transfusions (Hulbert et al., 2006) and whilst there are no specific comparable data in adults,
there seems no reason why findings should differ. Furthermore there is a high recurrence rate
of stroke without therapeutic intervention (Powars et al., 1978). Urgent exchange transfusion,
therefore, is necessary in the context of acute stroke.

Thrombolysis: limited data on use of thrombolysis in patients with SCD are available. The UK
National Clinical Guidelines for Stroke (Royal College of Physicians, 2016) and NICE guidelines
(National Institute for Health and Care Excellence, 2017) for the management of acute stroke in
adults over the age of 16 years without SCD which promote thrombolytic and antiplatelet
therapy include little evidence for these therapies in the management of adults with SCD. A
recent publication looked at the safety and outcome of thrombolytic therapy in acute ischaemic
stroke in patients with SCD (Adams et al., 2017). Comparison of outcomes in 832 SCD and 3328
non-SCD controls found no significant differences found in the fraction receiving thrombolytic
therapy or experiencing symptomatic intracranial haemorrhage.

Therefore there is no evidence of increased intracranial haemorrhage in adults with SCD with
acute stroke who have received thrombolytic therapy and the authors concluded that adults
with SCD and acute ischaemic stroke should be treated with thrombolysis if patients otherwise
qualify.

Both the SCD and traditional stroke risk factors are likely to contribute to the aetiology of acute
ischaemic stroke in adults with SCD. Current evidence suggests that adults with SCD with acute
ischaemic stroke may benefit from both acute exchange transfusion and from thrombolysis.
Management will therefore need careful collaboration between the hyperacute stroke team and
haematologists to decide whether to offer exchange transfusion, thrombolysis or both and to
ensure that both can be done in a timely fashion. This decision will need to consider patient age,
genotype, phenotype, MRI findings and traditional risk factors. If patients need both
thrombolysis and exchange transfusion and require central line insertion for the exchange
transfusion, this will need to be completed prior to thrombolysis.

Use of anticoagulant therapy in sickle-related stroke has not been well studied although there
are case reports of use in carotid dissection, cerebral sinus vein thrombosis (CVST) and cardio-
embolic stroke.

A negative MRI scan does not exclude acute ischaemic stroke and in patients with clear
neurological signs but initial normal MRI, exchange transfusion should still be considered, with
early repeat of MRI.

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Management of acute haemorrhagic stroke

There is lack of formal evidence promoting management of acute intracranial haemorrhage
(ICH) in adults with SCD but European Stroke Organisation guidelines (Steiner et al., 2014) for
generic management of adults without SCD are available. These are likely to apply to patients
with SCD. The role of transfusion therapy particularly in this context has not been fully
evaluated. Adults presenting with ICH require management within a multidisciplinary team
which includes neurosurgery, vascular interventional neuroradiology, specialist haematology,
neurology and acute stroke services. Early liaison and transfer to specialist centres with access
to these services is recommended. Standard management for haemorrhagic stroke should be
followed and patients cared for within a high dependency unit. Exchange transfusion should be
considered prior to neurosurgical intervention unless it will delay surgery when it should be
performed post-surgery. Careful attention should be paid to fluid balance and blood pressure
monitoring. Standard operative optimisation should be followed for emergency craniotomy and
clipping.

Recommendation
 In adults with SCD presenting with acute stroke, causes of stroke seen in adults without
SCD should also be considered (such as thrombophilia, CNS infection, illicit drug use,
arterial dissection and congenital heart disease).

Stroke prevention

Standards
 Adult patients who experience an acute ischaemic stroke attributed to sickle cell disease
should be offered long term transfusion therapy.
 Patients who have been started on chronic transfusion therapy for primary prevention
during childhood should be assessed by an expert in SCD at transition to adult care to
discuss the risks and benefits of ongoing transfusion. They should be offered
continuation of transfusion therapy or hydroxycarbamide if they have had a previous
abnormal transcranial Doppler (TCD) that has normalised and there is no evidence of
vasculopathy.
 Patients who have been started on chronic transfusion therapy for secondary stroke
prevention during childhood should be offered continuation of transfusion therapy.
 Patients who have been started on hydroxycarbamide for primary stroke prevention
during childhood should be offered ongoing hydroxycarbamide therapy after transition
to the adult service.

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 Anti-platelet therapy should be considered in patients with acute ischaemic stroke as

per national stroke guidelines unless there are any contra-indications.

Primary stroke prevention

Systematic review of the literature did not identify any randomised controlled trials (RCTs)
specifically addressing the management of primary stroke prevention in adults with SCD
(Estcourt et al., 2017).

The benefit of transfusion therapy for primary stroke prevention in children is well documented
(Abboud et al., 2011; Adams et al., 1998; DeBaun et al., 2014). Hydroxycarbamide is effective in
preventing strokes in children at high risk (Ware et al., 2016). There is little evidence to guide
optimal management once patients who have been started in childhood on a primary stroke
prevention programme reach adulthood. This group of patients should be offered life-long
transfusions or hydroxycarbamide if appropriate (consistent with the TWiTCH findings (Ware
et al., 2016)). The risks and benefits of treatment, including the risks of withdrawal of
transfusion therapy should be fully discussed with the patient on transition to the adult service,
and thereafter at least annually. Long-term transfusion should be strongly recommended if
there is progressive ischaemia, vasculopathy, or recurrent TIA. If adult patients on transfusion
for primary stroke prevention opt to stop transfusion it may be appropriate to offer interval
TCD and/or MRI scanning although there is little evidence for this.

Unlike in the paediatric population, there are currently no verified imaging techniques to
identify adults at risk of stroke. Adult patients studied with TCD have not been found to have
the increased velocities seen in at-risk children (Silva, 2009) and there is no supporting
evidence in adults for routine regular neuroimaging by either MRI or CT modalities (NIH, 2014)

Systematic review found no evidence to guide the management of de novo silent infarction in
adults (Estcourt et al., 2017), but in adults with an incidental finding of silent infarction on MRI
it may be appropriate to offer interval MRI scanning and consider intervention if there is
progressive ischaemia.

Stroke prevention strategies used for the general population are also relevant for adults with
SCD, including treatment of hypertension, use of antiplatelet therapy for those with vascular
risk factors, treatment of hyperlipidaemia and consideration of anticoagulation in the presence
of atrial fibrillation (Strouse et al., 2011).

Secondary stroke prevention

Systematic review of the literature did not identify any randomised controlled trials (RCTs)
specifically addressing secondary stroke prevention in adults with SCD (Estcourt et al., 2017)
but there are observational data supporting the role of transfusion therapy in secondary stroke
prevention. In 1978 Powars et al., looked at the natural history of stroke in sickle cell disease
and reported that 50% of patients with SCD and an overt stroke had a second stroke within two

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years and 66% within ten years (Powars et al., 1978). The highest risk appeared to be early
after the first stroke with 80% of the second strokes being seen within 36 months of the first
stroke. Long-term or chronic transfusion programmes have been shown in children to reduce
the risk of recurrent strokes (DeBaun, 2011; Lusher et al., 1976; Sarnaik et al., 1979). The
improvement in recurrent stroke rates means that a chronic transfusion programme aiming to
keep haemoglobin S at less than 30% is now a standard of care in children for secondary stroke
prevention. Following these studies, chronic transfusion therapy with the same goals is used in
adults for secondary stroke prevention. However transfusion therapy alone is not a guarantee of
stroke prevention and there are reported cases of children having overt strokes or developing
silent infarcts on imaging despite long term transfusion maintaining a low haemoglobin S
percentage (Hulbert et al., 2011; Scothorn et al., 2002). Conversely, it may be possible to relax
the target haemoglobin S percentage after 5-10 years post-stroke (Cohen et al., 1992).

Uncertainty exists about the duration of the chronic transfusion programme and in particular,
when it is safe to stop. Studies in children have reported both success in stopping transfusions
and cases of further stroke on stopping transfusions. These studies include a case series from
Rana et al., who reported on nine consecutive patients with sickle cell disease and stroke whose
long-term transfusion therapy was discontinued and in whom no ischaemic strokes developed
during 80.75 patient years of follow-up (Rana et al., 1997). However, Wang et al. reported a high
risk of stroke recurrence after discontinuation of 5-12 years of transfusion therapy (Wang et al.,
1991). They saw five recurrent cerebrovascular events in the ten patients studied. There are no
robust studies done in adult patients to help determine the length of transfusion therapy
required. Further, the role of neuroimaging to help guide this decision is not clear. The risks and
benefits of continuing long-term transfusion should be discussed with the patient. In patients on
long term transfusion for secondary stroke prevention, neuroimaging (usually MRI/MRA done
as regular intervals) may be reassuring to show a lack of progression of neurological damage
over time and may encourage adherence to therapy. Where chronic transfusion therapy is
undertaken in adults this should be done by exchange transfusion rather than regular top up
transfusions where possible and preferably by automated exchange rather than manual so as to
avoid iron loading and maintain a stable haemoglobin concentration (NICE guidance, 2016).

Consideration should be given to management of risk factors for stroke including both SCD-
related stroke (hypertension, anaemia, chronic lung disease, avascular necrosis, retinopathy,
sickle nephropathy and renal failure) and ischaemic stroke not related to SCD (diabetes
mellitus, atrial fibrillation, hyperlipidaemia and renal disease)

Other treatments for consideration in secondary prevention include hydroxycarbamide and

haematopoietic stem cell transplantation (HSCT) (see Chapter 23 - Haematopoietic stem cell
transplantation). Evidence from children has shown that hydroxycarbamide is not equal to
transfusion in terms of efficacy for recurrent stroke prevention but may be viable for
consideration where transfusion is not possible or not acceptable to patients (Bortolusso Ali et
al., 2011; Kassim et al., 2015). History of a previous stroke is one of the indications for HSCT in
SCD, but this potentially curative option is not currently available for adults in the UK.

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Recommendations
 There is inadequate evidence to recommend routine screening by TCD or MRI to predict
stroke risk in adults.
 Hydroxycarbamide should be considered for prevention of recurrent stroke where
transfusion is not possible or acceptable.

Other neurological complications

Standard
 Cognitive impairment should be considered in adults with SCD and they should have
access to cognitive assessment and rehabilitation.

Cerebral sinus venous thrombosis should be considered in patients with focal neurological
abnormality and negative MRI/MRA scans. Cases of posterior reversible leucoencephalopathy
syndrome (PRES) are most commonly seen in hospitalised patients although the risk factors for
this clinico-radiological syndrome are poorly understood. Pneumococcal meningitis and
recurrent seizures are more common in SCD than the general population.

Neurocognitive impairment
Neurocognitive impairment in adults is poorly researched but gradual neurocognitive decline is
recognised in SCD and in some cases may be related to silent cerebral ischaemia and small
vessel vasculopathy. A study of neurocognitive function assessment in neurologically intact
adults with sickle cell anaemia found that participants showed poorer performance on
neurocognitive tests, when compared to non-sickle cell peers; anaemia was associated with the
age related decline in cognitive performance; and MRI findings did not explain the differences.
Study participants were asymptomatic and had no end organ failure (Vichinsky et al., 2010).
Evidence from this study also suggests that early identification of patients suffering from
neurocognitive impairment allows them to benefit from accessing cognitive rehabilitation
programmes (Vichinsky et al., 2010). Further research would help identify other potential
interventional therapies.

Headaches
Headache is a common symptom in patients with SCD and although in most cases not indicative
of significant CNS pathology, the possibility of intracranial haemorrhage, cerebral sinus venous
thrombosis, CNS infection and ischaemic stroke should be considered. Studies are
predominantly paediatric with one study showing that one third of children had headaches and
15% had migraines (Dowling et al., 2014). Neither headaches nor migraines were found to be
associated with silent infarcts but have been associated with cerebral vessel stenosis on MRA

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(Niebanck et al., 2007) and higher rate of painful crises requiring admission to hospital
(Dowling et al., 2014).

There is no evidence base for the management of chronic headaches or migraines in adult
patients with SCD and referral to a neurologist may be needed. Headaches do seem to be more
frequent than in the general population (DeBaun & Kirkham, 2016). For the diagnosis of
migraine, family history is often an important factor with patients experiencing acute severe
and often incapacitating headaches. These are typically throbbing in nature and may be
associated with photophobia or phonophobia more commonly than with aura. Triggers include
stress, red wine, some foodstuffs, menstruation and missing meals. The duration of acute
migrainous symptoms may be reduced by early anti-emetics and analgesia. Triptans (serotonin
receptor agonists) are often effective and should be offered. Prophylaxis with propranolol or
other agents may be required if migraine frequency is greater than four per month.

Recommendations
 Review by neurologist should be considered for patients with chronic headaches and
migraines.
 Migraines should be treated with standard migraine treatment

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Acute chest syndrome

"I use to have yearly acute chest syndromes (ACSs) which had subsequently led to pneumonias so I
was asked by my consultant to consider hydroxycarbamide which has completely stopped the ACSs
and I haven’t had any since I started the treatment."

"Being taught how to use my spirometer has been really helpful to aid my breathing."

Introduction
Acute chest syndrome (ACS) is an acute illness characterised by fever and/or respiratory
symptoms, accompanied by a new pulmonary infiltrate on chest X-ray. The presence of hypoxia
is not included in the definition, but in clinical practice, hypoxia is a useful predictor of severity
and outcome (Vichinsky et al., 2000).

ACS can be a severe life-threatening condition and early recognition of progression to acute
respiratory failure is vital. Patients with SCD can present with ACS, or it may develop some time
after onset of severe pain. Vigilance for this complication should be maintained for the duration
of the hospital admission. ACS is the third leading cause of death in adult patients with SCD in
and may result in longer term morbidity such as chronic lung disease and pulmonary vascular
disease.

Standards
 All hospitals should have a treatment pathway for ACS.
 Antibiotics, with cover for both Streptococcus pneumoniae and atypical organisms,
should be prescribed for patients with ACS even if blood cultures and sputum cultures
are negative. Anti-viral agents should be used if there is clinical suspicion of influenza A.
 Early simple (‘top-up’) transfusion should be considered early in the hypoxic patient but
exchange transfusion is necessary if there are severe clinical features or evidence of
progression despite initial simple transfusion.
 Hydroxycarbamide should be recommended for prevention of recurrent ACS.

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Background evidence
The clinical features of ACS, management and outcome have been well described in large case
series studies (Vichinsky et al., 2000). The clinical features of ACS are non-specific and vary
depending on age. In adults common presenting symptoms are dyspnoea, chest pain and cough.
Clinical signs include fever, tachycardia, tachypnoea, hypoxia and pulmonary infiltration as
evidenced by reduced air entry, crepitations, pleural rub, bronchial breath sounds and/or
pleural effusions. Clinical signs often precede chest X-ray findings, although in some cases the
chest examination may be normal.

Chest X-ray changes include segmental, lobar and multilobar consolidation usually of the lower
lobes, and/or pleural effusions. The commonest finding on CT is pulmonary consolidation; the
finding of small vessel occlusion should be interpreted with caution as this can be part of the
pathophysiological process of acute chest syndrome (Mekontso Dessap et al., 2014).

The laboratory findings in ACS are non-specific but may include an acute fall in haemoglobin
concentration and platelet count, which are markers of disease severity. In patients with low
oxygen saturations SpO2 ≤94% on air (or >3% below patients baseline), arterial blood gas
(ABG) measurements are useful to support clinical decisions such as respiratory support and
transfusions and a Pa O2 of below 9kPa implies severe disease that may need transfusion
(Howard et al., 2015).

The severity of ACS is variable but there may be marked hypoxia and Type 1 respiratory failure.
Respiratory support with invasive and non-invasive ventilation may be required. There have
been several observational studies describing the benefit of supportive therapies for ACS such
as antibiotics, oxygen and respiratory support, including continuous positive airways pressure
(CPAP), bronchodilators and incentive spirometry (Fartoukh et al., 2010; Padman & Henry,
2004). Overall the quality of evidence for these interventions is low (Knight-Madden &
Hambleton, 2016; Martí-Carvajal et al., 2015). There are no data indicating benefit of specific
antibiotic therapy in ACS but common organisms include Chlamydophila pneumonia,
Mycoplasma pneumonia, Streptococcus pneumonia, Staphylococcus aureus and Haemophilus
influenza and therefore antibiotic choice should reflect this and local resistance profiles (Martí-
Carvajal et al., 2015). There is increasing evidence of the benefit of high flow humidified oxygen
in the treatment of non-hypercapnic hypoxaemic respiratory failure. Whilst no specific data
exist regarding the efficacy of high flow humidified oxygen in patients with SCD and ACS,
consideration should be given to its use in an attempt to reduce the need for invasive ventilation
and its complications. There is also inadequate evidence to support other interventions such as
inhaled nitric oxide or steroids.

A Cochrane review (Dastgiri & Dolatkhah, 2016) found one very small randomised trial of using
blood transfusion to prevent ACS. The majority of patients in this multicentre trial were
recruited to an observational arm and only ten participants met the inclusion criteria for
randomisation of whom four were randomised to the transfusion arm and received a simple
transfusion. None of these four participants developed ACS whereas 2/6 participants in

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standard care arm developed ACS (Styles et al., 2012). The review concluded this was
insufficient evidence to make a reliable conclusion about the role of transfusion.

The benefit of both top-up and exchange transfusions has been described in case series and
observational studies (Vichinsky et al., 2000). A pragmatic approach is to consider simple
transfusions for selected patients with milder degrees of hypoxia whose haemoglobin concentration is
low enough to allow for this, and exchange transfusions for more severe cases of ACS.

Hydroxycarbamide has been shown to reduce the incidence of ACS in patients with recurrent painful
vaso-occlusive crises (Charache et al., 1995) and is recommended for patients who have had a single
life threatening or recurrent episodes of ACS. Long term transfusion may be considered in those
patients for whom hydroxycarbamide is ineffective; the incidence of ACS is reduced in patients
receiving long term transfusion for other indications. Pre-operative transfusion reduces the incidence
of post-operative ACS and is recommended for patients with sickle cell anaemia and sickle cell/β0
thalassaemia prior to surgery (Howard et al., 2013).

The following recommendations have been published in national UK guidelines (Howard et al.,
2015).

Recommendations
 Essential investigations for the diagnosis and management of ACS are chest X-ray, full
blood count, basic biochemistry tests (creatinine and liver function tests) and blood
group and screen (or cross match). Blood cultures, sputum for microscopy and culture
and sputum and nasopharyngeal aspirate for viral testing including influenza A (and
H1N1 subtype) should also be performed if clinically indicated.
 Pulmonary embolism, fluid overload, opiate narcosis and hypoventilation may cause or
trigger ACS and should be considered when a diagnosis of ACS is made as these
conditions may require additional treatment.
 Patients should be monitored for predictors of severity, which include worsening
hypoxia, increasing respiratory rate, decreasing platelet count, decreasing haemoglobin
concentration, multilobar involvement on chest X-ray and neurological complications.
 Patients should be treated aggressively irrespective of their sickle genotype.
 Incentive spirometry should be offered to patients with chest or rib pain to prevent ACS
and may be of benefit in patients with ACS.
 Bronchodilators should be used if there is a history of asthma or evidence of acute
bronchospasm.
 Consider chronic transfusion for prevention of recurrent ACS if hydroxycarbamide
therapy is not effective.

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Chronic respiratory complications

Chronic respiratory pathology is common among individuals with sickle cell disease. Chronic
lung disease in adult patients includes a range of interstitial and pulmonary vascular
abnormalities which can lead to impaired pulmonary function including restrictive and
obstructive lung defects and impaired gas transfer. Sleep disordered breathing is also common.

Standards
 Assess all patients for respiratory symptoms and with respiratory examination at each
annual review.
 Monitor oxygen saturation SpO2 at least annually.
 Patients with respiratory symptoms or chronic hypoxia should be investigated with:
o Spirometry with transfer factor
o High resolution computerised tomography (CT) of the lung
 A sleep study should be recommended in all patients with:
o self reports of disturbed sleep
o excessive daytime sleepiness (Epworth sleep score >10)
o oxygen saturations awake <95%
o a history of snoring, priapism or early morning headaches.
 Patients with suspected chronic lung disease or abnormal sleep studies should be
referred to a respiratory physician for review and consideration of therapy.

Background evidence

Chronic lung disease

Mild restrictive lung defects are described in up to 70% of adults with SCD and ventilatory defects
are more common than in ethnically-matched controls. Some studies have shown that the degree of
reduction in lung function correlates to previous number of ACS episodes (Knight-Madden et al.,
2010). Chronic sickle lung disease (CSLD) describes an interstitial abnormality of lung
parenchyma characterised by progressively worsening restrictive lung disease, pulmonary
hypertension, hypoxaemia, and chest pain (Knight-Madden et al., 2010); and with fibrotic changes on
CT scan. It is reported to affect approximately 5% of patients with SCD with an average age of onset
of CSLD at 25 to 33 years (Powars et al., 1988). CSLD may develop as a result of repetitive damage
to lung parenchyma by recurrent episodes of ACS, although this is not always the case and it may be
seen in adults with no history of ACS.

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Sleep disordered breathing

Sleep disordered breathing (SDB) is a group of conditions characterised by complete or partial

cessation of normal respiration during sleep resulting in nocturnal hypoxia or obstructive sleep
apnoea (OSA). Nocturnal hypoxia and intermittent nocturnal desaturation/OSA are both
common in SCD (Rogers et al., 2010; Samuels et al., 1992) and have been correlated with
morbidity including frequent painful vaso-occlusive crisis (Hargrave et al., 2003), risk of future
central nervous system (CNS) event (Hollocks et al., 2011) and priapism (Roizenblatt et al.,
2012). Up to 40% of children and adolescents have nocturnal hypoxia, and OSA has been
reported in up to 60% of adults with SCD. Nocturnal hypoxia and OSA may co-exist.

Respiratory investigations
Pulmonary function tests (PFTs) objectively assess the function of the respiratory system, and
multiple studies have reported on the abnormalities found in SCD patients. The Cooperative
Study of Sickle Cell Disease (Klings et al., 2006) reported that 90% of 310 adult patients were
found to have abnormal PFTs. The most common abnormality was a mild restrictive defect, in
74% of the patients. Obstructive disease, either alone or mixed with restrictive disease, was
relatively uncommon in this study, occurring in only 3% of the patients. Other studies report
lower rates of restrictive change within this patient group of 22–36% with mixed
restrictive/obstructive change seen in 6–12 % (Sylvester et al., 2006). Fields et al also reported
a significant rate of decline in FEV1 in SCD adults over time after the age of 20 years (Field et al.,
2008) compared to the general population (Fletcher & Peto, 1977).

The utility of PFTs is not established and there are no randomised controlled studies comparing
screening versus non-screening approaches, nor are there randomised trials reported on what
management approaches should be undertaken in SCD patients with abnormal results. There is
little to be gained from screening asymptomatic patients but if symptomatic they are useful to
explain symptoms and to quantify abnormalities.

Imaging studies have also reported that between 40-90% of sickle patients (Aquino et al., 1994;
Sylvester et al., 2006) have abnormal results on high resolution CT (HRCT) chest scans.
Sylvester et al reported a reticular pattern to be the most prevalent finding, and positively
correlated to the presence of linear bands and subpleural curvilinear lines, with the main
abnormality being scattered foci of lung fibrosis predominantly in the lung bases.

The diagnosis of nocturnal hypoxia or OSA is made with overnight oximetry or formal
polysomnography (sleep study). In the general population, nocturnal hypoxia is diagnosed
when the time with SpO2 <90% is >30% of total sleep time. OSA is diagnosed if there are more
than ten episodes of significant oxygen desaturation per hour (over 4% from baseline)
overnight. This is known as the 4% Overnight Desaturation Index (ODI). However, the cut off for
nocturnal hypoxia and OSA have not been validated in SCD, and the figures are extrapolated
from other respiratory conditions.

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Treatment
A review of the Cochrane database in May 2016 found no randomised studies looking at the role
of long-term transfusion in managing chronic sickle lung disease (Estcourt et al., 2016a). One
study reported significantly improved oxygen saturations in patients on hydroxycarbamide
compared to patients not on this therapy, with significantly higher median SpO2 when awake,
asleep and at nadir.

There is little evidence to guide treatment options for SCD patients with nocturnal hypoxia or
OSA, although long-term low flow nocturnal oxygen has been reported in small cohorts to be
safe, with no detrimental effect on erythropoiesis. Current practice is based on evidence from
non-sickle patients. Treatment options offered include continuous overnight oxygen via a
concentrator, CPAP or mandibular advancement devices. There are no reported trials looking at
these therapies in sickle patients and where chronic sickle lung disease is suspected or
diagnosed, involvement of a specialist respiratory physician to guide therapy is recommended.

The Prevention Of Morbidity in Sickle cell disease trial, POMS 2b (Kirkham, 2015), comparing
standard treatment with auto-adjusting continuous positive airways pressure (APAP), will
address some of these questions.

Recommendation
 Routine pulmonary function tests (PFTs) in asymptomatic adult patients are not
recommended.

Cardiac complications

Cardiovascular manifestations are associated with premature mortality and are becoming more
evident with increasing longevity in adults with SCD. Pulmonary hypertension (PH), left
ventricular diastolic dysfunction, dysrhythmias and sudden cardiac death are all recognised
complications of SCD.

Standards
 Assess all patients for cardiac symptoms (dyspnoea, dizziness, chest pain, ankle
swelling) and perform cardiac examination that includes assessment for signs of right
heart strain at each annual review.
 Patients with cardiorespiratory symptoms and signs should be evaluated with
electrocardiography (ECG) and echocardiography.

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 In patients with sickle cell disease echocardiography should be performed at initial

presentation to adult service and at least once every three to five years even in
asymptomatic patients (or earlier if patients are symptomatic or hypoxic).
 Echocardiography should be repeated annually in patients with previously elevated
tricuspid regurgitant jet velocity (TRV) who have not had right heart catheterisation
(RHC).
 Patients should be referred to a pulmonary hypertension specialist centre for
consideration of RHC if:
o TRV >290 cm/sec
o TRV 250-290 cm/s and symptoms suggestive of pulmonary hypertension.

Background evidence

Pulmonary hypertension

Pulmonary hypertension (PH) is diagnosed by right heart catheterisation showing a mean

pulmonary artery pressure (mPAP) at rest of 25 mmHg or greater. This has been reported in 6
to 11% of adults with SCD (Fonseca et al., 2011; Gladwin et al., 2004; Mehari et al., 2012; Parent
et al., 2011). The pathogenesis of pulmonary hypertension in SCD appears to be multifactorial
(Simonneau et al., 2013). The causes of PH in adults with SCD include left sided heart disease,
chronic lung disease, chronic thromboembolic disease and pulmonary vascular disease. One
study showed features of precapillary pulmonary hypertension in 40% of patients but
postcapillary pulmonary hypertension (defined by pulmonary capillary wedge pressure >15
mm Hg) in the other 60% (Parent et al., 2011). Further, pulmonary pressures can rise acutely
during painful vaso-occlusive crises and acute chest syndrome.

Multiple mechanisms are postulated to contribute to the development of PH including chronic

intravascular haemolysis leading to reduced nitric oxide scavenging, thrombosis, hypoxaemia,
oxidant stress and asplenia. PH in SCD is associated with increased age, poor functional
capacity, prior history of cutaneous leg ulceration, anaemia, higher N-terminal pro–brain
natriuretic peptide (NT-proBNP) levels, renal insufficiency and markers of haemolysis (Fonseca
et al., 2011; Mehari et al., 2012; Parent et al., 2011).

Symptoms of PH may be nonspecific in nature. Patients may experience fatigue; limited exercise
tolerance; progressive evidence of dyspnoea on exertion (particularly worsening on walking up
an incline or climbing stairs); chest pain, light-headedness; and syncope. Physical examination
should include review of signs of right heart strain including right ventricular heave, ankle
swelling and raised jugular venous pressure (JVP). PH is associated with increased mortality
despite modest elevations of mPAP (Castro et al., 2003; Mehari et al., 2013; Mehari et al., 2012;
Parent et al., 2011).

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Screening and diagnosis

Doppler echocardiography is a useful non-invasive tool for the initial evaluation of suspected
cases of PH and for screening. The prevalence of TRV ≥ 250 cm/s in adults is approximately
30%. This threshold is associated with impaired functional status and increased mortality and
helps identify patients at greater risk of PH (Caughey et al., 2015; De Castro et al., 2008; Fonseca
et al., 2011; Gladwin et al., 2004; Parent et al., 2011). TRV ≥300 cm/s is present in 11% adults
and associated with at least ten fold increased risk of death (Gladwin et al., 2014; Gladwin &
Vichinsky 2008).

Raised TRV alone is not a good predictor of PH. In one study, the positive predictive value of
TRV of 250 cm/s to detect the presence of PH was 25% although this was increased with a
higher TRV threshold of 290 cm/s (Parent et al. 2011). Meta-analysis of pooled data from four
studies that performed RHC on the majority of patients with TRV 250 cm/s demonstrated that
only 53 out of 173 (31%) had PH confirmed (Niss et al., 2016).

The impact of screening for PH on patient outcomes is not established and a universal strategy
on screening for PH has not been adopted. Recommendations vary from screening with
echocardiography every one to three years to screening only if there are clinical and laboratory
findings associated with increased risk of PH and the USA expert panel was unable to make a
specific recommendation for or against screening for PH due to insufficient evidence (Gordeuk
et al., 2016; Klings et al., 2014; National Heart Lung and Blood Institute, 2014).

Screening with Doppler echocardiography should ideally be performed when patients are
clinically stable in the non-crisis state, preferably at least four weeks after an episode of acute
chest syndrome and two weeks after an acute painful episode.

N-terminal pro-brain natriuretic peptide and six minute walk (6MW) test may also be useful for
assessment of PH and if used in combination with echocardiography they increase its positive
predictive value (Parent et al. 2011). The 6MW may be challenging for patients with SCD and
chronic pain or other chronic health problems.

Apart from TRV, as per European Society of Cardiology/European Respiratory Society

guidelines, other features should be considered, in particular right ventricular or right atrial
dilation, pulmonary acceleration time, inferior vena cava (IVC) dilation and septal flattening.
Abnormalities in these measures provide supportive evidence that pulmonary pressures are
raised. However, invasive haemodynamic assessment (with right heart catheterisation) is
required to diagnose PH and guide treatment decisions.

In the investigation of PH it is also important to consider additional causes such as connective

tissue disease, portal hypertension and human immunodeficiency virus (HIV) infection. The
evaluation of PH should include autoimmune screen, pulmonary function tests and sleep study.
Ventilation perfusion scan is recommended as initial investigation for detecting
thromboembolic disease and pulmonary CT angiography may subsequently be required (see
Figure 4 overleaf).

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Figure 4: Algorithm for pulmonary hypertension screening

Baseline ECHO in
patients with SCD

Raised TRV 250-290

Raised TRV cm/sec
and Normal Raised TRV
> 290
raised NT-pro BNP ECHO but no RHC
cm/sec
or
reduced 6MWT

Refer to Refer to
Repeat Repeat
pulmonary pulmonary
every 3 ECHO
hypertension hypertension
years annually
centre centre

ECHO = echocardiography 6MWT = 6 minute walk test

TRV = tricuspid regurgitant jet velocity RHC = right heart catheterisation
NT pro-BNP = N-terminal pro-brain natriuretic peptide

Management: There have been no completed randomised controlled trials to guide treatment
for PH in SCD. Targeted PH therapies such as endothelin receptor antagonists,
phosphodiesterase-5 inhibitors and prostacyclin agonists have been tried (Machado et al., 2005;
Minniti et al. 2009). Bosentan appeared well tolerated in a placebo controlled trial but the study
closed early due to poor recruitment and it was not possible to determine efficacy due to limited
sample sizes (Barst et al., 2010). The use of sildenafil in the Walk PHaSST study resulted in
increase in hospitalisation for vaso-occlusive events (Gladwin et al., 2014). There have been no
clinical trials examining the efficacy of hydroxycarbamide or blood transfusion in PH. The
American Thoracic Society committee recommends hydroxycarbamide as first-line disease
modifying therapy for this high-risk population with PH (Klings et al., 2014). Management of
postcapillary PH involves treatment of fluid overload and systemic hypertension.

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Other cardiac abnormalities

Diastolic dysfunction is common in SCD. The prevalence rates reported in multiple studies vary
depending on the criteria assessed to define diastolic dysfunction (Niss et al., 2016). In one
study diastolic dysfunction was reported in 18% of adults and present in combination with
elevated TRV in 11% of patients (Sachdev et al., 2007). The combination of diastolic dysfunction
with elevated TRV was associated with additional increased mortality risk. Risk factors for
diastolic dysfunction included increasing age, higher systolic and diastolic blood pressure, lower
haemoglobin concentration and increasing creatinine (Sachdev et al. 2007). A recent study has
shown diffuse myocardial fibrosis is associated with diastolic dysfunction in SCD (Niss et al.,
2017).

Echocardiographic abnormalities are common in SCD and heart chamber dilatation is often
seen. Left ventricular ejection fraction is normal in the majority of patients. The opinion of a
cardiologist should be sought for significant abnormal or unexplained findings.

In addition to the usefulness of TRV in the evaluation of PH, elevated TRV itself is associated
with increased mortality risk. Disease modifying therapy has been recommended for patients
with elevated TRV due to associated mortality risk (Klings et al., 2014).

Cardiac iron overload

Cardiac iron deposition secondary to multiple transfusions is uncommon in SCD. The

pathophysiology of SCD may modulate iron distribution and myocardial iron loading is much
less common and non-transferrin bound iron levels are lower in SCD compared to thalassaemia.
Cardiac toxicity may manifest with conduction abnormalities, left ventricular dysfunction and
cardiac failure. Magnetic resonance imaging with cardiac T2* is used to evaluate cardiac iron
status. The frequency of assessment of iron overload and monitoring on chelation treatment
should follow specific guidance (see Chapter 22 - Iron chelation).

Recommendations
 Patients with PH should be evaluated for thromboembolic disease, chronic lung disease,
hypoxaemia, sleep-disordered breathing, HIV infection and autoimmune disease.
 Evaluation for risk factors of PH should include assessment of renal function, liver
function and systemic hypertension.
 Disease modifying therapy with hydroxycarbamide or blood transfusion should be
considered in patients with pulmonary hypertension.
 Consideration should be given to the use of vasodilator therapy for select patients with
precapillary PH under the supervision of a pulmonary hypertension specialist.

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 Chapter 8: Renal and urological
complications

Introduction

Renal complications (sickle cell nephropathy, SCN) occur in approximately 60% of patients with
the more severe forms of SCD (sickle cell anaemia and S/β0 thalassaemia) at some point during
their lives, although these figures are halved in individuals with compound heterozygosity for
haemoglobins S and C. In most cases, SCN develops slowly and insidiously over time, starting in
the very young with glomerular hyperfiltration and leading to microalbuminuria in late
childhood or early adulthood. The majority of patients do not progress further, but a number
will gradually develop unselective proteinuria and slowly progressive chronic kidney disease
(CKD) leading to decreased renal reserve. These patients are at increased risk of acute kidney
injury (AKI) complicating vaso-occlusive crises or other interim illnesses, events that often
precipitate a further decline in their baseline renal function following recovery from the acute
episode. End stage kidney disease (ESKD) is an uncommon complication, though its incidence is
on the rise.

The mechanisms of disease and the impact of treatment options are poorly characterised but an
increase in glomerular blood flow, reduction in medullary blood flow from ischemia, papillary
necrosis, and use of non-steroidal anti-inflammatory drugs are all recognised contributors to
sickle nephropathy.

Not all renal disease in patients with SCD is due to SCN. Urinary tract infections are common,
and these patients may have other conditions such as lupus nephritis, or glomerulonephritis
secondary to blood-borne viruses and so microscopic haematuria, proteinuria and renal
dysfunction should always be investigated with this in mind.

Renal disease

Standards
 Patients with acute renal failure or with evidence of declining renal function should be
managed jointly with a renal physician.
 Patients should be monitored at least annually for symptoms or signs of renal disease
(urinary tract infection, haematuria), for hypertension and for the presence/progression
of albuminuria, proteinuria and declining renal function.
 New-onset haematuria should be investigated, regardless of age, to exclude malignancy.

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 Patients with proteinuria (urinary protein to creatinine ratio (uPCR) >50 mg/mmol)
should be offered treatment with ACE inhibitors or angiotensin receptor blockers
(ARBs) and considered for Hydroxycarbamide therapy.
 Patients with end-stage kidney disease (ESKD) should be considered for renal
replacement therapy including transplantation.

Background evidence

Hyposthenuria

Hyposthenuria (the inability to concentrate urine >450 mOsm/kg under water-deprived

conditions) is a universal finding in patients with SCD. This is not the same as sickle cell
nephropathy. In children, hyposthenuria is usually reversible by blood transfusion, but with age,
the condition becomes irreversible and it becomes a permanent feature (Statius Van Eps et al.,
1970; Stevens & Levin, 2013). This may manifest as nocturnal enuresis and predisposes
patients to dehydration when unwell. All patients with SCD should be encouraged to have a
minimum fluid intake of at least 3-4 litres/day. The only randomised controlled trial conducted
in this field was the BABY HUG trial which demonstrated that 24 months of treatment with
hydroxycarbamide was associated with better urinary concentrating ability in children (Alvarez
et al., 2012).

Haematuria

Renal papillary necrosis, caused by vaso-occlusion of the vasa recta, manifests as haematuria in
patients with SCD and sickle trait (Alhwiesh, 2014). The clinical manifestations depend on the
degree of infarction and range from asymptomatic to frank haematuria. In rare cases, the
haematuria is severe with the passage of clots and severe pain (renal colic). Sloughing of the
renal papillae can lead to ureteric obstruction and hydronephrosis. Renal ultrasonography (US)
can be used to show the renal abnormalities but computed tomography (CT) urography may be
needed to confirm the diagnosis. The treatment of haematuria is conservative with maintenance
of a high urinary flow with intravenous saline and when necessary, blood transfusion support if
blood loss is significant. Urologists should be involved at an early stage to offer advice on
bladder irrigation. Radiological or surgical intervention may be required in severe cases with
prolonged haemorrhage.

Patients with renal medullary carcinoma may also present with haematuria, sometimes with
additional abdominal or back pain and weight loss. This rare and aggressive cancer is virtually
restricted to those with the sickle gene, particularly sickle trait, sickle cell/haemoglobin C
disease and occasionally sickle cell anaemia. It has usually metastasised at the time of
presentation and has a very poor prognosis with median survival of less than one year from
diagnosis (Davis et al., 1995).

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Haematuria may also be a sign of the more common renal cell carcinomas, renal calculi or non-
sickle related glomerular disease. For this reason new onset haematuria should always be
investigated (regardless of age) and patients should be referred to a urologist or nephrologist if
appropriate (Alvarez et al., 2015; Sharpe & Thein, 2014).

Acute kidney injury (AKI)

AKI can occur in as much as two to ten per cent of patients admitted with SCD (Sklar et al.,
1990) and is more frequent in those with acute chest syndrome (Audard et al., 2010). AKI can
be precipitated by dehydration, sepsis, drugs (e.g. non-steroidal anti-inflammatory drugs
(NSAIDs), intravenous contrast media); it can occur in the context of multi-organ failure or
develop on the background of chronic renal failure (either from sickle-related nephropathy or
other aetiologies). The management of acute renal injury should follow similar principles to
those applied in other patient groups.

Proteinuria

The appearance of albumin in the urine (albumin to creatinine ratio (ACR)) persistently >3.5
mg/mmol (30 mg/g) can be detected in 20% of children with SCD. This prevalence increases
with age to >60% in those 46 years of age or older (Sharpe & Thein, 2014). In a subset of
patients, microalbuminuria progresses to unselective proteinuria, occasionally becoming
nephrotic in range after many years; and is associated with increased mortality (Drawz et al.,
2015). Patients with an ACR persistently >30 mg/mmol should be monitored using the
unselective protein to creatinine ratio (PCR) as this will more accurately reflect their total
protein loss. Full nephrotic syndrome (heavy proteinuria, hypoalbuminaemia and peripheral
oedema) is uncommon at approximately 4%, but when it does occur, it is associated with a very
poor outcome (Bakir et al., 1987). A recognised trigger for nephrotic syndrome is a recent
infection with human parvovirus B19. All patients with nephrotic syndrome should be referred
to a nephrologist.

Proteinuria is associated with rapid progression of CKD, and reducing this proteinuria with
inhibitors of the renin angiotensin system (either angiotensin-converting enzyme inhibitors
[ACEi] or angiotensin receptor blockers [ARBs]) slows this progression in patients with either
diabetic or non-diabetic proteinuric renal disease (Chaturvedi & The EUCLID study group, 1997;
Jafar et al., 2001). Although a recent systematic review found insufficient evidence to offer
recommendations on treatment of proteinuria in SCD, observational data have shown responses
in patients with SCN and proteinuria treated with ACEi. (Aoki & Saad, 1995; Falk et al., 1992).
Based on the evidence available for other causes of proteinuric renal disease and international
guidelines for the management of proteinuric CKD (Stevens & Levin, 2013), ACEi or ARB
treatment should be considered when the uPCR is >50 mg/mmol (500 mg/g). These drugs must
be introduced cautiously, because many patients have a low/normal blood pressure and so
moderate doses can cause postural hypotension. Patients with SCN are prone to hyperkalaemia,
which can be exacerbated by ACEi and ARB treatment and patients and other care-givers should

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be informed that the medication should be temporarily stopped during episodes of acute kidney
injury or other acute illnesses associated with dehydration.

Based on evidence from a number of prospective and retrospective cohort studies and case
reports, hydroxycarbamide should also be considered for patients with microalbuminuria or
abnormal renal function alongside treatment with an ACE inhibitor or angiotensin-II receptor
antagonist, or in those intolerant of this treatment (Sharpe & Thein, 2014; Silva Junior et al.,
2014).

Monitoring renal function

Renal function should be monitored at least annually. Creatinine levels are often low in people
with sickle cell anaemia and sickle cell/β0 thalassaemia due to hyperfiltration and increased
proximal tubular excretion, resulting in a high estimated glomerular filtration rate (eGFR).
Increased rate of change of creatinine may, therefore indicate declining renal function before
the value moves out of the normal range. Anyone with an eGFR which is declining by >5
ml/min/year or an absolute value <60 ml/min should be identified and discussed with a
nephrologist. Rigorous blood pressure (BP) control is recommended, as higher BP is associated
with worse renal function in patients with SCD as in other causes of CKD (Gordeuk et al., 2008).
A blood pressure of 140/90 is permissible for dipstick negative patients or those with an ACR
<3.5 mg/mmol but a target of 130/80 should be used for those with an ACR >3.5 mg/mmol
(Stevens & Levin, 2013). Urinary tract infections should be promptly treated with suitable
antibiotics. Long-term use of NSAIDs should be avoided in patients with an eGFR <60 m/min; if
unavoidable, regular monitoring of renal function is recommended (Nderitu et al., 2013).

End stage kidney disease

Patients with CKD and symptomatic anaemia may benefit from erythropoietin therapy, with or
without hydroxycarbamide, although high doses are often required (Sharpe & Thein, 2014).
Renal replacement therapy, including haemodialysis and transplantation, should be explored in
patients with end stage kidney disease (ESKD), in conjunction with the local nephrologist
(McClellan et al., 2012). Survival of patients with SCD on haemodialysis is reduced compared
with other causes of ESKD of non-diabetic origin. Early referral and consideration for
transplantation should be considered (Huang et al., 2013) Delayed graft function and increase in
frequency of painful crises in individuals post-renal transplantation has been noted and
exchange blood transfusion (EBT) +/-hydroxycarbamide should be considered in patients on
the transplant waiting list and with functioning grafts (Sharpe & Thein, 2014).

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Recommendations
 Patients with SCD who develop acute renal failure should have close monitoring of their
renal function. These patients should have adequate hydration and fluid balance;
nephrotoxic drugs should be avoided.
 All patients with SCD should be encouraged to have a minimum fluid intake of at least 3
l/day.
 NSAIDs should be avoided in patients with stage 3-5 CKD not on renal replacement
therapy (eGFR <60 ml/min).
 Patients with hypertension and ACR <3.5 mg/mmol should be treated with a BP target
of <140/90 mmHg. Patients with hypertension and ACR >3.5 g/mmol should be treated
with a target of <130/80 mmHg.

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 Chapter 9: Priapism
“I am in my 40s and have never suffered priapism, however, there are people I know who struggle
with the embarrassing moment of going into A&E to treat this and sometimes, they just don’t go”

Priapism is defined as a persistent, prolonged and painful penile erection unrelated to sexual
stimulation. Stuttering priapism describes short episodes of recurrent or intermittent ischaemic
priapism. These are self-limiting and typically occur at night. It can lead to a more sustained or
fulminant episode (Adeyoju et al., 2002). This acute/fulminant priapism requires emergency
treatment to avoid long-term erectile dysfunction.

Standards
 All men should be educated about priapism and should be asked about both stuttering
and fulminant priapism as part of their annual review.
 Patients should have access to a multidisciplinary team including an urologist with a
specialist interest in SCD-related priapism.
 Each haemoglobinopathy unit should have an emergency pathway and access to
emergency urology services for cases of fulminant priapism.

Background information
Priapism has a lifetime incidence of up to 35-90% in male patients with SCD with the majority
of first episodes occurring before the age of 20 years. The initial presentation may be with
stuttering priapism or with fulminant priapism. It is a complication that causes significant
embarrassment and discomfort. It is often poorly discussed with patients (Olujohungbe &
Burnett, 2013). Patient education and discussion of management options is vital as delays in
treatment and exposure to repeated episodes risks permanent erectile dysfunction. Several
studies have described poor understanding and education about priapism with one case series
showing that only 5% of men with sickle cell disease presenting with an acute episode of
priapism recalled learning about priapism and the connection with SCD (Adeyoju et al., 2002;
Bennett & Mulhall, 2008). Patient education should focus on conservative management of
priapism (such as gentle exercise, trying to urinate and keeping warm) and simple steps of
trying to prevent episodes such as keeping hydrated at bedtime. It is also important that
patients know when to seek emergency treatment if prolonged priapism develops.

Opinion suggests that these patients should be managed in conjunction with an urologist who
has a specialist interest in SCD- related priapism (Kato, 2012).

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Priapism is categorised as either ischaemic (low flow) or arterial (high flow) in origin. Priapism
in SCD is of the low-flow ischaemic type and presents with rigid painful corpora but the glans
penis is soft. The low O2 tension caused by stasis of blood within the corporeal tissues
predisposes red blood cells to sickle, leading to obstruction of penile vessels ((Olujohungbe et
al., 2011). The priapism perpetuates local ischaemia leading to penile fibrosis and erectile
dysfunction (Levey et al., 2012).

Acute priapism
Patients with a painful, rigid, priapic episode of more than one hour should be encouraged to
attend hospital where initial management should include adequate treatment of their crisis with
pain relief, hydration, adequate oxygenation and an alpha adrenergic agent (usually etilefrine) if
not already taken at home. Patients should be encouraged to urinate and should only be
catheterised if they have a full bladder and are unable to void.

History taking during an initial assessment should include the duration of the episode, the
presence of pain, previous episodes of priapism and their treatment (both stuttering and
fulminant), any trauma, medications including analgesic and recreational drugs, and other
complications and current treatments of SCD. An understanding of the patients’ baseline normal
erectile function should also be sought and recorded.

Patients should be referred for urgent urological review. The longer the ischaemic priapism has
persisted, the greater the need for surgical intervention. Recent British Association of Urological
Surgeons (BAUS) genital emergencies guidelines have separated ischaemic priapism into 3
categories by time since onset:

 <48 hours
 48-72 hours
 >72 hours
The recommended treatment for priapism that does not settle with conservative treatment
presenting at <48 hours is penile aspiration of the stagnant ischaemic blood to decompress the
corpora cavernosum. This is best performed with a 19 gauge needle through the glans or
laterally from the penile shaft. It can be performed under local anaesthetic in the Emergency
Department after a penile block. Blood aspirated from the corpora is dark with a low pO2, pH
and glucose. The diagnosis of a low flow ischaemic priapism can be confirmed by sending of a
sample of the aspirated blood for blood gas analysis. Aspiration is combined with injection of an
alpha adrenergic agents directly into the corpus cavernosa. This is recommended to assist with
maintaining detumescence. Phenylephrine can be given intracavernosally in 200 μg aliquots up
to a maximum of 1000μg and this can achieve a higher rate of detumescence but must be done
with continuous blood pressure and pulse monitoring in a controlled setting (Broderick, 2012;
Mantadakis et al., 2000; Montague et al., 2003). If this fails surgical intervention should be
considered with a distal shunt procedure (Montague et al., 2003). The simplest of distal shunts
involves placing a wide bore cannula through the glans and into the corpora (Winter shunt).

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If these measures have been ineffective, or if the patients presents at 48-72hrs, a more
definitive distal shunt procedure by a specialist urologist may be required (T-shunt). While this
may achieve successful detumescence, the impact of larger distal shunts on erectile function is
more significant. Reported rates of successful detumescence with presentation times >48hrs is
only 30%, with severe erectile dysfunction in up to 100% (Zacharakis et al., 2014).

For those presenting at >72hrs, the BAUS emergencies guidelines recommend referral of the
patient to a specialist unit to consider a primary penile implant. Placement of a malleable
prosthesis is effective at treating both the low flow priapism and the subsequent erectile
dysfunction that will inevitably occur in cases, which present so late. An early insertion in the
acute setting is technically easier to do, with lower rates of complication and allows maximal
preservation of the penile length. However it can be difficult for patients to accept the insertion
of a permanent device at the time of an acute presentation, and careful discussion and
counselling is required.

There is no randomised trial evidence for either simple or exchange transfusion in acute
priapism and variable responses are described in the literature. Patients who require shunt
procedures under general anaesthesia may require simple transfusion prior to anaesthesia if
they have haemoglobin concentration (Hb) below 90 g/l (see Chapter 19 - Surgery). If shunt
procedures are not effective in relieving the priapism, exchange transfusion could be considered
prior to the definitive shunt procedure, which is major surgery. There are anecdotal reports of
high rates of neurological complications in patients with priapism receiving exchange
transfusion, but these were associated with high post-transfusion Hb, which may in turn be
associated with increased viscosity.

Patients with recurrent episodes of acute priapism will usually employ self-management
techniques at home including exercise, hydration and urination and they will usually be
prescribed an alpha adrenergic agent.

Stuttering priapism
The aim of treatment of stuttering priapism is to prevent further episodes and reduce long-term
sequelae but a paucity of large-scale studies make clear recommendations difficult. The
involvement of an urologist with an interest in priapism and SCD is important and Doppler
ultrasound may have some role in diagnosis and therapeutic monitoring to identify reduction of
changing smooth muscle tone (Patel et al., 2015).

In the UK alpha-adrenergic agonists and anti-androgens are most commonly used with oral
alpha-adrenergic agonists (e.g. etilefrine) having efficacy of up to 72% (Okpala et al., 2002).
These should be considered as first line therapy. Patients often take their treatment at bedtime
due to the prevalence of episodes of stuttering priapism occurring overnight. In the UK long
acting etilefrine is not currently available and short acting preparations are used. Starting dose

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is usually 5 mg at bedtime, increasing up to a maximum of 25 mg (or 10 mg repeated after 4

hours) if required, although there is little clear guidance. Given the short acting nature of
etilefrine, combined with the more frequent occurrence of stuttering priapism in the second half
of the night, patients on short acting drugs often benefit from setting an alarm to take a second
dose half way through the night. There is a risk of palpitations and hypertension at the higher
doses. Ephedrine at 15-30mg has also been used and appears to be effective.

Hormonal treatments (anti-androgens, gonadotropin-releasing hormone agonists or

antagonists and oestrogens) have been used to reduce testosterone levels, inhibiting the action
of androgens on erections (Salonia et al., 2014). In adults cyproterone is usually favoured as the
anti-androgen if alpha-adrenergic agents are not effective. It should be added to current therapy
rather than replacing it, unless the alpha adrenergic agonist is not tolerated. Patients should
have potential side effects discussed with them, including hot flushes, gynaecomastia, impaired
erectile function, and reduced libido. There are also concerns about fertility as it can affect
spermatogenesis. Hormonal treatments should be avoided if possible in teenage children or
others who have not achieved puberty or sexual maturity.

SCD is reported as a contra-indication to the use of cyproterone due to the potential increased
thromboembolic risk. Therefore this treatment should be discussed thoroughly with the patient
and the discussion documented. Further, the dose should be kept low (150 mg or less in divided
doses per day) and reduced gradually to 50 mg a day.

Studies have looked at the role of oral phosphodiesterase type 5 (PDE5) inhibitors proposing
that PDE5 inhibitors would increase the PDE5 levels, increase NO availability, regulate cGMP
expression and prevent priapism (Burnett et al., 2014; Burnett et al., 2006a, 2006b). A
randomised trial of sildenafil versus placebo showed no difference in the treatment arms but
some benefit of sildenafil in the open label phase of the study (Burnett et al., 2014). The side
effects of long term sildenafil in sickle cell disease also need to be considered (Lane & Deveras,
2011).

Many other medications (digoxin, ketoconazole, baclofen, gabapentin and 5-alpha reductase
inhibitors such as finasteride) have been described in historical small studies with some
benefits but all need further clinical trials to establish their role in the prevention of stuttering
priapism (Abern & Levine, 2009; Levey et al., 2012).

None of these agents are licensed for use in SCD related priapism and patients should be
counselled accordingly.

There is limited evidence for the efficacy of SCD disease modifying therapy. One small trial of
five patients (Saad et al., 2004) reported improvement in stuttering priapism in four patients
whilst receiving treatment with hydroxycarbamide but further reviews of the management of
priapism in SCD do not recommend routine use of hydroxycarbamide (Olujohungbe & Burnett,
2013). Transfused patients in the silent cerebral infarct transfusion (SIT) trial showed

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significantly decreased rates of priapism (0.8 vs 6.7 adverse events per patient year, p=0.02) but
observational data of the effect of long term transfusion on the rates of priapism have shown
opposing results, with some studies showing a benefit of transfusion and others showing no
benefit (Ballas & Lyon, 2016; Driss et al., 2011). Further research into pharmacological
therapies for priapism and into the benefit of SCD-directed therapies are required. The long-
term benefit of these treatment options on sexual function should also be recorded.

Recommendations
 Treatment options including alpha agonists and anti-androgens should be considered in
patients with stuttering priapism. If these are not successful, other drug therapies or
anti-sickling therapies can be considered.
 Blood transfusion should be considered when acute priapism does not settle with
conservative measures and prior to surgery.

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 Chapter 10: Fever and sepsis
Introduction
People with sickle cell disease (SCD) remain at risk of severe infections, in particular due to
encapsulated organisms such as Streptococcus pneumonia associated with hypo-and asplenism
(see Chapter 3 - Primary care). Defects in complement activation also contribute to risk of
morbidity and mortality from sepsis, along with localised ischaemia of bowel or bone, allowing
entry of enteric organisms into the circulation and predisposing an individual to both Gram-
negative bacteraemia and septic shock/disseminated intravascular coagulation (DIC) and
osteomyelitis. Indwelling vascular access devices, where present, further increase this risk.
Sepsis remains an important cause of mortality in adults with SCD (National Confidential
Enquiry into Patient Outcome and Death (NCEPOD), 2008; Yanni et al., 2009), related not only
to the increased risk of severe sepsis, but also due to the precipitation of sickling crises by fever
and infection (Booth et al., 2010). While risk is highest in sickle cell anaemia, other genotypes
are also at significant risk of serious infection (Leikin et al., 1989).

Standards
 Patients with sickle cell disease presenting with a fever ≥ 38.0°C require a full clinical
review, including cultures of blood, urine and any other potential sites of infection.
 Patients with sickle cell disease presenting with a fever ≥ 38.0°C should have broad-
spectrum antibiotics administered, to include coverage for pneumococcus as well as
Gram-negative organisms including salmonella.
 Where chest signs or symptoms are present, a chest X-ray should be requested and
acute chest syndrome considered (see Chapter 7 - Cardiorespiratory complications).

Background evidence
There is a paucity of good-quality, prospectively-collected evidence to guide recommendations.
Data are predominantly paediatric and observational.

Rates of serious bacterial sepsis have reduced significantly with the introduction of universal
penicillin prophylaxis from infancy and improved immunisation schedules for pneumococcus.
Sepsis, however, still remains an important cause of mortality in both children and adults with
sickle cell disease in the UK (National Confidential Enquiry into Patient Outcome and Death
(NCEPOD), 2008). Reported rates of bacteraemia in febrile children with sickle cell disease are
low (around 1 per cent) but Streptococcus pneumoniae (particularly non-vaccine serotypes)
continues to cause serious infection. Penicillin resistant strains are also resistant to other

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augmented penicillins e.g. co-amoxiclav, piperacillin/tazobactam, so if resistance is suspected

alternative antibiotics should be given. Other organisms such as salmonella also contribute
significantly to the burden of cases (Bansil et al., 2013; Baskin et al., 2013; McCavit et al., 2011;
Narang et al., 2012; Rogovik et al., 2010; Savlov et al., 2014; Wright et al., 1997).

For all patients with SCD presenting with fever above 38.0°C comprehensive review needs to
include:

 Full examination
 Cultures of blood, urine and any other potential site of infection, such as throat;
 Full blood count with differential and reticulocyte count
 Chest X-ray in all patients with respiratory symptoms or signs

Broad-spectrum parenteral antibiotics should be administered to include coverage for

pneumococcus as well as Gram-negative organisms including salmonella. Antibiotic choice
should be consistent with local microbiological advice. If the focus of infection is evident then
antibiotic therapy can be directed appropriately. Cover for atypical organisms should be
included in those with suspected acute chest syndrome (Booth et al., 2010). A diagnosis of
malaria should be considered if patients have a history of travel to an endemic region. Where
blood cultures are positive for Staphylococcus aureus or salmonella, even in the absence of focal
signs, a diagnosis of osteomyelitis (see Chapter 11 - Orthopaedic complications) should be
considered (Norris et al., 2003; Sadat-Ali, 1998).

Where a patient’s clinical condition suggests severe sepsis, or where deterioration is suspected,
early consideration should be given to the need for intensive care unit support. In
overwhelming sepsis with multi-organ failure, exchange transfusion should be considered.

Outpatient management of febrile children with SCD has been shown to be safe and effective in
prospective US studies (Wilimas et al., 1993; Williams et al., 1996) and these findings are
confirmed by a large retrospective review (Baskin et al., 2013). Although there are no
comparable studies in adults, these data support the safety of managing certain patients with
fever alone, without additional risk factors, as outpatients, after initial investigations and after
cultures have been taken. Patients and their family/carers must understand the importance of
the need to return in the case of any deterioration. If blood cultures become positive the patient
should be admitted for ongoing care including parenteral antibiotic therapy.

Patients should however be admitted for ongoing care and observation if they: have symptoms
or signs of acute chest syndrome (including hypoxia), tachycardia, dehydration, vomiting;
require supportive care such as intravenous (IV) fluid or oxygen; are ‘ill-looking’; have a history
of sepsis or a central venous access device in situ; have abnormal investigations (decreased
haemoglobin concentration or platelet count); do not have a reliable contact telephone number
and a reliable care-giver who can observe at home; or have a history of poor compliance.

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In an effort to contribute further to the available evidence, data on patient outcomes after
presentation with fever or infection should be collected prospectively and any episode of
proven bacterial sepsis should be recorded as an adverse event on the National
Haemoglobinopathy Registry.

Recommendations
 Patients presenting with fever alone who are otherwise well, and in whom no other risk
factors are present may be considered for outpatient management with appropriate
antibiotics after appropriate review and blood cultures have been taken.
 Comprehensive patient education regarding the risks, and the early signs, of infection, is
an important part of ongoing care of patients with sickle cell disease.
 While the recommendations above relate to patients presenting with fever ≥38.0°C, the
same measures should be considered in any patient who is unwell or who presents with
signs or symptoms suggestive of infection.

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 Chapter 11: Orthopaedic complications
“I suffered AVN and had a hip replacement after waiting for 4 years on a waiting list. It was a
terrible 4 years of agony. I would suggest that people do not make assumptions about any unusual
pain you may be having. Get it diagnosed and treated ASAP”

Osteomyelitis

Introduction
Osteomyelitis occurs at all ages in patients with sickle cell disease (SCD) and the prevalence is
higher in patients with the more severe haplotypes (Almeida & Roberts, 2005). Osteomyelitis
can be difficult to distinguish from vaso-occlusion. Both can present with pain, localised
tenderness, warmth, swelling, fever and leucocytosis. The commonest sites are the femur, tibia
and humerus. Bone pain is much more likely to be due to vaso-occlusion than osteomyelitis. It is
prudent to treat initially for the former and investigate for infection if pain persists or is atypical
and fever continues.

Standards
 Blood cultures should be taken in patients with ongoing bone pain and/or fever where a
clinical diagnosis of osteomyelitis is suspected. In selected cases radiological
examination or bone biopsy/aspiration should be considered to confirm the diagnosis.
 Treatment of osteomyelitis should be with a prolonged course of an antibiotic
appropriate to cover the organism isolated.

Background evidence
Salmonella (especially the serotypes: Salmonella typhimurium; Salmonella enteritidis;
Salmonella choleraesuis; and Salmonella paratyphi B), Staphylococcus aureus and other gram-
negative enteric bacilli are the most common causes of osteomyelitis (Atkins et al., 1997;
Burnett et al., 1998), perhaps due to bowel micro-infarcts facilitating the egress of these
organisms. Tuberculosis has also been reported to cause osteomyelitis in SCD.

In practice the diagnosis is usually based on clinical findings and positive blood cultures.
Positive cultures from bone aspiration or biopsy will confirm the diagnosis of osteomyelitis but
bone aspiration should be limited to specific cases bearing in mind the potential risk of
introducing infection.

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Imaging
Plain X-rays show no specific changes in early osteomyelitis and should be reserved for cases
with persistent pain and high clinical suspicion and not be performed routinely in patients with
fever and bony pain. Lucent areas are seen much later in the course of infection. Ultrasound
changes such as subperiosteal fluid can be seen with vaso-occlusion but fluid depths >4 mm are
strongly associated with a diagnosis of osteomyelitis (William et al., 2000). Routine bone scans
and radiolabelled leucocyte scans do not reliably distinguish between infection and vaso-
occlusion. Magnetic resonance imaging (MRI) scans similarly are not discriminatory showing
reactive bone marrow oedema and hyperaemia. MRI is most useful for localising lesions and
monitoring the response to treatment.

Treatment
Initial therapy in patients suspected of having osteomyelitis should be broad spectrum to cover
salmonella and staphylococcus pending culture results. There are no relevant trials on
the efficacy and safety of the antibiotic treatment approaches for patients with SCD suffering
from osteomyelitis (Martí-Carvajal & Agreda-Pérez, 2016). Once an organism has been isolated,
antibiotic therapy can be tailored; a prolonged course is recommended, often up to six weeks,
although duration will depend on local microbiological advice and response. Drainage is
recommended for fluid accumulation that does not respond to antibiotic therapy.

Avascular necrosis

Avascular necrosis (AVN) – also referred to as osteonecrosis – results from bone death due to
loss of blood supply. It can result in chronic pain as well as impairment and disability. It is most
common in the head of the femur but can occur in other bones. The treatment for AVN is
dependent on the grade of joint involvement.

Standards
 AVN in SCD patients should be managed using a multidisciplinary team (MDT) approach
involving the haematologist and a specialist orthopaedic surgeon.
 AVN should be considered in SCD patients presenting with either sudden onset or
progressive joint pain especially in the hip or shoulder joints and initial investigation
should begin with plain X-ray, MRI should considered if the plain X-ray is normal.
 Analgesia and physiotherapy should be offered in the early stages of AVN
 Total hip replacement is indicated in patients with persistent, intractable hip pain and
disability affecting daily activities who have failed non-operative management.
 Major joint arthroplasty surgery should be carried out in centres experienced in
managing patients with SCD.

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Background evidence

Presentation and diagnosis

Avascular necrosis may affect up to 50% of patients with sickle cell disease (Martí-Carvajal et
al., 2016) and most commonly affects the femoral head (Issa et al., 2013) and the humeral head
although it has also been reported to affect multiple other joints including the knees, feet and
back. It commonly affects multiple joints. AVN may be asymptomatic in the early stages but the
majority of patients present with intermittent, progressive or acute pain. Patients with hip AVN
commonly present with groin pain, but may also present with pain in the buttock, knee or with
diffuse lower limb pain.

Diagnosis of AVN is primarily based upon imaging findings. Plain radiographs are the most
appropriate initial investigation of hip pain, but have low sensitivity for early stage disease. If
the plain X-ray is normal, and symptoms are persistent, MRI should be considered as it has the
highest sensitivity and specificity for AVN compared to other modalities (Choi et al., 2015).

AVN of the femoral head is a progressive disease leading to eventual collapse of the femoral
head and over 80% of hips with early disease, seen only on MRI, will progress to collapse within
8 years (Poignard et al., 2012). The prognosis of AVN is related to the location and size of the
osteonecrotic lesion as well as the presence or absence of collapse of the necrotic segment.
Whilst it can be helpful to stage hip AVN to quantify the disease and help guide treatment there
is no universally agreed classification system for hip AVN and the most widely used are shown
in Figure 5 (Choi et al., 2015).

[Figure 5 shown overleaf]

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Figure 5: Ficat and Steinberg classification systems (Choi et al., 2015)

Stage Radiographic signs

Ficat + Arlet Steinberg

0 Inconspicuous/normal findings Radiographs and MRI scan are
normal
I Inconspicuous findings or minor changes Radiographs are nondiagnostic;
(slight patchy osteoporosis, blurring of MRI is abnormal
trabecular pattern, subtle loss of clarity)
IIA Diffuse/ focal radiological changes
(osteoporosis, sclerosis, cysts)
IIB Subchondral fracture (“crescent sign”) Radiographs demonstrate
segmental flattening of femoral head abnormalities consistent with
(“out-of-round appearance”) osteonecrosis; head is round
III Broken contour of femoral head, bone Radiographs reveal crescent sign
sequestrum, joint space normal
IV Flattened contour of femoral head, Flattening of the femoral head
decreased joint space, collapse of femoral
head, acetabular osteoarthritic changes
V Acetabular involvement and
narrowing of joint space
VI Loss of joint space; advanced
arthritic changes

MRI: magnetic resonance imaging

Treatment
The Cochrane systematic review on treatment of AVN in SCD concludes there is inadequate
evidence to guide practice (Martí-Carvajal et al., 2016) and notes that AVN is a complex
condition and should be managed with an MDT approach involving a specialist orthopaedic
surgeon and haematologist.

Treatment is broadly divided into conservative and surgical approaches with non-surgical
management largely the preserve of early stage disease.

Conservative or non-surgical management

Management approaches useful in patients with early stage disease include: physiotherapy;
pain management approaches, including injection of local anaesthetic into the joint; activity
modification; and walking aids. Although helpful, conservative treatment of AVN alone does not
provide prolonged symptomatic relief and does not prevent disease progression.

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Surgical management

Core decompression

This surgical approach is based on the theory that avascular necrosis is similar to a
compartment syndrome of bone. Hence decompression will promote revascularisation and
healing. Its use as treatment of AVN of the hip is controversial. Well-controlled prospective
trials are lacking and the most recent Cochrane review in 2016, identified only one randomised
clinical trial (Neumayr et al., 2006), which reported no additional benefit of core decompression
over physiotherapy for symptom improvement. They note that this conclusion is based on one
trial with high attrition rates and further trials are needed to evaluate hip core decompression.

Some studies, mostly small case series have reported positively on this therapy option in early
stage disease only. (Kamath et al., 2015; Mukisi-Mukaza et al., 2009; Styles & Vichinsky, 1996).
It remains in use in clinical practice and may have a role in selected younger patients with early
stage disease that produces significant pain.

Results of core decompression for shoulder AVN in sickle patients is similar to that for hip AVN,
with some studies reporting good outcomes (LaPorte et al., 1998), although these were
retrospective studies with broad aetiology for shoulder AVN not just SCD. Kennon et al reported
100% of SCD patients with stage I/II AVN of the shoulder progress to collapse despite
decompression, compared to 50% of chronic steroid induced AVN patients who did not
experience disease progression (Kennon et al., 2016).

Joint replacement surgery

Essentially when there is collapse, the prognosis is poor and treatments other than total hip
replacement (THR) are unlikely to be effective. In patients who have intractable pain and are
medically fit to undergo the procedure it has the potential to dramatically improve function and
relieve pain. Hip arthroplasty in sickle patients can be technically difficult due to the narrowing
of the medullary canal within the bone, sclerosis and associated deformities. Early studies
reported high failure rates with over 59% failures at five years, alongside high associated
infection rates. However, more recently reported case series have shown marked improvement
in patient outcomes – with reduced infection rates and with a low revision rate (13.5%) at 13
years – when the surgery is undertaken in a centre with experience of managing sickle cell
patients and adequate precautions are taken against infection (Clarke et al., 1989; Hernigou et
al., 2008).

The three most recently published studies on total hip replacement surgery in sickle cell
patients have reported markedly improved results (Gulati et al., 2015; Issa et al., 2013; Jack et
al., 2016) and advocate the use of cementless ceramic prosthetic devices over cemented ones
and pre-surgical optimisation. They report improved outcomes with low rates of sickle
complication rates if preoperative exchange transfusion is used (6% reported by Jack et al) as
well as low infection rates of 0-9% (Gulati et al., 2015; Jack et al., 2016).

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There are fewer studies reported for shoulder surgery in sickle patients. However good
outcomes have been reported with regard to both arthroplasty and resurfacing surgery in sickle
patients with AVN, with 81% satisfaction and significant clinical score improvements post
operatively (Kennon et al., 2016)

The decision to proceed to joint replacement surgery should be taken in the specialist
multidisciplinary setting with involvement of the orthopaedic surgeon, a haematologist, the
patient and if appropriate the anaesthetist and pain management team. Pre-surgical
management of the patient should focus on optimisation of SCD with preoperative transfusion
and medical management of co-morbidities and post-operative management should include
infection prevention, thromboprophylaxis and appropriate rehabilitation. Major joint
arthroplasty surgery should only be carried out in centres experienced in managing patients
with SCD and should not be performed as occasional cases in smaller units.

Recommendations
 The anaesthetic and pain management team should be involved in preoperative
management of patients with SCD prior to joint replacement surgery.
 Core decompression can be considered in selected cases of non-collapsed femoral head
in the young patient.
 The use of cementless prosthetic devices is preferred for hip replacement surgery in
SCD.
 Post-operative infection prophylaxis and thromboprophylaxis are recommended unless
contra-indicated.

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 Chapter 12: Gastroenterological and
hepatobiliary complications
Introduction
Abdominal pain is common in sickle cell disease (SCD) and may be due to complications of SCD
or to other causes of abdominal pain, as in other patients. The differential diagnosis of
abdominal pain includes sequestration syndromes, mesenteric syndrome, constipation, gall
stone complications, infective aetiologies (e.g. pyelonephritis, intra-abdominal abscesses and
diverticulitis) and dysmenorrhoea. Hepatobiliary complications in SCD are common and have a
multifactorial aetiology. They may be caused by the sickling process itself; by hypoxic injury due
to vaso-occlusion; or by iron overload secondary to multiple blood transfusions. In addition,
patients with SCD may develop coexistent liver disease such as viral hepatitis and autoimmune
liver disease. Mild abnormalities in liver function tests are common and may be seen in
uncomplicated vaso-occlusive crises, but some patients develop progressive liver disease and
end-stage liver disease. Biliary tract complications are common in patients with SCD, especially
in those with sickle cell anaemia, primarily due to the development of gallstones.

Depending on the nature of the problem, referral to a specialist centre with expertise in sickle
hepatopathy may be appropriate. In progressive liver disease, treatment may include an
exchange transfusion programme and liver transplantation can be considered for highly
selected patients with end stage liver disease.

Standards
 Liver function (liver enzymes and bilirubin) should be monitored at least annually.
 Symptomatic gallbladder stones should be treated with laparoscopic cholecystectomy
because of the shorter hospital stay and fewer immediate surgical complications.
 Exchange transfusion should be considered early in the presentation of patients with
intrahepatic cholestasis.
 Simple transfusion to baseline haemoglobin can be considered for patients with acute
hepatic sequestration associated with anaemia.
 Liver biopsy should only be considered in cases of genuine diagnostic dilemma and
should be done via the trans-jugular route to minimise bleeding risk.

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Background evidence

Splenic complications

There is a paucity of data relating to splenic complications in adult patients with SCD; most
reports are in paediatric patients due to the higher prevalence of splenic complications in
children. Case reports and observational studies in adult patients describe complications such
as splenic sequestration, hypersplenism and splenic infarction. Splenic enlargement in SCD in
adulthood may imply a lesser disease severity (Asnani et al., 2013). Splenic sequestration in
adults may develop insidiously often with abdominal pain. Patients with chronic splenomegaly
can develop hypersplenism and may be predisposed to acute splenic sequestration (Subbannan
et al., 2009). The largest case series of splenic complications in 124 adults with sickle
cell/haemoglobin C compound heterozygosity reported a splenectomy rate of 9.6 per cent for
infarction, sequestration, hypersplenism and subcapsular bleeding (Subbannan et al., 2009).
The patients who required splenectomy had lower haemoglobin concentration and a more
severe clinical course. Splenectomy was well tolerated in most reports. Other therapies
described were supportive care and blood transfusions (Koduri & Nathan, 2006).

Mesenteric syndrome

The mesenteric or girdle syndrome is a rare complication of SCD that manifests as acute bowel
pseudo-obstruction. Patients present with an ileus, a distended abdomen without localising
signs or rebound, and distended bowel loops or fluid levels on X-ray. Preceding pain in back,
abdomen or limbs maybe reported. Patients can have a degree of hepatomegaly and there is
often associated bi-basal lung consolidation.

There are few case reports to guide optimal treatment. Other surgical pathologies should be
excluded. The management is largely conservative (intravenous hydration, analgesia,
nasogastric aspiration if vomiting). There is a potential for progression to bowel complications
(Qureshi et al., 2006) and acute chest syndrome; exchange transfusion should be considered
early in management of these patients.

Monitoring liver function and investigating liver disease

Liver function should be monitored at least annually and testing should include liver enzymes
as well as total and conjugated bilirubin. Unconjugated bilirubin is almost always raised in
people with sickle cell anaemia and sickle cell/β0 thalassaemia, due to haemolysis; conjugated
bilirubin and ALT give a better indication of liver problems. Mild derangement of liver enzymes
is common and is not independently associated with mortality (Gardner et al., 2016).

Further investigation of liver dysfunction should be prompted by clinical signs of liver disease
or persistent abnormalities in liver function testing. Drug and alcohol history may be relevant
and non-SCD causes of hepatic disease should be excluded: autoimmune studies and viral

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hepatitis serology must be performed. Ultrasound is accurate in the assessment of cirrhosis,

ascites, portal vein anatomy, and the biliary system. Magnetic resonance
cholangiopancreatography (MRCP) is the imaging technique of choice in the diagnosis of
cholangiopathy. Iron status can be monitored with ferritin but is best assessed with magnetic
resonance imaging (MRI) scanning such as FerriScan® R2. Liver biopsy should be avoided in
the acute setting, due to an increased risk of bleeding and liver rupture (Zakaria et al., 2003). In
rare cases of diagnostic dilemma after specialist hepatology assessment, if a liver biopsy is
conducted, a trans-jugular route minimises bleeding risk. The role of non-invasive markers of
liver fibrosis with transient elastography and enhanced liver fibrosis score has yet to be
elucidated in this patient group (Drasar et al., 2017).

Jaundice

Most patients with SCD have a baseline degree of hyperbilirubinaemia. Elevations in bilirubin
levels can be due to:

 Haemolysis which may be exacerbated in a vaso-occlusive crisis, delayed transfusion

reaction and hyperhaemolysis
 Obstructive causes such as gallstones or biliary sludge
 Intrahepatic cholestasis
 Progressive liver disease

Management depends on the underlying cause.

Gallstones

Gallstones are a common occurrence in SCD present in up to 30% of children and 70% of adults
(McCall et al., 1977). They are more common in sickle cell anaemia than in other genotypes.
They are usually asymptomatic and are often detected incidentally on routine imaging. Gall
stone complications may develop due to infection and inflammation of the gall bladder and
biliary duct (acute cholecystitis, gallbladder empyema, ascending cholangitis) or due to
obstruction of the biliary ducts and acute pancreatitis. Despite the high prevalence of gallstones,
symptomatic biliary tract disease occurs in around 20% of patients with SCD (Amoako et al.,
2013) and symptoms include jaundice and acute abdominal pain. The management of acute
cholecystitis, ascending cholangitis and gall bladder empyema is no different from that in the
general population (National Institute for Health and Care Excellence, 2014a). Antibiotics
should be instituted early in view of the risks of infection and should be broad spectrum
including cover for Salmonella species and anaerobic organisms.

Asymptomatic gallstones do not require treatment but patients should be informed of possible
complications.

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Elective cholecystectomy is appropriate after acute complications such as cholecystitis or

pancreatitis settle. In some instances endoscopy and/or surgery may be required on a more
urgent basis. When gallstones are symptomatic and require surgical intervention,
cholecystectomy should be done via the laparoscopic route, following preoperative transfusion,
as this is associated with fewer postoperative complications and a shorter stay in hospital (Al-
Mulhim & Al-Mulhim, 2009; Howard et al., 2013).

Hepatic sequestration

Acute hepatic sequestration refers to liver enlargement caused by intrahepatic trapping of red
cells accompanied by acute anaemia. Patients can present with right hypochondrial pain
accompanied by an enlarging, tense liver (compared to baseline) due to stretching of the liver
capsule. The laboratory features are acute anaemia, reticulocytosis, a mild to moderate
hyperbilirubinaemia and normal transaminases levels. Circulatory collapse is less frequent and
sudden than with splenic sequestration. The management is supportive. Transfusion may be
indicated for symptomatic anaemia. Episodes may be recurrent. There are small numbers of
case reports and no published studies on hepatic sequestration.

Acute intrahepatic cholestasis

Intrahepatic cholestasis is an uncommon but severe form of acute sickle hepatopathy. The
clinical picture consists of severe right upper quadrant pain, acute hepatomegaly, coagulopathy,
extreme hyperbilirubinaemia (mainly conjugated) but moderately elevated liver enzymes. Some
patients progress to acute hepatic failure. The pathophysiology is due to intrasinusoidal sickling
leading to vascular stasis causing hypoxic injury and swelling of hepatocytes which leads to
intracanalicular cholestasis. Assessment should include exclusion of other causes of liver
dysfunction and imaging of the biliary tract by ultrasound and/or MRCP to look for other causes
of cholestasis. Liver biopsy is relatively contraindicated due to the risk of bleeding and other
complications. Supportive management should include hydration, adequate pain relief and
treatment of co-existent infection.

There are no randomised trials to assess interventions for patients with intrahepatic cholestasis
but there is a suggestion that early exchange transfusion can improve outcomes and reduce
mortality (Ahn et al., 2005; Brunetta et al., 2011; Gardner et al., 2014; Sheehy et al., 1980).

Chronic sickle hepatopathy

Chronic sickle hepatopathy includes a spectrum of presentations, with varying degrees of

severity: some patients manifest with modest derangements in liver function and hepatomegaly
but a subset will develop progressive liver disease and cirrhosis. These patients may progress
over months to years towards end stage liver disease. Recurrent episodes of
extreme conjugated hyperbilirubinaemia are sometimes a prognostic feature. The natural
history of liver disease and predictive factors for those who will develop end stage liver disease

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are poorly characterised. A variety of pathologies are described including biliary type cirrhosis
and sclerosing cholangitis.

For those with sickle-related liver disease, referral to a specialist centre with expertise in sickle
hepatopathy is appropriate. Hepatic dysfunction is not an indication for starting
hydroxycarbamide therapy.

In patients with chronically progressive liver disease, there are case reports supporting the use
of an exchange red cell transfusion programme (Altintaş et al., 2003; Blinder et al., 2013;
Gardner et al., 2014; O'Callaghan et al., 1995).

Cholestasis in the non-SCD setting has been treated successfully with the bile salt
ursodeoxycholic acid for over 20 years (Cotting et al., 1990) but its efficacy has not been
assessed in the context of SCD. However, it seems a reasonable inference to use ursodeoxycholic
acid in SCD patients with chronic cholestasis.

Viral hepatitis

Hepatitis B and C infection may arise due to transfusion therapy, although the incidence is low.
The course of acute hepatitis is similar to the general population. The indications for treatment
of chronic viral hepatitis should be similar to other patient groups. Viral hepatitis should be
managed by hepatologists. The majority of patients are now treated with highly effective and
well tolerated anti-viral therapy. Careful monitoring of the haemoglobin concentration is
recommended when ribavirin is used, as it causes haemolytic anaemia.

It is also possible to transmit Hepatitis E through transfusion or through contact with

contaminated food products. Blood products are now screened for Hepatitis E in the UK, but
there is a small persistent risk of transmission.

Iron overload

Iron overload can contribute secondary insult to the liver in patients with hepatic dysfunction.
In these patients, particular attention must be paid to iron overload monitoring and
management. Iron overload should be treated with iron chelation and therapy should be
considered appropriate when liver iron concentration exceeds 5-7 mg Fe/g dry weight (DW).

Liver transplantation

There are very limited data on the use of liver transplantation for end stage liver disease due to
sickle hepatopathy. Initial transplantation results were poor, but experience is slowly accruing,
with at least 22 cases reported in the literature (Gardner et al., 2014). Results are improving as
a result of better patient selection and perioperative management of sickle cell disease. The role
of transplantation has yet to be fully defined but it can be considered in patients who have no
significant end organ damage aside from the liver which could increase their perioperative risk.

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Recommendations
 Patients with sickle-related liver disease should be managed by a multi-disciplinary
team including haematologists and specialist hepatologists.
 Patients with liver dysfunction should be investigated for other causes of liver disease
including autoantibody screen, viral hepatitis serology and hepatobiliary imaging.
 The investigation and management of patients with acute complications of gallstones
should follow general treatment guidelines for these conditions.
 Patients with progressive liver disease should be considered for exchange transfusion
programmes under the supervision of a specialist sickle/liver service.
 Patients with chronic cholestasis may be treated with ursodeoxycholic acid.
 Liver transplantation in SCD should be considered in highly selected patients, and in
specialist centres with dual expertise in sickle cell disease and hepatology.

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Chapter 13: Ophthalmological complications
“I have sickle cell retinopathy, it would be good to see someone in the same hospital instead of
going somewhere else because when that happens there is often communication breakdown and I
suffer for it."

“I started to get blurred vision. It was sickle retinopathy. I advise others not to wait until their next
consultant appointment before going to an eye specialist or A&E.”

Introduction
The most important ophthalmic complication of sickle cell disease (SCD) is sickle retinopathy,
which can cause significant visual impairment. Patients with sickle cell/haemoglobin C
compound heterozygosity have a higher risk of sickle retinopathy than patients with sickle cell
anaemia.

Standards
 All patients with SCD should be informed about the risk of ophthalmic complications
and asked about visual symptoms at their annual review.
 All patients with SCD should have baseline retinopathy screening.
 Patients should be educated about acute symptoms (including trauma) and how to
access help.
 Patients with visual symptoms should be referred for ophthalmic review.
 Patients with a history of retinopathy should have regular ophthalmic review.
 Laser photocoagulation therapy should be considered for patients with proliferative
sickle retinopathy.

Background evidence
Sickle retinopathy is the most common ophthalmic complication of SCD and is classified into
non-proliferative and proliferative forms. It is an occlusive vascular condition, with a
predilection for the peripheral retinal vasculature, leading to retinal ischaemia and infarction.
The pathophysiology involves mechanical obstruction of retinal capillaries by sickled
erythrocytes, though direct endothelial damage may also occur (Elagouz et al., 2010).

Non-proliferative sickle retinopathy (NPSR) does not normally lead to visual loss unless the
vaso-occlusive process involves the macula, which can be detected on OCT scanning (‘foveal
splaying’) or on angiography (fluorescein or OCT angiography) with evidence of macular
ischaemia and loss of the capillary bed. Other NPSR features include salmon patch
haemorrhages (pinkish-red superficial retinal haemorrhages), which resolve to leave iridescent

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spots (intraretinal deposits of haemosiderin) or black sunbursts (patches of retinal pigment

epithelial hyperplasia).

Retinal venous tortuosity is a common finding, caused by peripheral arteriovenous shunting.

Retinal arteriolar occlusion may occur, typically involving the peripheral retina if the major
branches are involved and can cause acute loss of vision. Other findings in NPSR include dark,
dilated capillaries on the optic disc and angioid streaks. These, however, rarely cause visual
problems.

The chronic peripheral retinal ischaemia leads to the release of angiogenic factors (such as
VEGF) and subsequent development of neovascular fronds at the border of perfused and non-
perfused retina. Proliferative sickle retinopathy (PSR) is characterised by the development of
peripheral retinal neovascularisation (termed ‘sea fans’). PSR is the more severe form of sickle
retinopathy due to the risk of visual loss from vitreous haemorrhage and/or retinal detachment
(Moriarty et al., 1988).

The incidence and severity of PSR is greater in sickle cell/haemoglobin C disease than in sickle
cell anaemia. The peak prevalence is around 20 - 35 years, with PSR developing earlier in sickle
cell/haemoglobin C disease than sickle cell anaemia (Elagouz et al., 2010). In one natural history
study, PSR had developed in 14% per cent of sickle cell anaemia subjects and 43% of sickle
cell/haemoglobin C subjects by their mid-twenties (Downes et al., 2005). Spontaneous
regression of PSR occurred in 32% of affected eyes. Visual loss was more common in patients
with a history of vitreous haemorrhage or visual loss in the contra-lateral eye.

The ophthalmic complications of SCD are generally asymptomatic in the early stages. PSR
usually develops insidiously with no symptoms until vitreous haemorrhage or retinal
detachment occurs. This leads to visual loss which can be treated by vitreoretinal surgery with
restoration of useful vision in selected cases (Williamson et al., 2008). Surgery can be
challenging due to the presence of peripheral vitreoretinal pathology.

PSR, and the subsequent risk of visual loss, therefore remain undetected until visual symptoms
occur or an eye examination is performed by an optometrist or ophthalmologist. The question
arises whether patients should have regular ophthalmic screening to identify those at risk of
visual loss, but screening is only of value if there is an effective intervention that would prevent
visual loss.

Laser photocoagulation therapy has been suggested as treatment for PSR, involving ablation of
peripheral ischaemic retina leading to regression of retinal neovascularisation (Farber et al.,
1991) aiming to prevent visual loss due to vitreous haemorrhage and/or retinal detachment.
This trial indicated that laser treatment did prevent the occurrence of vitreous haemorrhage but
there was no difference in the incidence of retinal detachment, complete regression of PSR or
development of new PSR between eyes treated with laser photocoagulation therapy and those
not treated.

Despite limited evidence regarding the benefit of this intervention, a recent systematic review

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concluded that laser photocoagulation therapy for eyes with PSR may prevent visual loss and
vitreous haemorrhage and should be considered as a therapeutic intervention for patients with
PSR (Myint et al., 2015). There is insufficient evidence to suggest that laser photocoagulation
therapy will prevent the development of new proliferative lesions. No intervention is required
for small, asymptomatic neovascular fronds but some centres would consider treatment for
large elevated sea fans, rapid growth of retinal neovascularisation, or vitreous haemorrhage,
although outcomes without treatment are unclear.

The role and frequency of regular ophthalmic screening is therefore uncertain (Myint et al.,
2015) and there may be a benefit of targeted screening for those patients who are most likely to
develop visual loss (sickle cell/haemoglobin C disease and patients with previous episodes of
visual loss or vitreous haemorrhage). One pragmatic approach is that all patients should have a
baseline review, with repeat screening at two-three years if they have no evidence of
retinopathy and remain asymptomatic, although there is limited evidence of benefit from this
approach. Patients with evidence of retinopathy should have more frequent review, at least
annually but more frequent if severity and extent of changes suggest this is necessary. All
patients with SCD should, however, be informed about the risk of ophthalmic complications and
asked to report visual symptoms. Patients presenting with acute visual symptoms must be
referred on an urgent basis to an ophthalmologist with expertise in the management of sickle
retinopathy.

SCD can also affect the anterior segment of the eye. Anterior segment involvement includes
conjunctival vascular lesions (corkscrew and comma-shaped vessels), sectoral iris atrophy and
pupillary abnormalities. Hyphaema following trauma is a sight-threatening emergency in
patients with SCD because sickled erythrocytes can clog the trabecular meshwork leading to
elevated intraocular pressure with the risk of optic nerve damage.

Central and peripheral retinal arterial occlusion have been reported with a possible
improvement of symptoms with exchange transfusion.

Another potential cause of visual loss in SCD is drug-induced retinopathy due to iron chelating
agents (such as desferrioxamine). Patients with SCD requiring iron chelating agents because of
repeated blood transfusions should be monitored for visual problems, particularly since early
detection of retinal toxicity may prevent long-term visual sequelae (Haimovici et al., 2002).
There are no studies to guide the frequency of review.

Recommendations
 Patients with SCD should be treated by ophthalmologists with sub-specialty expertise in
retinal disorders and SCD.
 Patients on desferrioxamine or deferasirox should also be monitored for visual
problems due to the development of drug-induced retinopathy.
 The role of routine ophthalmic screening in asymptomatic patients is not clear but could
be considered in patients with sickle cell/haemoglobin C disease.

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 Chapter 14: Anaemia
Introduction
Patients with sickle cell disease (SCD) have a variable degree of anaemia due to ongoing
intravascular and extravascular haemolysis. In the steady state, individuals with sickle cell
anaemia and sickle cell/β0 thalassaemia will usually have a haemoglobin concentration (Hb) of
60-90 g/l and those with sickle cell/haemoglobin C disease and sickle cell/β+ thalassaemia will
usually have a higher Hb. A patient’s baseline Hb should be determined by successive values in
the steady state. Traditionally patients with SCD have been thought to tolerate significant
anaemia and have not been offered treatment for stable chronic anaemia. Fatigue is increasingly
being described as a significant symptom for patients with SCD and may be associated with
chronic anaemia, even if this is stable. Furthermore, patients may tolerate their anaemia for
many years but with increasing age and co-morbidities (e.g. cardiac or respiratory disease) may
develop symptomatic anaemia despite a stable Hb.

A rapid, significant fall in Hb, usually of at least 20 g/l, may result in the individual becoming
symptomatic and major reductions may lead to cardiovascular compromise. Acute anaemia in
SCD may be due to an increase in haemolysis, e.g. due to a transfusion reaction, infection or
glucose-6-phosphate dehydrogenase (G6PD) deficiency, reduction in erythropoiesis, blood loss
and sequestration, in the spleen and less commonly in the liver.

Standards
 Any patient presenting acutely unwell should have a full blood count and reticulocyte
count performed to assess for acute anaemia.
 A diagnosis of parvovirus infection should be considered in patients with anaemia and
reticulocytopenia.
 Clinical examination of a patient presenting with acute anaemia should include an
assessment of spleen and liver size.
 Simple (‘top-up’) transfusion, aiming for the patient’s baseline Hb, may be necessary for
patients with acute anaemia. The threshold level for transfusion will depend on the
clinical state of the patient.
 Patients with progressive anaemia should be evaluated for both sickle-related
aetiologies (most importantly renal impairment) and non-sickle related pathologies.

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Background evidence

Transient red cell aplasia

Transient red cell aplasia (TRCA) in SCD is most commonly due to human parvovirus B19
infection, which causes an arrest in erythropoietic maturation. This results in anaemia, which
can be severe, accompanied by reticulocytopenia. Associated symptoms may include fever,
headache, myalgia, arthralgia and respiratory and gastrointestinal symptoms. Other
complications include acute chest syndrome, acute splenic sequestration, acute hepatic
sequestration, kidney injury, neutropenia, thrombocytopenia and neurological complications
(Smith-Whitley et al., 2003).

Parvovirus B19 infection is usually self-limiting, with the cessation of red cell production lasting
on average four to eight days. Diagnosis is confirmed by the presence of immunoglobulin (Ig)M
to parvovirus B19 or the presence of parvovirus DNA. Immunity conferred following infection is
considered to be life-long.

Blood transfusion is indicated for severe anaemia, particularly for patients who are
symptomatic or show signs of imminent or established cardiovascular compromise. Non-
immune close contacts of these patients may develop red cell aplasia and should be monitored.
In hospital, isolation facilities should be utilised particularly as a precaution for pregnant staff,
as infection may result in hydrops fetalis, foetal death or congenital anaemia.

Splenic sequestration

Acute splenic sequestration occurs when large numbers of red cells are trapped in the spleen.
This results in splenomegaly and profound anaemia. This can develop rapidly, usually within
hours. Though more common in children, it is occasionally seen in adults in whom
autoinfarction has not occurred, usually in the milder forms of SCD (sickle cell/haemoglobin C
disease, sickle cell/β+ thalassaemia) (Asnani et al., 2013). In contrast to TRCA, the acute
anaemia is accompanied by reticulocytosis, circulating nucleated red blood cells (NRBCs) and
thrombocytopenia due to trapping of red cells and platelets in the spleen.

The management of acute splenic sequestration is fluid resuscitation followed by cautious red
cell transfusion to the patient’s baseline Hb. Overzealous transfusion may result in
hyperviscosity from too high an Hb as the sequestered red cells gradually return to the
circulation. Recurrent episodes of acute splenic sequestration may warrant splenectomy.

Other causes of acute anaemia

A mild fall in haemoglobin may occur in an uncomplicated vaso-occlusive crisis. Acute
haemolysis may be due to transfusion reactions, infections and G6PD deficiency. Patients with

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SCD may develop anaemia due to any of the causes seen in the general population including iron
deficiency which may be due to use of non-steroidal anti-inflammatory drugs. Megaloblastic
anaemia due to excessive nitrous oxide use has been described.

Chronic anaemia

Patients with SCD may develop gradually progressive anaemia. This should be fully
investigated. Important causes of anaemia to consider are renal impairment, haematinic
deficiency, hypersplenism (patients with genotypes other than sickle cell anaemia) and chronic
infection or inflammation. Non-sickle aetiologies (primary haematological disorders, bleeding)
should also be considered.

A progressive anaemia may be seen with increasing age and older patients with SCD have been
demonstrated to have lower Hbs, absolute reticulocyte count and indirect bilirubin levels when
compared to their younger peers (McKerrell et al., 2004). Possible explanations for the fall in Hb
are reduced haemopoiesis as the platelet count has also been shown to be reduced in older
patients. Deteriorating renal function, which is common with increasing age, is also an
important cause of progressive anaemia, and a decrease in Hb has been correlated with
worsening creatinine clearance in older patients. This may be in part due to decreased
erythropoietic drive as serum erythropoietin levels are lower than expected for the degree of
anaemia in patients with SCD and decrease further as the renal function deteriorates (Ataga &
Orringer, 2000).

For patients with significant fatigue or other symptoms of anaemia, intervention may be
appropriate. Hydroxycarbamide has been shown to significantly increase Hb (Charache et al.,
1995; Keikhaei et al., 2016; Wong et al., 2014), and reduces transfusion requirements in some
instances (see Chapter 20 - Hydroxycarbamide). Erythropoietic stimulating agents (ESAs) may
be appropriate in patients with decreased creatinine clearance. Occasionally intermittent
simple transfusion may be required to treat symptomatic anaemia, although this carries the
attendant risk of iron overload.

Recommendation
 Baseline haemoglobin (Hb) should be included in clinic letters (or annual review) to GPs
to enable them to diagnose worsening anaemia.

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 Chapter 15: Leg ulceration
Introduction
Leg ulceration is a frequent and disabling complication of sickle cell disease (SCD). Once they
occur they may persist for months or years and are associated with severe chronic pain;
recurrence is frequent. There is little evidence about best management but a multidisciplinary
approach is necessary and treatment may include both local wound care and systemic
treatments.

Standards
 Annual review should include questioning about leg ulceration and inspection of the
lower extremities for active or healed leg ulcers.
 Patients with leg ulceration should be treated by a multidisciplinary team which
includes wound care experts.
 Patients with sickle-related leg ulcers should be assessed for venous insufficiency with
venous reflux studies.
 Multi-component compression bandaging should be offered, particularly in patients
with evidence of venous insufficiency.
 Zinc levels should be measured in patients with leg ulcers and supplements should be
offered to those with deficiency.

Background information
The frequency of leg ulceration shows marked variation in different populations with quoted
incidences varying from 75% in Jamaica to 25% in United States and close to zero in Saudi
Arabia (Alsultan et al., 2012; Koshy et al., 1989; Serjeant, 1974). Leg ulceration is less common
below 20 years of age and is more frequent in males and in sickle cell anaemia (Alavi & Kirsner,
2015; Koshy et al., 1989; Minniti et al., 2010). They most commonly occur on the ankles and
may occur secondary to trauma or insect bites. They are prolonged in duration, may take
several years to heal and are often recurrent. Even after healing they may be associated with
local discolouration and scarring.

The pathophysiology of leg ulceration is not fully understood but they are more common in
patients with higher levels of haemolysis. In addition, mechanical obstruction, high blood
viscosity, venous incompetence, hypercoagulability and thrombosis may also play a role in the
development of ulcers (Bartolucci et al., 2012; Connes et al., 2013). These factors place patients
at higher risk of developing ischaemia and once tissue damage occurs the cycle repeats leading
to further tissue damage with fluid retention and inflammation encouraging ulcer formation
and limiting healing.

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Treatment
Once diagnosed, treatment of leg ulcers should be multidisciplinary and should include
haematologists, dermatologists, vascular/plastic surgeons, and wound care teams. Specialist
pain team input may be required as leg ulcers can be extremely painful and psychology support
is often helpful.

Topical treatments and wound care

Wound care is an important element of ulcer care (Minniti & Kato, 2016). Effective debridement
is important to remove non-viable tissue and to encourage healing. A moist wound surface
should be encouraged and whilst randomised controlled trials (RCTs) have not shown a benefit
of particular dressings a simple moist wound-healing approach does seem to be as effective as
advanced medical and surgical treatments.

Guidelines for the treatment of non-SCD related venous ulceration recommend compression
therapy to increase venous leg ulcer healing and to decrease the risk of ulcer recurrence. The
use of multi-component compression bandages is also recommended in preference to the use of
single component bandaging (O’Donnell et al., 2014); in the absence of sickle-specific advice,
these recommendations should be used for treatment of SCD ulcers particularly where venous
disease is present.

Infection should be identified and treated early. In patients with deep ulcers or ulcers
associated with bony pain or systemic evidence of infection, osteomyelitis should be considered
and magnetic resonance imaging (MRI) performed.

The 2014 Cochrane Review reported six randomised controlled trials of topical treatments but
reported that only one trial achieved noticeable benefit (Martí-Carvajal et al., 2014). This trial
used an arginine-glycine-aspartic acid matrix (RGD peptide matrix) and found a decrease in
ulcer surface area, but the Cochrane review noted a high risk of bias in this study and
recommended further trials. Case reports and phase 1 studies of topical sodium nitrate,
granulocyte-macrophage colony-stimulating factors, a bi-layered epidermis/dermis construct, a
collagen matrix, an autologous platelet gel and a synthetic bioengineered heparan sulphate
solution have all suggested benefit, but need further systematic study (Altman 2015). Case
reports of energy-based modalities (low frequency ultrasound or low level laser therapy) have
been published, but again these need confirmatory study.

Systemic treatments

Zinc supplementation is used in patients with chronic wounds who have zinc deficiency. There
is only one small study of oral zinc supplementation in SCD ulcers; this was suggestive of benefit
but did not provide statistical analysis of results (Serjeant et al., 1970). Despite the lack of
evidence it may be appropriate to measure zinc levels in patients with leg ulcers and consider
zinc replacement in deficient individuals.

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Pentoxifylline improves red cell and white cell deformability, inhibits platelet aggregation and
thrombus formation and improves microcirculation flow. It has been used extensively in the
treatment of venous leg ulcers and is recommended for long-standing or large venous leg ulcers.
There is only a case report of its use in SCD, but it has been suggested that pentoxifylline could
be used as an adjunct in SCD patients where there is venous insufficiency (Altman et al., 2016).
Other systemic therapies that have been used in the treatment of SCD ulcers include L-carnitine,
arginine butyrate and bosentan, but none have conclusive evidence of efficacy.

Hydroxycarbamide is commonly used for treatment of SCD (see Chapter 20 -

Hydroxycarbamide), but its role in leg ulcers is not clear. Hydroxycarbamide has been shown to
be associated with leg ulceration in patients with myeloproliferative neoplasms, but this
association has not been seen in multicentre studies in SCD. There is insufficient evidence to
interrupt hydroxycarbamide treatment in patients with SCD and leg ulceration.

There are no RCTs investigating the role of blood transfusion in the treatment of SCD ulcers.
Case reports have reported efficacy of simple transfusion, aiming to increase Hb and improve
oxygen delivery, and of exchange transfusion which will also decrease haemoglobin S
percentage. The lack of evidence and complications associated with blood transfusion means it
is difficult to recommend routine transfusion in patients with leg ulcers, or to recommend a
particular modality of transfusion. However a trial of transfusion may be appropriate in a
patient with intractable leg ulcers, particularly if they are significantly anaemic.

Surgical treatments

Surgical treatments of leg ulceration in SCD include microsurgical free flap transfers and skin
grafting but have been associated with high rates of failure and ulcer recurrence. Surgical
intervention may be appropriate for some intractable ulcers. However further investigation is
needed before a surgical approach can be recommended as part of routine care.

Other treatments

Bed rest is often recommended but is generally impractical. It may work by reducing ankle
oedema and venous pressure.

Sickle leg ulcers are usually associated with severe pain and adequate pain relief should be
prescribed; this may require the involvement of chronic pain teams. Regional nerve blocks may
be of benefit.

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Prevention
Patient education is a vital part of ulcer management and advice should include:

 Eating a nutritious and well balanced diet;

 Avoiding injury, especially to your feet, ankles and legs;
 Avoiding dry skin by using local moisturisers;
 Wearing socks and well-fitting shoes;
 Using insect repellents and protection against insect bites;
 Treating minor trauma around the ankles quickly;
 Avoiding blood tests or intravenous line insertion in the lower limbs; and
 Considering wearing compression stockings to reduce oedema.

Recommendations
 Education about the prevention and management of leg ulcers should be offered to all
patients with SCD.
 Patients with SCD-related leg ulcers should be offered appropriate analgesia and may
require support from a specialist pain team.
 Hydroxycarbamide should not be withheld from patient with leg ulceration.
 A trial of blood transfusion therapy should be considered in patients with intractable leg
ulcers.

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Acute multisystem organ failure

Multisystem organ failure (MSOF) is a clinical syndrome of severe life threatening acquired
physiological dysfunction in at least two organs usually associated with a vaso-occlusive crisis
and/or sepsis. The complications that most commonly occur are failure of the lungs, liver
and/or kidneys (Hassell et al., 1994; Hiran, 2005).

Standards
 Patients with MSOF should be transferred to the intensive care setting for supportive
therapy.
 Patients with MSOF should be transfused early as this can reduce further organ damage
and improve survival.

Background evidence
MSOF may occur after several days of hospitalisation and treatment for an unusually severe
vaso-occlusive crisis. Some cases result from fat embolism syndrome. In most cases, patients do
not have a prior history of chronic organ failure. Clinical deterioration is rapid with the onset of
fever, a fall in haemoglobin concentration (Hb) and platelet count, and respiratory distress.
Acute respiratory failure is usually associated with development of acute chest syndrome (ACS).
Hepatic failure is associated with marked elevations in total and direct bilirubin and
transaminases, and deranged coagulation. Acute renal failure is associated with a rapid
elevation of serum creatinine, with or without the presence of oliguria and hyperkalaemia.
Rapid diagnosis and treatment of MSOF is necessary to prevent death and will involve early
transfer to an Intensive Care Unit for consideration of haemofiltration and ventilation and other
organ support.

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 Section C: Treatment and additional
management issues

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“I get a quarterly outpatient appointment with my haematologist and have had this for most of my
adult life. We discuss any changes or issues with my sickle”

Introduction
The aims of outpatient management of adults with sickle cell disease (SCD) are to promote
health maintenance and to recognise and manage emerging disease complications in a
multidisciplinary setting. Patients and their families should be fully informed about the sickle
condition, kept up to date about changes to their therapy and be made aware of new and
evolving therapy options including clinical trials.

Standards
 All adults with SCD should be offered comprehensive review from a specialist centre at
least annually.
 A pro forma should be used for the annual review visit to ensure thorough and
consistent care and to facilitate data collection.
 A written summary of outpatient appointments (including the annual review) should be
shared with the patient, his or her general practitioner and the local hospital team.

Background information
The specialist service specification for haemoglobinopathies (NHS England, 2013) stated that all
patients with sickle cell disease should receive comprehensive assessment by a healthcare
professional with a specialist interest in SCD at least annually either in a specialist centre or as
part of an outreach clinic by a team from a specialist centre.

The aim of this specialist annual review is to improve equity in patient care and ensure access to
specialist investigations, such as magnetic resonance imaging (MRI) for liver and cardiac iron
assessment, and to multidisciplinary specialist and supra-specialist teams.

The annual comprehensive review provided by the specialist haemoglobinopathy team (SHT) or
its delegate should aim to cover all aspects of care including:

 Education around the condition and lifestyle factors that may affect health
 Discussion or confirmation of the personalised analgesia plan for pain crisis and review
of the analgesia plan upon acute presentation to the Accident and Emergency unit
 Review of chronic pain and prescriptions used to treat this

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 Discussion of therapeutic options currently available and new information including

ongoing trials open to the patient
 Review of adherence to drug therapy including such as ACE inhibitors
 Review of immunisation status and prophylaxis against infection
 Review of disease complications encountered over the previous year and previously
 Assessment of any new or ongoing symptoms
 Referral for specific investigations e.g. MRI hip and specialist clinics (ideally joint clinics
where possible) if appropriate (e.g. orthopaedic, respiratory and renal)
 Assessment of emotional and psychosocial well-being with referral onto to psychology
teams if required
 Ensuring patient has a named contact within the service
 Discuss/consent for National Haemoglobinopathy Registry (NHR)
 Discussion about contraception, fertility, pregnancy and (where appropriate) genetic
information (see Chapter 18 - Reproductive health)
 Documentation of clinical observations including oxygen saturations and clinical
examination

It should also include review of appropriate screening investigations (echocardiography,

respiratory investigations, ophthalmology review, renal function and proteinuria, liver
function).

A suggested pro forma for the annual review is outlined in Appendix 4: Annual review pro-forma.

In addition to the annual review, routine or steady state reviews should be provided local to the
patient’s home. This may be at a local trust, or may be with the SHT if this is the patient’s
nearest hospital. These reviews will aim to review clinical progress and manage issues arising
since the previous review. This visit should include discussion of acute pain episodes and
hospital admissions since the previous appointment and discussion of other sickle-related
complications and other medical issues. Medications and immunisation history should be
reviewed, examination findings (including vital signs) and investigations (including full blood
count and renal profile) should be documented. The patient’s understanding and adherence to
prescribed therapy should be discussed at each visit and referral on to specialist teams or
clinics including psychology considered as required. The frequency of these reviews will depend
on the severity of the patient’s sickle cell phenotype with some patients likely to require review
as often as two monthly whilst others may only be seen at the annual review.

For patients managed with hydroxycarbamide, additional attention must be given to the efficacy
of the current dose as well as the patient’s adherence to the medication. Patients must be made
aware of the requirement for contraception and any side effects and concerns should be
addressed.

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Patients on long term transfusion programmes should, during their comprehensive annual
review, have additional attention given to ensuring that they understand the rationale for
transfusions and the associated risks. They should also be asked to provide annual consent to
continue transfusions. The rationale for long term transfusion should be reviewed in light of any
new clinical evidence at least annually and transfusion targets should also be reviewed to
ensure they are being met. Patients on regular transfusions must additionally have their iron
status monitored and have their hepatitis B serological status checked annually. It may also be
helpful to review Hepatitis C and HIV status annually. Patients on chelation therapy should have
their current therapy reviewed including adherence and medication efficacy. Investigations for
assessment of iron load must be requested at least annually for iron loaded patients or those
suspected to be developing iron overload.

A written summary with results of relevant investigations, highlighting any changes and making
clear recommendations should be sent to the patient, the general practitioner (GP) and the local
hospital team if the patient has one. This summary should include recent blood results (e.g. full
blood count and renal profile). A suggested letter pro forma is given in Appendix 5.

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Contraception

Introduction
The unmet need for contraception in women with sickle cell disease (SCD) remains high
(O’Brien et al., 2011; Whaley et al., 2015) due in part to confusion among health care providers
about the safety of various options (Haddad et al., 2012; Smith-Whitley, 2014). Evidence based
guidelines on the safety of various contraceptive methods in chronic medical conditions,
including SCD, were consulted in preparation of this chapter (Faculty of Sexual and
Reproductive Healthcare (FSRH), 2016; National Heart Lung and Blood Institute, 2014; National
Institute for Health and Care Excellence (NICE), 2005 updated 2014; World Health Organization
(WHO), 2015).

Standards
 Each woman, man or couple affected by SCD should be encouraged to have a
reproductive life plan.
 All women of childbearing age and all men with SCD should receive contraceptive
counselling to prevent unintended pregnancy at least as part of annual review.

Background evidence
A systematic review of nine studies examining the safety of hormonal and intrauterine
contraceptive use among women with SCD concluded that, although the evidence was of fair to
poor quality, progestogen-only and combined hormonal contraceptive methods did not increase
the frequency or severity of sickle cell crises and were not associated with an increased risk of
adverse clinical events (Haddad et al., 2012). There was a lack of evidence on the risk of venous
thrombo-embolism (VTE) among combined hormonal users with sickle cell disease and on
intrauterine contraceptive device (IUD) use among women with SCD. Another systematic
review of progestogen-only contraceptive use among women with SCD did not identify any
adverse events or clinically or statistically significant adverse changes in haematological or
biochemical parameters associated with use of progestogen-only methods (Legardy & Curtis,
2006). Some studies have suggested that progestogen-only contraceptive users experienced a
decrease in symptoms and less frequent and severe painful crises compared with non-users and
improvement in biochemical & haematological parameters (de Abood et al., 1997; De Ceulaer et
al., 1982) but systematic review of the data found insufficient evidence to recommend
progestogen-only contraception above other contraceptive options (Haddad et al., 2012).

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A Cochrane review on steroid hormones for contraception in women with SCD (Manchikanti
Gomez et al., 2007) reported on one randomised controlled trial (RCT) (De Ceulaer et al., 1982)
which compared use of three monthly depot medroxyprogesterone acetate (DMPA) versus
intramuscular saline placebo in 25 patients in a crossover study design with a six month wash
out period. During DMPA use, there was a non-significant trend towards reduced painful sickle
episodes (OR 0.23; 95% CI 0.05 to 1.02), however, because of the short crossover period results
may be biased.

Contraception choices and effectiveness of contraceptive methods

A wide range of contraceptive methods is available with varying effectiveness, particularly for
the methods that require consistent and correct use (Figure 6).

The following table compares the percentage of women experiencing an unintended pregnancy
during the first year of contraceptive use when the method is used “typically” (which includes
both incorrect and inconsistent use) or “perfectly” (correct and consistent use). Methods
considered as long-acting reversible contraception (LARC) are highlighted in Figure 6. Use of
LARC methods such as injectables, implants and intrauterine devices are more effective in
preventing pregnancies than user-dependant methods such as oral contraceptive pills (NICE
guideline, 2005).

[Figure 6 shown overleaf]

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Figure 6: Percentage of women experiencing an unintended pregnancy within the first year of use
with typical use and perfect use (Faculty of Sexual and Reproductive Healthcare (FSRH), 2016).
Modified from (Trussell, 2011).

Method Typical use (%) Perfect use (%)

No method 85 85

Fertility awareness-based methods 24 0.4-5

Female diaphragm 12 6

Male condom 18 2

Combined hormonal contraception

(includes combined oral contraception, 9 0.3
transdermal patch and vaginal rings)

Progestogen-only pill 9 0.3

Progestogen-only injectable (DMPA) 6 0.2

Copper-bearing intrauterine device 0.8 0.6

Levonorgestrel-releasing intrauterine
0.2 0.2
system

Progestogen-only implant 0.05 0.05

Female sterilisation 0.5 0.5

Vasectomy 0.15 0.1

From UKMEC 2016. https://www.fsrh.org/ukmec/ (Faculty of Sexual and Reproductive Healthcare (FSRH),
2016). Reproduced under licence from FSRH. Copyright © Faculty of Sexual and Reproductive Healthcare
2006 to 2016.

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Patient information on contraception can be found on the Family Planning Association website
(www.fpa.org.uk ).

The UK Medical Eligibility Criteria for contraceptive use (UKMEC) (Faculty of Sexual and
Reproductive Healthcare (FSRH), 2016) adapted from WHO guidelines (WHOMEC) (World
Health Organization (WHO), 2015) offers guidance to providers of contraception for individuals
in the UK with certain health conditions or characteristics. The UKMEC has provided guidance
on the use of following types of contraceptive methods in women with SCD:

Progestogen-only contraception is classified as UKMEC 1, meaning these agents can be used

without restrictions. Progestogen-only contraception includes the following methods:

 Progestogen-only subdermal implant (single-rod implant containing 68 mg etonogestrel

licensed for 3 years of use in the UK)
 Progestogen-only injectable: depot medroxyprogesterone acetate (DMPA) (given
intramuscularly or subcutaneously at 13 week intervals)
 Progestogen (levonorgestrel)-releasing intrauterine system (LNG-IUS) (licensed for 3 or
5 years of use)
 Progestogen-only pills (POP) (containing norethisterone 350 µg, levonorgestrel 30 µg or
desogestrel 75 µg, currently available in the UK). Theoretically, the desogestrel pill may
be expected to be more effective than norethisterone or levonorgestrel POP, especially
with typical use, because ovulation is suppressed more consistently and it has a longer
missed-pill window.

Progestogen-only contraceptives are a good choice in women with SCD due to a lower risk of
thromboembolism compared to combined hormonal contraception (CHC) and possible
reduction in acute painful events (Smith-Whitley, 2014). Unpredictable vaginal bleeding is a
known side-effect which can affect user-acceptability.

Combined hormonal contraceptives are classified as UKMEC 2, meaning that “the advantages
of using the method generally outweigh the theoretical or proven risks”.

Combined Hormonal Contraception includes the following methods:

 Combined oral contraception

 Combined contraception transdermal patches
 Combined contraception vaginal rings

The recommendations in the UKMEC refer to low-dose combined oral contraception (COC)
containing ≤ 35 µg ethinylestradiol combined with progestogen. Recommendations are the
same for all COC formulations, irrespective of their progestogen content. Recommendations for
COC are also applicable to the combined contraceptive patch and ring.

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Combined hormonal contraceptive users have additional benefits of predictable bleeding

pattern with reduced menstrual flow and pain.

There is an increased risk of venous thromboembolism (VTE) in users of CHC with an increased
relative risk of about 2 compared with non-users, translating to a low absolute risk of about 9-
10 events per 10,000 users per year (Reid et al., 2010). Studies have found differences in risk of
VTE associated with COC containing different progestogens with evidence suggesting that COC
with levonorgestrel, norethisterone and norgestimate are associated with lowest risk (Faculty
of Sexual and Reproductive Healthcare (FSRH), 2014). Individuals with SCD have been shown to
have a chronically activated coagulation system and have an increase in risk of VTE compared
with healthy controls; however, the exact risk is unclear (Haddad et al., 2012). Given the
increased risk for VTE among healthy individuals on combined hormonal contraceptives and
the potential for increased VTE with SCD, there is a theoretical concern that the interaction will
lead to further increased risk for VTE for SCD patients who use CHC (Haddad et al., 2012). The
systematic review by Haddad et al. did not identify any studies that specifically examined the
risk of arterial and venous thromboembolism in CHC users with SCD which represents a major
gap in literature.

When assessing safety of combined hormonal contraception in women with SCD, any co-
existing medical conditions which may contra-indicate use of the method must be taken into
consideration; For example, history of stroke is a contraindication to combined hormonal
contraception (National Heart Lung and Blood Institute, 2014).

The copper intrauterine device (Cu-IUD) is classified as UKMEC 2, meaning that “the
advantages of using the method generally outweigh the theoretical or proven risks”. Only one
small cross-sectional study has been reported examining the use of IUDs among women with
SCD. This did not report any serious adverse events but nor did it provide any comparative
statistics to a non-IUD group or to a non-sickle cell group. There is, therefore, insufficient
evidence to comment on the safety of this method for this population (Howard et al., 1993).
However, theoretical concerns about IUD use in this population are few, and there is no current
evidence to support limiting IUD use among women with SCD (Haddad et al., 2012).

There is concern about an increased risk of menstrual blood loss with Cu-IUD and an
intrauterine system (IUS) which is generally associated with reduced blood loss may be
preferable in women with SCD.

Emergency contraception. Advice to women with SCD about emergency contraception (EC)
options as a means of preventing unintended pregnancy following any unprotected sexual
intercourse (UPSI) should not differ to advice given to the general population. Methods of
emergency contraception currently include the Cu-IUD (the most effective form of EC, for use
between 0 and 120 hours of UPSI or within 5 days of expected ovulation), and two methods of
oral EC – ulipristal acetate 30 mg (licensed for use within 120 hours of UPSI) and levonorgestrel
1.5 mg (licensed for use up to 72 hours after UPSI).

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Recommendations
 Progestogen-only contraceptives (pills, injections and implants), progestogen-releasing
intrauterine systems and barrier methods have no restrictions for use in women with
SCD.
 The advantages of using low-dose combined hormonal contraceptives (pills, patches and
rings) and intrauterine devices generally outweigh the theoretical or proven risks in
women with SCD.
 Women should be informed that in the general population the risk of venous
thromboembolism with use of combined hormonal contraception is approximately
doubled compared to non-users, but that the absolute risk remains low. There is lack of
evidence on whether this risk increases further due to their sickle cell disease.
 When assessing safety of contraceptive methods in women with SCD, any co-existing
medical conditions that may contra-indicate use of the method must be taken into
consideration.
 Use of long acting reversible contraceptive methods such as injectables, implants and
intrauterine devices are more effective in preventing pregnancies than user-dependant
methods such as oral contraceptive pills and barrier methods.
 Due to the significant health risk during pregnancy in women with SCD, women should
be advised to consider LARC methods, which are highly reliable and effective. The sole
use of barrier methods and user-dependent methods of contraception (e.g. oral
contraception) may not be the most appropriate choice for these women given their
relatively higher typical use failure rates.
 Due to the potential teratogenic effects of hydroxycarbamide, sexually active couples
should use contraception if one person is using hydroxycarbamide. Hydroxycarbamide
should be stopped prior to conception.
 Health care professionals should have access to specialist advice about appropriate
contraception for people with SCD when required.

Pre-conceptual advice

Introduction
The wish to have children is a realistic expectation for adults with SCD and they should be
supported in this. Discussions about conception should, therefore, be part of routine care. Pre-
conceptual advice may be given in an ad hoc fashion in response to patient enquiry but should
also be part of the routine care offered by the general practitioner, community nursing team,
hospital specialist and other health care professionals. This discussion will include advice about
optimisation of health prior to conception, partner screening, folic acid supplementation, pre-
implantation genetic diagnosis (PIGD) and antenatal diagnosis.

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Standards
 Adults of reproductive age with SCD should be counselled about their reproductive
choices as part of their annual review. This should include discussion of partner
screening and medications that may affect conception.
 Adults with SCD who have a partner who is a carrier of a haemoglobin variant that puts
them at risk of a child with sickle cell disease should be given information about pre-
natal or pre-implantation genetic diagnostic options.

Background evidence
Discussion of conception should be embedded into routine care and (as a minimum) should be
part of the annual review from young adulthood onwards. Women who are planning pregnancy
should be reviewed to optimise their underlying SCD prior to conception and to ensure the
chronic complications of SCD are under control. This includes ensuring she is up to date with
immunisations, is offered penicillin (or equivalent) prophylaxis and is taking regular folic acid.
Medications that are contraindicated in pregnancy, such as hydroxycarbamide, angiotensin-
converting enzyme (ACE) inhibitors and chelation therapy, should also be stopped prior to
conception (Byrd et al., 1999; Diav-Citrin et al., 1999). Consideration should also be given to
screening for end organ damage including baseline proteinuria, echocardiography screening for
pulmonary hypertension and ophthalmological review.

Male patients should be advised to stop hydroxycarbamide for at least three months prior to
conception.

All adults with SCD should be encouraged to engage with partner screening before embarking
on pregnancy. If the partner of a patient with sickle cell anaemia is found to be a carrier of a
relevant β globin variant (e.g. haemoglobin S, haemoglobin C) or β thalassaemia there will be
50% chance of the child having a SCD. It is important that anyone who is at risk of having an
affected infant (i.e. partner is a carrier or is affected by haemoglobinopathy) is aware of this and
receives appropriate counselling, which will include discussion of the reproductive options:
non-intervention, pre-natal diagnosis once pregnancy is achieved or pre-implantation genetic
diagnosis. Further information can be accessed at the NHS Sickle Cell and Thalassaemia
screening programme website (www.gov.uk/topic/population-screening-programmes/sickle-
cell-thalassaemia).

Pre-implantation/prenatal diagnosis should be offered to couples at risk of having a foetus

affected by a haemoglobinopathy. Counselling should be given by appropriately trained
professionals and pre-natal diagnosis should be offered as early as possible in pregnancy.
Current Public Health guidance is that patients are booked within 10 weeks of conception to
ensure access to termination of an affected pregnancy if required as soon as practicable, but it is
clear that this is often not offered in a timely fashion. PIGD is a technique designed to help
couples at risk of having a child with a serious genetic condition. It involves using in vitro

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fertilisation (IVF) to create embryos in the laboratory from the eggs/sperm of the couple. Each
embryo is tested for SCD by an embryo biopsy and one or two unaffected (or trait) embryos are
transferred back to the woman. This is a complicated and lengthy technique, requiring
numerous hospital appointments and only approximately 1 in 5 couples who start PIGD
treatment will have a baby. Couples who request this intervention will need to be referred to
one of the few centres that provide this service. Currently the majority of patients
(approximately 75%) will receive funding for their treatment from their Primary Care Trust, the
others self-fund, but this is subject to change due to commissioning and political priorities.
Treatment will currently only be funded by the NHS if the couple do not have a living healthy
child.

Pregnancy

"I am currently pregnant and the care I am receiving is excellent."

“I know a specialist hospital that has a haematologist obstetrician which should be encouraged.
However, with my current pregnancy, I get a multi-disciplinary team with my haematologist,
specialist midwife and obstetrician attend my visit with me”.

Introduction
Pregnant women with SCD are at high risk of complications with an increased risk of maternal
and foetal perinatal mortality and morbidity (Oteng-Ntim et al., 2015a; Oteng-Ntim et al.,
2015b). A Royal College of Obstetricians and Gynaecology (RCOG) green-top guideline is
available to guide management (Royal College of Obstetrics and Gynaecology, 2011).

Standards
 Pregnant women with SCD should be managed by a multidisciplinary team of
obstetricians, midwives and haematologists with an interest in SCD in a unit that
manages high risk pregnancy.
 Units which manage SCD pregnancy should have a clear protocol for patient
management.
 Pregnant women with SCD should be prescribed low-dose aspirin 75 mg once daily from
presentation to reduce the risk of developing pre-eclampsia, providing there is no
contraindication.
 Routine prophylactic transfusion is not recommended during pregnancy for women
with SCD but is indicated in certain situations.

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Background evidence
SCD is associated with a high incidence of foetal and maternal complications (Oteng-Ntim et al.,
2015b) with highest rates found in patients with sickle cell anaemia and in lower income
countries. Maternal complications include increased maternal mortality, increased sickle
complications (acute pain crisis, acute chest syndrome and infection, particularly urinary tract
infection) and increased pregnancy complications (pre-eclampsia, pregnancy-induced
hypertension, thromboembolism and caesarean rate). Rates of hospital admission and
admission to the high dependency unit during pregnancy are higher with women with SCD than
in the general population. Foetal complications include increased rates of miscarriage, still birth
and perinatal mortality and an increased risk of premature labour and foetal growth restriction.
This morbidity is thought to be secondary to an increased tendency towards vascular stasis, a
pro-coagulant state and increased metabolic demand. There are difficulties surrounding trials in
pregnancy, particularly those involving an intervention, and therefore evidence in this area is
limited and mainly observational. The published data are derived predominantly from women
with sickle cell anaemia; whilst such women are more likely to experience complications during
pregnancy, these complications can also affect women with sickle cell/haemoglobin C and other
sickle genotypes. Consequently these recommendations apply to all genotypes.

All women with SCD (regardless of genotype) should be made aware of the potential morbidity
and mortality that are associated with pregnancy, ideally prior to conception (Howard & Oteng-
Ntim, 2012; Oteng-Ntim et al., 2015b).

Antenatal period
Women with SCD should be encouraged to let their haematologist know as soon as they are
pregnant. This will allow early referral to a multidisciplinary high-risk pregnancy team.
Screening for chronic complications and partner screening (if not already on record) should be
completed early and medication history should be reviewed. If women have not undergone a
preconception review they should be advised to take daily folic acid and the need for
prophylactic antibiotics should be reviewed. Drugs that are unsafe in pregnancy (e.g. ACE
inhibitors, iron chelators) should be stopped immediately (Royal College of Obstetrics and
Gynaecology, 2011). Women receiving hydroxycarbamide should have been specifically
counselled not to become pregnant but if a woman does conceive whilst taking it she should be
counselled about possible risks, it should be stopped immediately and she should be offered a
detailed anomaly scan at 20 weeks gestation (see Chapter 20 - Hydroxycarbamide).

Women should be encouraged to attend antenatal and haematology clinics (or joint obstetric-
sickle clinics) regularly. At a minimum, women should be reviewed in clinic monthly to 24
weeks, fortnightly to 34 weeks and weekly thereafter, although some women need more
frequent review. Regular monitoring should include blood pressure monitoring and urinalysis.
Careful monitoring of foetal growth is recommended due to risks of foetal growth restriction. A
viability scan should be offered at 7-9 weeks gestation with a routine first-trimester scan (11-14

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weeks) and a detailed anomaly scan at 20 weeks gestation. Growth scans should be performed
every 4 weeks from 24 weeks of gestation. These enable early detection of foetal growth
restriction and allow appropriate delivery planning (Royal College of Obstetrics and
Gynaecology, 2013).

A VTE assessment should be performed at 12/40 weeks gestation and the assessment should be
repeated throughout pregnancy as per the Green Top Guidelines for reducing the risk of venous
thromboembolism during pregnancy and the puerperium (Royal College of Obstetrics and
Gynaecology, 2015). This document rates women with SCD as intermediate risk for
thromboprophylaxis and recommends that thromboprophylaxis with low molecular weight
heparin (LMWH) is considered from 28 weeks gestation. A number of studies have indicated
that women with SCD have an increased risk of pre-eclampsia and pregnancy-induced
hypertension (Chakravarty et al., 2008; Oteng-Ntim et al., 2015a; Oteng-Ntim et al., 2015b;
Villers et al., 2008) and although there is no specific evidence for the role of aspirin in SCD, it
has been shown to decrease the risk of pre-eclampsia in high risk pregnancies and should be
offered to all women unless there are contra-indications to its use.

The evidence is conflicting regarding transfusion in pregnancy although a decrease of acute pain
crises in women on prophylactic transfusion was shown in a randomised controlled trial (Koshy
et al., 1988). A Cochrane review (Okusanya & Oladapo, 2016) found the data available to be
biased and of low quality. It concluded that there was no clear evidence of benefit of
prophylactic transfusion over selective transfusion (current standard of care). In contrast a
recent meta-analysis (Malinowski et al., 2015) demonstrated an association with prophylactic
transfusion and reduction in maternal mortality and sickle-specific and neonatal complications,
including acute pain crises, pulmonary complications, pyelonephritis, perinatal mortality,
neonatal death and pre-term birth. They concluded however that the evidence resulted from a
small number of studies - many with methodology limitations - and that a randomised trial is
required to fully assess the balance of risks and benefits.

On current evidence prophylactic transfusion is not recommended routinely in pregnant

women with SCD. The need for prophylactic transfusion should be discussed prenatally or in the
antenatal clinic and should be considered in women with twin pregnancies, women with
significant complications during previous or current pregnancy (e.g. acute chest syndrome,
multiple admissions with painful episodes) and in women who are established on long-term
transfusion programmes (Davis et al., 2017a; Royal College of Obstetrics and Gynaecology,
2011). In the acute setting transfusion may be required for the management of anaemia –
consider treatment if the haemoglobin concentration (Hb) is <70 g/l or there is symptomatic
anaemia – or for the treatment of acute complications such as acute chest syndrome. In the
latter situation the woman should be offered ongoing transfusion therapy for the rest of her
pregnancy.

Acute pain is common during pregnancy, occurring in up to 50% of women and therefore
centres should have guidelines to aid management. These usually mirror management outside
pregnancy but non-steroidal anti-inflammatory agents should be avoided before 12 weeks and

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after 28 weeks of gestation. In addition, patients and their carers, as well as medical and nursing
staff should be aware of the presentation of complications of sickle cell disease, including acute
chest syndrome, acute stroke and acute anaemia. A low threshold for admission should be in
place particularly for patients presenting with fever, an acute fall in Hb or lower oxygen
saturations. Patients should be aware of where to present for care during their pregnancy
including out of hours and arrangements should be made for the multidisciplinary team to be
contacted in an emergency. Women with SCD should be advised to receive prophylactic LMWH
during antenatal hospital admissions.

Delivery
Timing and mode of delivery should be guided by obstetric indications and if there are no
contra-indications women should be encouraged to continue to term, anticipating spontaneous
labour and normal vaginal delivery. There appears to be an increase in painful episodes and
acute chest syndrome in the intrapartum period in SCD (Oteng-Ntim et al., 2015a), which
increases if the labour is prolonged. Women in labour and post-delivery should be managed
with input from the specialist haematology team. Sickle cell disease is not a contraindication for
a standard vaginal delivery but continuous foetal heart monitoring is recommended due to an
increased rate of still birth and other complications. Women with SCD should be offered
anaesthetic assessment in the third trimester of pregnancy with regional analgesia being
recommended for caesarean section. Routine transfusion is not recommended prior to
caesarean section but should be considered if Hb is <70g/l or if the Hb falls more than 20 g/l
below baseline.

Post-partum
Pregnant women with SCD should have a clear postnatal care plan to ensure good transition of
care to the haematology and community teams. The increased risk of pain crises continues into
the postnatal period, as does the increased risk of VTE. Women should be aware of these risks
and appropriate post-partum thromboprophylaxis should be given as per ‘Green top’ Guideline
no. 37a (Royal College of Obstetrics and Gynaecology, 2015). This document rates women with
SCD as intermediate risk and recommends that they all receive 10 days post-partum
thromboprophylaxis with LMWH. In addition, it recommends that any woman who received
antenatal LMWH should receive six weeks of post-partum thromboprophylaxis. As most women
will receive antenatal thromboprophylaxis from 28 weeks gestation, they will also receive six
weeks post-partum treatment. There is no contra-indication to breastfeeding and this should be
encouraged. Women who were taking hydroxycarbamide prior to conception should not
recommence this until they stop breastfeeding.

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 Chapter 19: Surgery
Introduction
Many people with sickle cell disease (SCD) undergo surgical procedures. There are
perioperative risks associated with SCD, such as acute chest syndrome and acute painful crisis.
It is therefore important that these episodes are managed optimally. Recent national guidance
on the use of transfusion on SCD should improve practice in this area and the relevant
standards are based on that guidance (Davis et al., 2017a).

Standards
 All hospitals should have a protocol in place for preoperative screening for SCD.
 All hospitals should have a protocol in place for the perioperative management of
patients with SCD, which will include recommendations for oxygenation, hydration,
warmth and surgical and anaesthetic techniques.
 Preoperative transfusion (simple transfusion to Hb 100 g/l if Hb <90 g/l or partial
exchange if Hb >90g/l) is recommended for patients with SCA undergoing low and
medium risk surgery.
 Exchange transfusion is recommended for all patients with SCD undergoing high risk
surgery.
 Preoperative transfusion should be considered for patients with non-SCA genotypes
undergoing low and moderate risk surgery taking into account previous history and
complexity of surgery.

Background evidence
Because of the risk of perioperative and post-operative complications, patients with SCD should
be identified prior to surgery. Koshy et al. found that overall mortality during a 6-year follow up
period of SCD patients was 0.3% (Koshy et al., 1995). This compared to an overall mortality rate
of 1.1% in a 30-day post-operative period in those patients who had undergone surgery. Post-
operative complications increased with age and varied with the type of surgery. The risk was
thought to be secondary to acute tissue injury and chronic organ damage from vaso-occlusion.

Preoperative testing

For routine operations SCD testing should be performed with diagnostic tests, such as high
performance liquid chromatography (HPLC), isoelectric focussing or mass spectrometry, at the
pre-assessment visit in all non-Northern Europeans. In emergencies the majority of cases of

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sickle cell anaemia can be identified by a positive sickle solubility test and full blood count
showing anaemia. If there is doubt about the diagnosis, and confirmatory testing cannot be
performed rapidly, the haematologist must decide whether or not the patient is high risk.
Examination of the blood film may be helpful.

For patients with known SCD it is essential to have a full blood count, red cell phenotype and
antibody screen checked preoperatively. Phenotyped red cells (full Rh and Kell typed) should be
available for all but the most minor surgery.

Perioperative management

There should be collaboration between haematologists, surgeons and anaesthetists to produce

an individual preoperative treatment plan for any patient with SCD undergoing surgery. Routine
operations should not take place if the patient is febrile or has a sickle cell crisis because of the
increased risk of complications. Perioperative hydration, oxygenation and warmth should all be
managed expectantly. In patients who are ‘nil by mouth’ for more than 4-6 hours, the use of
intravenous fluids should be considered and should be continued until the patient is able to take
oral fluids. The patient should be kept normothermic throughout the operation and warming
blankets may be required.

Oxygen supplementation should be considered from pre-medication until the patient is fully
awake and oxygen saturations should be monitored. Intensive post-operative monitoring on a
High Dependency Unit should be considered for those patients with a severe disease phenotype
or with chronic respiratory disease. Respiratory support with incentive spirometry (Ahmad et
al., 2011) or continuous positive airways pressure (CPAP) (Leff et al., 2007) post-operatively is
not proven but could be considered. In view of the increased risk of infection in patients with
SCD, the use of prophylactic antibiotics should be considered. Patients should receive an
assessment of risk for venous thromboembolism and should receive appropriate
thromboprophylaxis as per local or national guidance. Adequate analgesia should be provided
post-operatively. Patients who require frequent opiate analgesia at home may have a higher
than expected post-operative analgesia requirement. It may be helpful to involve the acute pain
team preoperatively to develop an analgesia plan.

Local anaesthesia or regional anaesthesia should be encouraged where feasible. The use of
tourniquets may be associated with an increased risk of sickling complications and should be
avoided.

Role of transfusion
The role of preoperative transfusion in SCD has recently been reviewed by the British Society of
Haematology (Davis et al., 2017a) and data are summarised below. Vichinsky et al. randomly
assigned patients to one of two transfusion arms: either an aggressive regimen of transfusions
to maintain a preoperative Hb of 100 g/l and a haemoglobin S of 30% or less or a conservative

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transfusion regimen to maintain the Hb at 100 g/l, regardless of the percentage of haemoglobin
S (Vichinsky et al., 1995). The conservative approach was as effective as the aggressive
approach in preventing complications and was associated with fewer short-term complications
of blood transfusion.

Haberkern et al. looked further at the subjects from the same study who had cholecystectomy
and transfusion (Haberkern et al., 1997). These randomised subjects were compared to those
who were eligible for study registry but not randomised. The number of patients receiving no
transfusion was small but they had a worse outcome (five fatalities) than patients randomised
to either conservative or aggressive transfusion preoperatively (no fatalities). Untransfused
patients also had a higher incidence of acute chest syndrome (19% vs 8%) and vaso-occlusive
pain (19% vs 5%) than transfused patients.

Transfusion had a negative impact when studied by Al-Jaouni et al. who randomised sickle cell
anaemia patients into two groups: Group I (n=181), received no preoperative transfusion and
Group II (n=188) received simple or partial exchange transfusion preoperatively (Al-Jaouni et
al., 2006). Within the preoperative transfusion group, 14% developed postoperative
complications versus 7% in the non-transfused group (p=0.002). These investigators
considered avoidance of preoperative transfusion is a safe practice in properly selected steady
state sickle cell patients. Unfortunately the article was very brief and it is difficult to assess the
validity of these conclusions.

A significantly more detailed report than that of Al-Jaouni et al. was provided by the Transfusion
Alternatives Preoperatively in SCD (TAPS) study investigators, although fewer patients were
randomised (Howard et al., 2013). This was an international multi-centre trial where patients
with sickle cell anaemia or sickle cell/β0 thalassaemia scheduled for low-risk or medium-risk
elective operations (under general or regional anaesthesia) were randomised to no transfusion
or transfusion within 10 days before surgery (Howard et al., 2013). For the transfusion arm if
the patient had an Hb of lower than 90 g/l then a top up transfusion was given (target Hb 100
g/l) but a partial exchange transfusion was used if the Hb was greater than this threshold (with
an aim to achieve a haemoglobin S <60%). A significant increase in clinically important
complications (39% vs 15%) and serious adverse events (30% vs 3%) were seen in the non-
transfused arm and this was predominantly due to an increase in acute chest syndrome in the
non-transfused arm (27% vs 3%). The study closed early because of the excess of serious
adverse events in the non-transfused arm. Subgroup analysis of low risk operations was not
possible because of the small numbers. Consequently, the finding of reduced acute chest
syndrome applies mainly to medium risk operations. The study acknowledged the use of
preoperative transfusion in sickle cell/haemoglobin C disease (which constitutes up to 30% of
patients with SCD) requires a similar study.

The Cochrane review concluded there was low quality evidence that preoperative blood
transfusion may prevent development of acute chest syndrome and insufficient evidence from
randomised trials to determine whether conservative preoperative blood transfusion was as

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effective as aggressive preoperative blood transfusion in preventing sickle related or surgery

related complications in sickle cell anaemia. The review did not comment on management of
people with sickle cell/haemoglobin C disease or sickle cell/β+ thalassaemia or for those with a
high baseline Hb. (Estcourt et al., 2016b).

Sickle cell anaemia and sickle cell/β0 thalassaemia patients having medium risk surgery under
general anaesthesia should have preoperative transfusion. A simple transfusion will usually be
appropriate for patients with Hb <90g/l but an exchange transfusion may be indicated for
patients with Hb >90g/l or a very severe disease phenotype. The benefits in low risk surgery for
sickle cell anaemia and sickle cell/β0 thalassaemia are less clear, but a simple transfusion should
be considered for patients with Hb <90g/l. In high risk surgery (e.g. cardiac or neurosurgery)
most clinicians would recommend exchange transfusion in all disease genotypes. In a non-high
risk situation transfusion in sickle cell/haemoglobin C disease and other milder phenotypes
needs to be considered on a case by case basis, depending on preoperative Hb, type of surgery
and disease phenotype.

There is little evidence to support the role of preoperative transfusion in the emergency
situation. In a patient with Hb <90 g/l having medium or low risk surgery a simple transfusion
should be considered if time allows; if not blood should be cross-matched for perioperative or
post-operative transfusion. For patients with Hb >90g/l, type of surgery, urgency of surgery and
disease phenotype should be considered. If surgery is urgent it should proceed with exchange
transfusion being carried out post-operatively if required.

Recommendations
 The decision for preoperative transfusion and methodology for transfusion in other
situations will depend on genotype, phenotype, preoperative Hb and type of surgery.
 Preoperative transfusion prior to emergency surgery will depend on genotype,
phenotype, type and urgency of surgery and preoperative Hb.

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 Chapter 20: Hydroxycarbamide
“I currently attend the Hydroxycarbamide monitoring clinic at the Medical Day Unit at my hospital
on a monthly basis. The clinic is run by the senior specialist nurse and the care I receive is efficient.
I am listened to and all my needs are addressed. She is an excellent nurse and brings a lot of value
to the sickle clinics”.

“I have had fears about my levels of fertility and that is why I haven’t taken this medication”

Introduction
Over the last 30 years, sustained evidence has accumulated regarding the efficacy, experience
and safety of hydroxycarbamide (HC) (also known as hydroxyurea) in SCD in adults. Until
recently it has been the only drug licenced by the Food and Drug Administration (FDA) (granted
1998) and the European Medicines Agency (EMA) (granted 2007) for use in SCD. Given as a
once daily oral medication, it is effective in reducing the frequency of vaso-occlusive crises
(VOC), acute chest syndrome (ACS) and the need for transfusions and hospitalisation in adults
with sickle cell anaemia (SCA) (Charache et al., 1995). There is good evidence for its efficacy and
safety, with clinical benefit in the majority of patients, potentially modifying the natural history
of SCA including the onset or progression of end organ damage.

Unfortunately for a number of reasons, HC is underutilised in patients with SCA who might
otherwise benefit from its use. Recent national guidance should improve consistency of use
(Qureshi et al., 2017 (in press)). Further studies evaluating the optimal dosing, role in
preventing organ damage as well as the benefit in other sickle cell disease (SCD) genotypes are
warranted to advance the understanding of its benefits.

Standards
Adapted from (Qureshi et al., 2017 (in press))

 In adults with SCA and sickle cell/β0 thalassaemia with three or more moderate to
severe pain crises in a 12 month period, recommend treatment with HC.
 In adults with SCA and sickle cell/β0 thalassaemia who have a history of severe and/or
recurrent ACS, recommend treatment with HC.
 HC should be offered to adults with SCA and sickle cell/β0 thalassaemia and sickle
associated pain or severe symptomatic anaemia that interferes with quality of life (QOL)
or activities of daily living (ADL).

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 HC should be discussed with adults with sickle cell/β+ thalassemia or sickle

cell/haemoglobin C disease who have three or more moderate to severe VOC in a 12
month period, a history of severe/recurrent ACS or recurrent pain that interferes with
QOL or ADL.
 All hospitals looking after adults with SCD should have a prescribing and monitoring
protocol for HC to maximise benefits and safety.
 Male adult patients should be offered sperm analysis and cryopreservation before
commencing HC.
 Specialist centres should audit their use of HC to ensure it is discussed with all patients
who may benefit from its use.

Background evidence

Mechanism of action

There are several potential mechanisms for the action of HC that are relevant for patients with
SCD including haemoglobin F induction. HC most importantly inhibits ribonucleotide reductase
(RR), an enzyme critical in the transformation of ribonucleotides into deoxyribonucleotides,
leading to inhibition of DNA synthesis and eventual cellular cytotoxicity (Elford, 1968). The in
vivo effects of HC on RR are predictably transient leading to intermittent cytotoxic suppression
of erythroid progenitors and cell stress signalling. This affects erythropoietic kinetics and
physiology, culminating in a gradual increase of haemoglobin F.

In addition, HC reduces surface expression of adhesion receptors as well as bone marrow

production of neutrophils and reticulocytes both of which promote vaso-occlusion via vascular
adhesion (Ware, 2010). Further observations include improved cellular deformability and
rheology of red blood cells with increased blood flow and a decrease in haemolysis. Finally
donation of a nitric oxide (NO) moiety by HC has beneficial effects on vascular endothelium
including local vasodilation (Gladwin et al., 2002). This compensation for haemolysis-induced
NO consumption (Reiter et al., 2002) might explain the clinical improvement some patients feel
soon after HC initiation before maximal haemoglobin F induction.

Clinical efficacy

A recent Cochrane review concluded that HC was effective in decreasing the frequency of pain
episodes and other acute complications in adults with SCA and sickle cell/β0 thalassaemia
(Nevitt et al., 2017). However it concluded that there was insufficient evidence on its long-term
benefits for the prevention of chronic complications or for a role in sickle cell/haemoglobin C
disease. The Multicentre Study of Hydroxyurea in Patients with Sickle Cell Anaemia (MSH), a
placebo-controlled randomised controlled trial, was the first trial to confirm the efficacy and
tolerability of HC. The trial enrolled 299 adults with a mean age of 30.5 years. Patients in the

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study received the maximum tolerated dose (MTD) or a maximum dose of 35mg/kg/day. The
primary end point was reduction in frequency of painful crises and the trial was terminated
early due to clinical benefit (Charache et al., 1995). Significant findings from MSH trial include:

 Lower annual rates of pain crises (median 2.5 crises per year vs. 4.5 crises per year)
 Longer time to a first crisis on study (3.0 months vs. 1.5 months) and longer time to a
second crisis (8.8 months vs. 4.6 months)
 Lower incidence of ACS (25 patients vs. 51 patients)
 Reduced need for blood transfusion (48 patients vs. 73 patients)
 Increased total Hb and haemoglobin F

More recently, extension of follow-up analysis to 17.5 years for nonrandomised adults indicated
continued safety and benefit of HC, including reduced mortality (Steinberg et al., 2010) related
to haemoglobin F levels and frequency of VOC. Long term follow up of a prospective non-
randomised study from Greece which enrolled individuals >16 years with SCA, sickle cell/β0
thalassemia and sickle cell/β+ thalassemia also showed benefits in survival for those who
received HC (Voskaridou et al., 2010). In addition, two paediatric cohort studies have
demonstrated that children with severe SCA who received HC had higher survival rates than
children with less severe complications not on HC (Lê et al., 2015; Lopes de Castro Lobo et al.,
2013).

Further supporting evidence arises from more than 20 observational studies enrolling >3000
adults followed up for 2-8 years consistently showed a reduction in VOC and hospitalisation and
an increase in haemoglobin F (National Heart Lung and Blood Institute, 2014).

Patient selection
Initial clinical trials restricted enrolment to individuals with substantial clinical severity and
certainly HC should be offered to any individual with recurrent hospital admissions for acute
pain or ACS. Consideration should be given to use beyond eligibility criteria used in the MSH
trial, to recurrent acute and chronic pain as well as symptomatic chronic anaemia affecting the
ability of adults with SCD to participate in desired daily activities (Platt et al., 1994). The BABY-
HUG study showed that HC was effective in decreasing recurrent pain, ACS and hospital
admission in unselected children with SCA, leading to recommendations that all young children
with SCA are offered HC therapy. These results are not necessarily generalisable to adults, but
certainly adults with SCA should be made aware of the results of the BABY-HUG study and
should be given information about the drug to allow them to make informed choices about its
use.

Prospective multicentre randomised trials are assessing the role of HC in preventing organ
dysfunction in SCA based on encouraging but uncontrolled single institution reports suggesting
efficacy of HC for children and adults with sickle-related end organ damage (Fitzhugh et al.,
2015).

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HC administration
The optimal dose of HC for an individual patient is still a source of debate and the Cochrane
review found insufficient evidence to recommend a standard dose or dose escalation to MTD
(Nevitt et al., 2017). The initial phase 1/2 trial using HC demonstrated a near linear dose
response, with treatment dose (mg/kg/day) correlating with percentage haemoglobin F
response (Charache et al., 1995). This observation coupled with a greater treatment response
demonstrated the feasibility of a stepwise escalation of dose towards the MTD. The MTD is
defined as a stable once daily dose that leads to the greatest benefits without causing side
effects or toxicities (Ware et al., 2016).

The MSH trial enrolled patients at a starting dose of 15 mg/Kg/day escalated to a MTD. Doses
were increased in 5mg/kg/day increments at eight week intervals until myelosuppression was
caused, at which point the dose was reduced to the previous dose increment; this was
designated the MTD. Studies across multiple age ranges have shown that impressive laboratory
and clinical benefits occur when HC is used at the MTD which typically averages 25 mg/kg/day
(Kinney et al., 1999; Thornburg et al., 2009; Ware et al., 2011; Ware & Helms, 2012). Several
studies have used a ‘clinically or minimally effective dose (MED)’ of 15 to 20 mg/kg/day with
good clinical outcomes or a standard dose of 10-20 mg/kg/day (de Montalembert et al., 1997;
Ferster et al., 1996; Wang et al., 2011a; Wang et al., 2011b). The maximum dose used in these
studies was 30-35mg/kg (Wong et al., 2014).

Studies utilising HC at MTD typically achieve higher haemoglobin F percentages than the MED,
typically 15-20 mg/kg/day defined operationally as the dose whereby patients improve
clinically and feel better. Treatment at the MTD generally yielded better laboratory values with
Hb >90 g/l, MCV >110 and haemoglobin F >20% (Ware et al., 2016). A prospective multicentre
clinical trial comparing low-dose HC with MTD is warranted.

A starting dose of 15mg/kg/mg in adults is usually well tolerated, with dose reductions for
those with chronic kidney disease. The target of treatment should be an increase in HbF, a
neutrophil count of 1.5 – 2.0 × 109/l and absolute reticulocyte count of 100-200 × 109/l.

In view of the risk of myelosuppression a full blood count and reticulocyte count should be
checked two weeks after commencement and after every dose increment and should be checked
every 8-12 weeks throughout treatment. Treatment should be halted if the neutrophil count is
</= 1 x109/l, platelet count is <= 80 x109/l, Hb <45g/l or >20% decrease or reticulocyte count <
80 x109/l.

Most patients will achieve MTD within 12 months; maximum laboratory effects are also reached
within the time-frame (Bridges et al., 1996).

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Use of a treatment protocol

Every centre treating patients with HC should have a treatment protocol to enable appropriate
dosing and monitoring to maximise safety and benefits of therapy.

Toxicity
Most frequently recorded side effects of HC include leukopenia, neutropenia and
thrombocytopenia. These tend to be mild and reversible with dose reduction or discontinuation.
Less commonly reported side effects include gastrointestinal disturbances (Charache et al.,
1995), skin and nail changes, and leg ulcers. There is no definitive evidence that HC is causative
of the latter (Voskaridou et al., 2010).

There have been concerns about the long term toxicity of HC, particularly with regard to
carcinogenesis, teratogenicity and fertility. Studies in cohorts with over 17 years of exposure to
HC show no increase in stroke, myelodysplastic syndrome, leukaemia or cancer (Steinberg et al.,
2010). Long term follow-up from the MSH trial reported 94 pregnancies in enrolled male and
female subjects regardless of their HC exposure. Of 16 pregnancy outcomes in female subjects
with known HC exposure at conception or during gestation or male subjects exposed to HC at
the time of conception, 8 live births, 5 elective and 3 spontaneous abortions were reported. Of
the live births, no birth defects were reported, consistent with other studies reporting
pregnancy outcomes (Ballas et al., 2009; Gilmore et al., 2011).

HC and abnormal spermatogenesis

Sperm abnormalities, such as oligospermia, azoospermia, decreased motility, and increased
morphological abnormalities, occur in males with SCD receiving HC (Garozzo et al., 2000; Grigg,
2007). Baseline sperm abnormalities are frequent in males with SCD, with rates as high as 91%
(Berthaut et al., 2008; Nahoum et al., 1980) but are increased in patients with SCD treated with
HC (Berthaut et al., 2017; Sahoo et al., 2016).

The published literature is limited on the risk of developing sperm abnormalities or infertility
on exposure to HC with inconsistencies in the age of initiation, length of exposure and follow-up
studies once HC is discontinued. One small study compared serial sperm counts and
morphology before, during and after HC treatment and showed decreased sperm counts in five
patients after starting HC with azoospermia in one patient (Berthaut et al., 2008). Another
paper has shown 4% of azoospermia prior to HC treatment, 10% whilst on treatment with 73%
reversion to normality after stopping hydroxycarbamide for 3 months (Sahoo et al., 2016).
However it is difficult to determine if fertility was impaired in these cohorts.

There is therefore limited information regarding the reversibility of azoospermia or

oligospermia which makes counselling patients starting HC challenging. Sperm banking should
be offered prior to commencing HC.

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Evidence of effectiveness in adults with genotypes other than sickle

cell anaemia or haemoglobin S/β0 thalassaemia.
For SCD individuals with genotypes other than SCA or haemoglobin S/β0 thalassaemia there
have been no phase 3 trials of HC. The non-randomised study from Greece enrolled 165 subjects
with haemoglobin S/β+-thalassemia, 44 of whom received HC. The 10-year survival for the
subset of patients with haemoglobin S/β+ thalassaemia receiving HC was not significantly
different from those receiving conventional therapy (Voskaridou et al., 2010). Some phase 2 and
retrospective studies have suggested a beneficial effect of HC on laboratory and clinical
parameters in patients with sickle cell/haemoglobin C disease but the Cochrane review
concluded that evidence was limited for this genotype (Luchtman-Jones et al., 2016; Nevitt et al.,
2017; Wang et al., 2011a; Wang et al., 2011b).

Recommendations
 Consider HC in adults with SCA and sickle cell/β0 thalassaemia with symptomatic
chronic anaemia or proteinuria unresponsive to ACEi or angiotenisn receptor blocker
treatment.
 Adults with SCA should be aware of the evidence of efficacy of HC and be given
information about the drug to enable joint decision making about its use.
 Females of childbearing age should be counselled regarding the need for contraception
while taking HC. HC should be discontinued if pregnancy is planned, immediately an
unplanned pregnancy is recognised and during breast-feeding.
 Males should be counselled regarding the need for effective contraception while taking
HC.

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 Chapter 21: Blood transfusion
“The last blood transfusion I had resulted in hyperhaemolysis with ITU admitting me for several
weeks as my body rejected the newly transfused blood. It would be interesting to know how others
cope”

Introduction
The use of transfusion in patients with sickle cell disease (SCD) is increasing but there is marked
variation in rates of - and indications for - transfusion between different hospitals. In part this is
due to a lack of evidence and clear guidelines for use, but a recent national audit demonstrated
that transfusion modality choice is often based on availability (NHS Blood and Transplant,
2016). Recent national guidance should improve consistency (Davis et al., 2017a, 2017b). Red
cell transfusion may be required as an emergency life-saving measure for the treatment of acute
complications while regular red cell transfusion may be used for the prevention of long-term
complications. Modality of transfusion includes simple transfusion and exchange transfusion;
the latter may be performed as a manual or automated procedure. The choice of volume and
modality of transfusion can be complicated and it is advisable that emergency cases are always
discussed with an expert in the field. Patients should be provided with information on
transfusion and any alternatives if clinically appropriate.

Standards
Based on (Davis et al., 2017a, 2017b)

 Automated exchange should be available to all patients with SCD and should be
provided by all specialist centres.
 All hospitals that admit SCD patients should have protocols and training in transfusion
for SCD including manual exchange procedures.
 SCD patients needing transfusion must be given ABO Rh (CcDEe) and Kell compatible
units. Blood should be antigen negative for clinically significant antibodies that are
currently or have previously been detected.
 All patients should have a red cell genotype/phenotype available. A genotype that offers
analysis of Rh variants may be preferable as these are common in this patient group.
 Adverse events involving transfusions should be reported using the local hospital
adverse events reporting system, to the National Haemoglobinopathy Registry, and to
Serious Hazards of Transfusion/Serious Adverse Blood Transfusion Reactions and
Events (SHOT/SABRE).

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 Simple transfusion to steady state haemoglobin concentration (Hb) may be indicated for
patients with acute exacerbation of anaemia due to aplastic crisis or sequestration crisis.
 Transfusion is not recommended in uncomplicated vaso-occlusive crisis.
 Urgent red cell exchange is recommended for patients with a sickle-related acute
ischaemic stroke.
 Adult patients who have experienced an ischaemic stroke should continue on long term
transfusion therapy.
 Simple (‘top-up’) transfusion should be considered early in the hypoxic patient with
acute chest syndrome (ACS), but exchange transfusion is necessary if there are severe
clinical features or evidence of progression despite initial simple transfusion.
 Chronic transfusion should be considered for prevention of recurrent ACS if
hydroxycarbamide therapy is not effective.
 Exchange transfusion should be considered early in the presentation of patients with
intrahepatic cholestasis and/or multi-organ failure.
 Specialist centres should audit their use of blood transfusion in the acute and chronic
setting to ensure its use is consistent with national guidance.

Aim of transfusion therapy and choice of modalities

The aim of transfusion therapy in patients with SCD is both to increase the Hb and therefore
improve oxygen carrying capacity and to decrease the haemoglobin S percentage, which will
decrease vaso-occlusion. Transfusion therapy may be administered as simple or ‘top-up’
transfusion or as an exchange transfusion which involves venesection and transfusion.
Exchange transfusions can be performed manually or may be automated. A summary of the
characteristics of each method is summarised in Figure 7. Transfusions may be required as an
isolated procedure in the acute setting for treatment of an acute complication or may be
required in the long term for prevention of acute or chronic complications.

Simple transfusion is effective in increasing Hb and in improving oxygen carrying capacity and
is the best option when the primary reason for acute transfusion is severe anaemia. The
patient’s baseline Hb should be used as a post-transfusion Hb target, which should not exceed
110 g/l because of the risk of hyperviscosity with transfusion to higher Hbs. The change in
haemoglobin should be considered carefully when deciding transfusion volumes as a rapid
change in Hb leads to a change in viscosity and can result in a stroke or other large vessel
occlusion. A change of 40g/l in 24 hours is usually the maximum recommended. Simple
transfusion is not as effective as exchange transfusion in reducing haemoglobin S percentage in
the acute situation, unless the starting Hb is very low.

Exchange transfusion offers an advantage in the acute situation if a rapid reduction of

haemoglobin S percentage is required to reverse an acute sickle complication (e.g. ACS or
stroke). Targets for pre- and post- transfusion Hb are usually similar and targets for post-
transfusion haemoglobin S percentage is usually <30%, depending on the indication for

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transfusion. Exchange transfusion may be a time critical, life-saving intervention and the
procedure for manual exchange should be included in education programmes for advanced
trainees in paediatrics and haematology, with appropriate support from consultant
haematologists and specialist nurses (Royal College of Nursing, 2011; West Midlands Quality
Review Service, 2016a).

When choosing a modality for a long term transfusion programme, the considerations will be
availability of procedure, venous access, iron loading/need for chelation and frequency of
procedures. Simple transfusions are easy to administer but iron loading can occur rapidly and
transfusion will be required every 3-4 weeks. In this context a low haemoglobin S percentage
can be maintained. Manual exchanges need to be administered as often but iron load less
quickly.

Long term automated exchange transfusion programmes offer good control of haemoglobin S
percentage. They rarely result in iron overloading and whilst they involve increased blood use
and thus donor exposure, paradoxically have been shown to decrease alloimmunisation in
retrospective cohort data (Michot et al., 2015). The increased costs of staff and equipment may
be offset by fewer hospital visits and less iron loading and need for chelation. Exchange
transfusion has been shown to be cost effective and is the recommended modality for long term
transfusion therapy (National Institute for Health and Care Excellence, 2016a).

Obtaining robust venous access can be a problem in patients with SCD but ultrasound guidance
may facilitate intravenous access (Putensen, 2015). Some patients may require intermittent
central venous access or indwelling venous access, although the latter has been associated with
high rates of infection and thrombosis in patients with SCD.

[Figure 7 shown overleaf]

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Figure 7: Comparison of different transfusion modalities (all times approximate)

MODALITY

Top-up transfusion Manual exchange Automated

FEATURE
exchange

Staffing and training Basic Moderate High

Frequency 3-4 weekly 3-4 weekly 4-8 weekly

2-4 hours

(up to 4-8 h if acute

Length of procedure 4-6 hours 2 hours
exchange in a
previously
untransfused patient)

Units of red cells 2-3 3-6 8-10

Volume shifts Large Minimal / Moderate Minimal

Ability to predict %
haemoglobin S and Hb Moderate Moderate Very accurate
post-transfusion

Iron loading (long term

High Moderate Minimal
use only)

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Selection of blood and communication with transfusion laboratory

Poor communication may contribute to the failure to meet special transfusion requirements.
Emergency transfusions for SCD patients may happen out of hours when their usual medical
teams are not available, or at hospitals where the previous transfusion history is unknown.

Compatibility testing
This should be undertaken according to the British Society for Haematology compatibility
guidelines (British Committee for Standards in Haematology et al., 2013; Bruce et al., 1999).
Fully automated systems should be used for ABO typing to reduce the risks of interpretation
and transcription error. Antibody screening should always be undertaken as part of pre-
transfusion testing. If an alloantibody is detected its specificity should be determined. If the
patient has a known red cell alloantibody, each new sample should be fully tested to exclude
further alloantibodies. Samples should be sent to a red cell reference laboratory if there is
difficulty in antibody identification.

Extended red cell phenotype/genotype

An extended phenotype (or genotype) including C, c, E, e, K, k, Jka, Jkb, Fya, Fyb, M, N, S and s
should be performed at baseline. If the patient is S- s-, then U typing should be performed. If the
patient has not been transfused within three months then testing can be undertaken
serologically, otherwise genotyping is needed. Extended phenotype matching for additional red
cell antigens is not performed routinely and even with this strategy the formation of allo-
antibodies is not completely abolished (Chou et al., 2013; O'Suoji et al., 2013). High resolution
Rh genotyping using DNA-based testing has showed high rates of variant or altered Rh alleles in
patients with SCD and this explained the occurrence of some of the cases of alloimmunisation
from Rh antigens despite using phenotypically matched blood (Chou et al., 2013). The accuracy
of red cell matching may be enhanced with DNA based testing and this is now provided by NHS
Blood and Transplant (NHSBT), although it is not clear if this should be routinely offered to all
patients and what impact this will have on provision of blood for transfusion.

Blood product selection

As a minimum, red cells should be ABO Rh (D, C, c, E, e) and Kell compatible (British Committee
for Standards in Haematology, 2004; Royal College of Obstetrics and Gynaecology, 2011; Sickle
Cell Society, 2008) and haemoglobin S negative (British Committee for Standards in
Haematology, 2004; Sickle Cell Society, 2008). If there are clinically significant red cell
antibodies (current or historical) then the red cells selected should be negative for the
corresponding antigens. If possible, red cells should be less than 10 days old for simple
transfusion and < 7 days old for exchange transfusion. This may not be possible in individuals
with multiple alloantibodies or in a true emergency when the freshest units available should be
used. Alloimmunisation increases clinical risk through delays in securing compatible units and

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because of potential delayed haemolytic transfusion reactions. Careful planning and

communication between all teams is essential; this includes liaising with NHSBT.

Adverse transfusion reactions

Patients should be counselled regarding possible adverse reactions to transfusions. Transfusion
adverse events should be identified and monitored according to local guidelines and should be
reported using the local hospital adverse events reporting system, the National
Haemoglobinopathy Registry, and SHOT/SABRE.

Iron overload is discussed in Chapter 22 - Iron chelation. Rates of transfusion-transmitted

infection are very low in the UK. Virology testing (hepatitis B, C and human immunodeficiency
virus) should be undertaken at first presentation and then yearly in those receiving
transfusions. Hepatitis B vaccination should be given to all SCD patients and boosters given
when antibodies to hepatitis B surface antigen fall below 100 mIU/ml.

Alloimmunisation is more common in SCD than in the general population, in part due to ethnic
differences between recipient and donor population. Rates of alloimmunisation have been
decreased by routine extended phenotypic red cell matching for Rh and Kell typing (Vichinsky
et al., 2001) but the role of further extending phenotyping or genotyping blood provided to SCD
patients is not currently clear. Red cell alloimmunisation may result in delayed haemolytic
transfusion reactions (DHTR) or subsequent haemolytic disease of the new born and can lead to
difficulties in obtaining compatible blood for transfusion.

DHTR typically presents 5-15 days following red cell transfusion and varies in severity. More
severe presentations may include pain, rapid decrease in Hb, cola-coloured urine and renal
dysfunction accompanied by increased haemolytic markers and a new allo-antibody. There is
observational evidence of response to methylprednisolone and high dose intravenous
immunoglobulins in addition to erythroid stimulating agents. Rituximab or eculizumab have
been used in cases resistant to these therapies (de Montalembert et al., 2011; Noizat-Pirenne et
al., 2015; Vidler et al., 2015).

Hyperhaemolysis in which both transfused red cells and the patient’s own red cells are
destroyed has also been described. It is characterised by a rapid decrease in Hb below the pre-
transfusion level and destruction of both transfused and the patient’s own red cells. While it
may be triggered by a new red cell antibody there is frequently no evidence of an allo-antibody.
Treatment with methylprednisolone and high dose intravenous immunoglobulins can be
effective in slowing and halting the red cell destruction and is recommended (Danaee et al.,
2015; Win, 2009). There will be evidence of both HbS and HbA in the urine during the episode.

Both DHTR and hyperhaemolysis may recur with subsequent transfusions and there are case
reports of pre-transfusion immunosuppression being used to reduce recurrence. Expert advice
from the Specialist Haematology Team (SHT) and from NHSBT should be sought if these
complications are suspected.

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 Chapter 21: Blood transfusion

Indications for transfusion

Adapted from (Davis et al., 2017a, 2017b)

The evidence regarding the indications for blood transfusion has recently been reviewed
thoroughly by the British Society for Haematology and these standards have used the review’s
conclusions (Davis et al., 2017a, 2017b).

Acute anaemia: Simple transfusion should be used in the situation of acute anaemia where the
primary goal of transfusion is to correct this anaemia and improve oxygen carrying capacity
(see Figure 8). There is insufficient evidence to recommend transfusion for the treatment of
acute painful crisis but simple transfusion should be considered if there is worsening anaemia
or haemodynamic compromise. Transfusion should be avoided if the acute anaemia is due to a
delayed haemolytic transfusion reaction unless the anaemia is severe or life-threatening.

Figure 8: Indications where primary goal is to correct acute anaemia

Indication Grade

Aplastic crisis 1B

Acute splenic sequestration 1B

Acute hepatic sequestration 1B

Other acute complications (see also Section B - Management of acute and chronic
complications): In patients experiencing other acute sickle complications the primary goal of
transfusion is usually to reduce the haemoglobin S concentration in relation to haemoglobin A.
This will usually be best achieved by an exchange transfusion. In ACS simple transfusion may be
effective in patients with mild or moderate symptoms, but an exchange transfusion will be
required for patients with evidence of severe disease or in those who baseline Hb is high
(Chapter 7 - Cardiorespiratory complications). For acute ischaemic stroke there is some
observational evidence that initial exchange transfusion is more effective in reducing the risk of
stroke recurrence (Hulbert et al., 2006), so exchange transfusion is recommended unless the
patient is significantly anaemic, when they will require a simple transfusion followed by an
exchange transfusion (Chapter 6 - Neurological complications). Exchange transfusion is
recommended for patients with acute life threatening complications of SCD including acute
multi-organ failure, severe sepsis, mesenteric (girdle) syndrome and acute intrahepatic
cholestasis. The role of transfusion in acute priapism is discussed in Chapter 9 - Priapism.

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Indications for chronic transfusion

See also: Section B - Management of acute and chronic complications

The use of chronic transfusion programmes for primary stroke prevention for children with
raised transcranial Doppler (TCD) measurements or silent infarcts is well supported by high
quality evidence. There is no such evidence to guide practice in adults, but similar principles
may apply in adults. Children who have commenced transfusion for these indications in
childhood should be reviewed during transition to adult care and continuation of the
transfusion programme considered. Following the TWiTCH study that showed non-inferiority of
hydroxycarbamide versus transfusion in patients with raised TCDs with normal brain imaging,
there will be some patients who can be offered hydroxycarbamide. This should be done after
appropriate imaging, consultation and discussion with the specialist centre.

Whilst data on secondary stroke prevention in adults are limited, current recommendations are
that adults who have a sickle-related stroke should continue on long term transfusion therapy.
Similarly adults who have had a stroke in childhood and have been commenced on transfusion
therapy should be reviewed on transition and should be continued on long term transfusion
therapy (see Chapter 6 - Neurological complications).

Both transfusion therapy and hydroxycarbamide are effective in reducing recurrent pain and
recurrent ACS. Patients with these complications should be initially treated with
hydroxycarbamide and offered blood transfusion therapy only if treatment with
hydroxycarbamide fails (see Chapter 20 - Hydroxycarbamide).

There is limited evidence for the use of chronic transfusion in other indications but its use has
been reported in the treatment of renal disease, pulmonary hypertension, leg ulcers and
recurrent priapism.

The role of transfusion in pregnancy and for preoperative management is discussed in chapters
18 and 19.

Recommendations
 A transfusion history should be obtained in all SCD patients requiring transfusion
whether elective or emergency. Additional information on red cell genotype/phenotype
and antibody history may be available from other hospitals and from NHSBT.
 Close communication is essential between clinical and laboratory teams so that
appropriate blood is given.
 Centres should consider transfusion reactions in patients presenting unwell following a
transfusion and should contact specialist teams for advice in management.
 Patients with a history of red cell allo-antibodies or haemolytic transfusion reaction
should be given an alert card.

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 Chapter 22: Iron chelation
“I am currently on the exchange programme so I haven’t had to worry about iron overload and
chelation therapy as I did previously, although when I travel outside London, the machine isn’t
available”

Introduction
The aim of chelation is to reduce the risk of complications of iron overload, which may develop
with intermittent or regular blood transfusions. A large body of evidence has accumulated in
thalassaemia patients showing the improved survival in patients who are chelated, but there are
relatively few published data sets on iron overload in patients with sickle cell disease (SCD).
Whilst iron overload related complications tend to be less frequently encountered in sickle
patients, MRI evidence does support iron deposition in extrahepatic organs (Wood et al., 2016).
The clinical relevance of this iron deposition remains unclear however post mortem data
identifies iron overload related complications such as liver cirrhosis and cardiac failure as
causes of death (Darbari et al., 2006). Iron tends to accumulate in the liver rather than the heart
in patients with SCD in contrast to thalassaemia and other iron loading conditions. Thus iron
overload in SCD is associated with liver damage, fibrosis, cirrhosis and sometimes even liver
failure.

Standards
 All patients with serum ferritin persistently raised >1000 μg/l who have been
previously transfused should have quantitative monitoring of liver iron concentration
using magnetic resonance imaging (MRI).
 Iron chelation is recommended in patients who have a liver iron concentration of >
7mg/g dry weight on MRI scanning.
 Patients receiving long term blood transfusion should have regular monitoring for iron
overload and appropriate iron chelation therapy according to their iron burden.
 All patients receiving iron chelation therapy should be regularly monitored for
therapeutic effect and chelator toxicity.
 Support should be provided to patients to help improve adherence to chelation therapy.

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 Chapter 22: Iron chelation

Background evidence

Iron monitoring

Serum ferritin remains a convenient, cheap and widely used way of assessing body iron but
levels can be very variable, probably due to inflammatory processes related to crises. Studies of
iron chelation in patients with SCD have shown variable responses of ferritin measurements
(Cappellini et al., 2010; Vichinsky et al., 2011). Serial ferritin trends in between quantitative
hepatic iron measurements can be useful, provided the serum ferritin tests are always carried
out when the patient is in steady state and other methods are used to assess iron overload and
response to chelation.

Liver biopsy, which was historically used for monitoring iron overload, has been superseded by
MRI technology and MRI monitoring of liver iron concentration is now available in the UK and
should be part of standard of care. Assessment of iron load in SCD is extrapolated from other
diseases. Liver iron concentration (LIC) <7 mg/g is not associated with obvious hepatic
pathology while >15 mg/g is consistently associated with liver fibrosis (Bassett et al., 1986).
Liver MRI can accurately assess response to chelation. MRI methods routinely used in the UK
are R2 Liver (FerriScan®), T2* (cardiac and liver iron) and R2* for liver. The methods are not
interchangeable and therefore consistently the same method should be used to monitor the
trend in liver iron.

Although serum ferritin correlates less well with MRI LIC in patients with SCD when compared
with patients with thalassaemia, a ferritin persistently raised >1000 µg/l, on at least two
occasions in the steady state, should be an indication for MRI monitoring of iron overload
(Adamkiewicz et al., 2009; Smith et al., 2014). This is approximately equivalent to transfusion of
20 units of packed red blood cells (PRBC).

The role of iron chelation in SCD according to transfusion strategy

Previously or currently on intermittent transfusions for acute complications.

Patients receiving intermittent/occasional simple transfusions over many years can accumulate
considerable amounts of iron. Ferritin should be assessed regularly, at least at annual review,
and appropriate MRI monitoring undertaken if the ferritin is persistently >1000µg/l. Iron
chelation should be offered to all patients with liver iron values above 7mg/g/dw and
considered for those with liver iron concentration of 5-7mg/g/dw dependant on co-existing
morbidity in the heart or liver.

Patients on regular simple transfusions

These patients should be offered iron chelation therapy once 10-20 units of blood have been
administered or the ferritin is above 1000µg/l. Iron chelation should be continued for as long as
the patient remains on transfusions with the aim to keep liver iron <5mg/g/dw and cardiac
T2*>20ms.

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Patients on regular exchange transfusions

Many patients on long-term transfusion therapy will receive automated exchange transfusions.
These are less likely to cause iron loading than long term simple transfusion and are
recommended by the National Institute of Health and Clinical Excellence (NICE). Some patients
may still gain iron, particularly if the post-exchange haemoglobin is higher than that pre-
exchange. Patients receiving manual exchange transfusions can gain iron, albeit at a slower rate
than with simple transfusions.

MRI scanning is indicated if there is a raised or increasing ferritin level (>1000 µg/l). Patients
who are iron loaded (LIC >7mg/g) when they embark on long-term automated transfusion
therapy should be treated with iron chelation therapy and be monitored for iron overload with
serial serum ferritin and MRI LIC. Iron chelation can be stopped once the ferritin is <500µg/l or
liver iron <5mg/g/dw.

Iron chelation
Deferasirox and desferrioxamine are both licensed as iron chelators in SCD and lead to similar
dose-dependent liver iron concentration (LIC) reductions in transfused SCD patients (Vichinsky
et al., 2007). Deferiprone is not licensed for SCD but there is evidence that it is as effective as
desferrioxamine. (Calvaruso et al., 2014).

Desferrioxamine

Desferrioxamine (DFO) is usually given as a subcutaneous infusion, most often 8-12 hours
overnight but can also be given as a continuous intravenous infusion in heavily iron-loaded
patients. Patients are usually treated between four and seven days per week depending on the
degree of iron overload (electronic Medicines Compendium (eMC), 2017a). DFO can also be
given by continuous intravenous infusion to reverse cardiac dysfunction, but this is rarely
needed in patients with SCD.

DFO is now usually given via portable, light-weight, pre-filled infusion pumps rather than
battery operated infusers, which has improved ease of use and adherence. Fine ‘thumbtack’ or
‘drawing-pin’ style needles introduced at 90 degrees to the skin into the subcutaneous tissues
have the fewest reactions. The skin of the abdomen, arms or legs can be used in rotation to
reduce scarring that can affect absorption.

The usual daily dose is 20-40 mg/kg/day.

Oral vitamin C (maximum 200 mg daily, in divided doses) may enhance iron excretion when on
regular desferrioxamine. Vitamin C should not be administered within the first month of
desferrioxamine therapy.

The most frequent side effect is local effects at infusion sites. Hydrocortisone can be added to
the infusion fluid if this is a problem. Optic nerve damage and sensorineural hearing loss are

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serious adverse effects, occurring more commonly with high doses. They can be reduced by
keeping the ratio of the mean daily dose (mg/kg of desferrioxamine) divided by the serum
ferritin (μg/l) below 0.025. Retinal examination and audiometry should be done prior to
starting treatment and then annually.

Desferrioxamine promotes infections such as by Yersinia enterocolitica or Klebsiella spp.

(Adamkiewicz et al., 1998). Patients should be advised that if they develop fever with
pharyngitis, diffuse abdominal pain or enteritis/enterocolitis, they should stop desferrioxamine
therapy and seek urgent medical advice so that appropriate antibiotic treatment can be
instituted.

Deferasirox

Deferasirox (DFX) is an orally active iron chelator, given once daily. It was previously given as a
dissolvable tablet but this has now been replaced by a film coated tablet.

The starting dose of the film coated tablet is 14 mg/kg/day.

Serum ferritin should be monitored monthly and the dose adjusted every 3 to 6 months, if
required. In patients whose serum ferritin level has reached the target (usually between 500
and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be considered. Interruption of
DFX should be considered if ferritin is persistently < 500 µg/l.

Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in
adults) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first
month after initiation or modification of therapy with deferasirox and monthly thereafter.
During clinical trials, increases in serum creatinine of more than 33% on at least two
consecutive occasions, sometimes above the upper limit of the normal range, occurred in about
36% of patients. This should lead to dose reduction and interruption of treatment, if persistent.
Cases of acute renal failure have been reported following post-marketing use of deferasirox
(electronic Medicines Compendium (eMC), 2017b).

Serum transaminases, bilirubin and alkaline phosphatase should be checked before the
initiation of treatment, every two weeks during the first month and monthly thereafter.
Deferasirox may be a contributing or aggravating factor for hepatic failure, but the most
common cause of liver dysfunction and failure in the iron loaded patients is the iron itself.

If there is a persistent and progressive increase in serum transaminase levels that cannot be
attributed to other causes, deferasirox should be interrupted. Once the cause of the liver
function test abnormalities has been clarified or after return to normal levels, cautious re-
initiation of treatment at a lower dose followed by gradual dose escalation may be considered.
Deferasirox is not recommended in patients with severe hepatic impairment (Child-Pugh Class
C).

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The Summary of Product Characteristics should be consulted regarding dose adjustments in

relation to renal or liver changes (electronic Medicines Compendium (eMC), 2017b).

Long term safety data was provided by Vichinsky et al. who followed transfusion-dependent
SCD patients for five years, but only 33.5% completed the study (Vichinsky et al., 2011).
Deferasirox adverse events were predominantly gastrointestinal (including nausea and
diarrhoea), mild-to-moderate and transient in nature. Creatinine clearance remained within the
normal range throughout the study. Serum ferritin levels in patients with 4 or more years of
deferasirox exposure significantly decreased by, on average, 591 µg/l. Gastrointestinal
haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer and gastritis occur but
are uncommon.

Another side effect is skin rash which resolves spontaneously in most cases. When interruption
of treatment is necessary, treatment may be reintroduced after resolution of the rash, at a lower
dose followed by gradual dose escalation.

Deferiprone

Deferiprone is an oral iron chelator, given three times a day. It is not licensed for use in SCD.
Consequently, patients should be made aware of this and the reasons for its use should be
clearly documented in the notes. Adverse effects include agranulocytosis, neutropenia and
arthropathy, as well as gastro-intestinal disturbance, intermittent elevation in alanine
transaminase (ALT) and zinc deficiency. Agranulocytosis (neutrophil count < 0.5 × 109/l) has
been described in up to 1.5% of patients, at a median of 162 days after starting treatment, and is
the most severe side effect of this drug. Weekly full blood count monitoring is recommended
whilst on this treatment. Deferiprone therapy has been given in combination with
desferrioxamine in patients with significant iron overload and it is thought to have a particular
benefit in those with cardiac iron overload. Combination therapy should only be instigated after
discussion with a specialist centre.

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 Chapter 23: Haematopoietic stem cell
transplantation
“Is stem cell transplant a safe cure for sickle cell and what are the risks if any”?

Introduction

Haematopoietic stem cell transplantation (HSCT) is a potentially curative option for sickle cell
disease (SCD) albeit one which is not without risk. Most HSCTs for SCD have utilised matched
siblings as donors and are performed in children and adolescents and currently the National Health
Service (NHS) only funds HSCT those up to age 19 with SCD.

Adults have only recently been regarded as acceptable transplant candidates, given the unpredictable
prognosis and cumulative organ damage from SCD, coupled with an increased risk of dying from
transplantation with increasing age due to toxicity of the conditioning regimen. In recent years,
‘reduced intensity’ or ‘non-myeloablative’ preparative regimens prior to HSCT in adults with SCD
have emerged as feasible options for HSCT in adults. In addition the encouraging results of using
alternative donor HSCT such as haplo-identical donors have led a worldwide interest in establishing
clinical trials of transplantation of adults with SCD

Standards
 Adults with SCD who are being considered for HSCT should be discussed at a
multidisciplinary team (MDT) meeting with appropriate expertise which must include
the specialist haemoglobinopathy team.
 Trials for haematopoietic stem cell transplantation (HSCT) in adults with SCD should be
available in the UK.

Background evidence
Systematic review has found no randomised controlled trials assessing the risks or benefits of
HSCT in adults with reports limited to observational studies (Oringanje et al., 2016). Reports in
the literature on the outcomes of HSCT in adults with SCD include small series of patients
transplanted with different types of conditioning regimens and most frequently from HLA-
identical siblings and in selected patients.

One report of 15 young adults receiving HLA-identical sibling donor stem cells with a
myeloablative conditioning regimen showed relatively high rates of graft-versus-host disease
(GVHD) but with a median follow-up of 3.4 years (range 1-16.1), overall disease-free survival

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was 93% (Kuentz et al., 2011). All survivors currently enjoy a normal quality of life without
immunosuppression. Chimaerism at 1 year was full-donor in 12 patients and mixed but >75%
donor in 2 patients.

Prospective evaluation of 10 adults, aged 16 to 45 years, undergoing a non-myeloablative

transplant (consisting of alemtuzumab, total-body irradiation and sirolimus) from a matched
sibling donor (MSD) found that all patients were alive at a median of 30 months after
transplantation. Eligibility was irreversible vasculopathy or unmanageable symptoms from SCD.
Nine patients had long-term, stable donor engraftment, at levels sufficient to reverse the SCD
phenotype (Hsieh et al., 2009). In a later update on 30 patients aged 16-65 years with severe
disease enrolled in this non-myeloablative transplant study 29 patients survived a median of 3.4
years (range 1-8.6), with no non-relapse mortality (Hsieh et al., 2014). These results, while
encouraging, are applicable to the, at best, approximately 10-20% of patients with SCD who
have a matched sibling donor.

Bolanos-Meade and colleagues reported on 17 patients, 14 from HLA haplo-identical and 3 HLA-
matched sibling donors, transplanted with a reduced-intensity conditioning regimen
(fludarabine, cyclophosphamide and total body irradiation). All received bone marrow grafts.
With a median follow-up of 711 days (minimal follow up 224 days), 11 patients engrafted
durably. Graft failure was observed in 43% of haplo-identical pairs but overall survival (OS) was
100% due to the high rates of graft-failure disease-free survival (Bolaños-Meade et al., 2012).

In a recent series of 1000 patients with SCD, transplanted from an HLA-identical sibling, 154
patients were adults or young adults (>16 years old) (Gluckman et al., 2017). Seventy-one
adults were transplanted in Europe and 83 in North America. Median age at HSCT was 19 years
(16-54). All received bone marrow or peripheral blood stem cells (PBSC) from an HLA-identical
sibling. Conditioning regimen was reduced intensity in 40 patients and myeloablative in 114.
The 5 year overall survival (OS) was 95% and 81% for patients younger than 16 years
compared with those 16 years and over. The 5 year probability of GVHD-free survival was 86%
and 77% for patients younger than 16 years compared with those 16 years and over.

Results from these studies indicate that non-myeloablative HSCT in adult patients with severe
SCD is safe and has curative potential. Patients with significant transfusion requirements and
sickle cell-related complications can achieve stable donor chimaerism with associated
stabilisation of end organ dysfunction, donor-derived haematopoiesis and decrease in health
care utilisation. Barriers yet to be overcome include: advanced disease precluding
transplantation; conditioning-related early and late toxicities; Graft versus host disease (GVHD);
lack of related donors; high graft rejection rates; lack of full-donor chimaerism; and long-term
use of immunosuppression.

Given recent advancements in HSCT for adults with SCD, several investigators have suggested
that transplantation should be offered to patients with severe disease, in whom the risk of
transplant-related morbidity and mortality is judged similar to the risk of long-term SCD-
related morbidity and mortality. At the time of these standards HSCT is not available for adults

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and there are no clinical trials open for adults in the UK. The decision for HSCT is complex and
should be made in a multi-disciplinary forum. Suggested patient selection criteria are given in
appendix 6.

Recommendation
 Protocols for HSCT in adult patients with SCD should be agreed nationally.
 There needs to be ongoing discussion with commissioners around funding for stem cell
transplants in adults.

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 Chapter 24: Emerging therapies
“I have been advised by my consultant that I meet the criteria for a new clinical trial, but I am
unsure what the side effects are”.

“The NHS still do not fund any emerging therapies for the sickle population. More and more people
are travelling abroad to receive curative treatments for sickle”

Introduction
Outside of hydroxycarbamide, blood transfusion and haematopoietic stem cell transplantation
there are no agents in routine use that are of proven clinical benefit in SCD. Treatment therefore
remains supportive and reactive. A growing appreciation of the underlying pathophysiological
mechanisms in SCD, is leading to an expansion of potential therapeutic targets. This section
reviews these targets and the rationale underlying their further exploration. A collaborative
approach nationally and internationally is required to set priorities for sickle cell clinical
research and to ensure optimal trial design.

Standard
 All patients with SCD should have access to information regarding current clinical trials,
to enable participation if the patient so chooses.

Drugs currently under evaluation

The Clinical Trials databases of the United States National Institutes of Health (NIH) and the UK
clinical trials gateway have a number of agents under active investigation at the time of writing
(see www.clinicaltrials.gov and www.utctg.nihr.ac.uk). Most remain in early phase, although
some agents are showing considerable promise as a means for altering the underlying
pathophysiology associated with sickling (Ataga, 2009; Conran, 2015; Kato, 2016).

Reducing vascular endothelial adhesion and cell-cell interactions

‘Anti-adhesive therapies’ are drugs that, through diverse mechanisms, disrupt the interactions
between blood cells and the vascular endothelium that are critical for the development of vaso-
occlusive crises. Upregulated expression of selectins, the adhesion molecules present on blood
cells and on the vascular endothelial surface, is associated with severity of phenotype in sickle
cell disease (SCD) and contributes directly to vaso-occlusion (Okpala, 2015). The inhibition of
selectin binding is therefore a rational target for drug development in SCD and is the focus of
agents in advanced phase assessment.

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Amongst these, rivipansel is a pan-selectin inhibitor that has demonstrated the capacity to
reduce requirements for parenteral opiates in patients suffering acute vaso-occlusive crises
(though the duration of painful crises was not reduced by a statistically significant margin in
phase II studies). A phase III multicentre randomised placebo-controlled trial of rivipansel
(Rivipansel: Evaluating Safety, Efficacy and Time to Discharge (RESET) trial) is currently
enrolling.

Results from a multicentre randomised phase II trial (the SUSTAIN trial) using crizanlizumab,
an antibody against P-selectin, have shown a significant decrease in median number of crises
per year and in median time to first and second crisis (Ataga et al., 2017).

Other agents under active assessment as a consequence of recognised impact on selectins

include the low molecular weight heparin, tinzaparin. This was included in a recent Cochrane
review of the effectiveness of low molecular weight heparins for the reduction of painful crises.
Despite superficially promising results in phase II trials, the Cochrane team downgraded the
evidence as a result of poor trial design leading to serious risk of bias (van Zuuren &
Fedorowicz, 2015).

Selectin inhibition is not the only mechanism by which cellular adhesion to the endothelium
may be subverted. Vepoloxamer (MST-188) is an amphipathic triblock copolymer, which is
thought to adhere to hydrophobic domains on cell membranes, reducing cell adhesion and
blood viscosity. A phase III trial (Evaluation of Purified Poloxamer 188 in subjects in crisis –
EPIC trial) assessing its efficacy in reducing the duration of painful episode failed to meet the
primary endpoint.

Closely allied to the issues of cellular adhesion and endothelial activation is platelet recruitment
and activation. However, the ‘Determining Effects of Platelet Inhibition on Vaso-Occlusive
Events (DOVE) trial, a paediatric phase III trial of the P2Y12 inhibitor prasugrel, which reduces
platelet aggregation, failed to show a statistically significant impact on the frequency of painful
crises (Heeney et al., 2016). Importantly, even a negative result for this trial was afforded high
impact publication, in large part due to its careful design and broad geographical reach. In this
regard, the DOVE trial clearly demonstrates that high quality, patient-focused, multinational
clinical research in SCD is achievable.

The (non-significant) trend toward a reduction in crisis frequency in older children treated with
prasugrel may prompt further study of this agent in young adults and older patients with SCD.
Meanwhile, phase II trials assessing the potential impact of antiplatelet agents on the duration
of painful episodes continue with the alternative ADP receptor blocker ticagrelor.

Modifying nitric oxide signalling

A second major group of investigational drug targets in sickle cell disease focuses on the
modification of nitric oxide signalling. Haemolysis has a multifaceted effect in decreasing nitric
oxide availability, via free haemoglobin scavenging, release of arginase, and inhibition of nitric
oxide synthase (Kato, 2015).

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Trials to replenish arginine, the substrate for nitric oxide synthase, include a single centre,
randomised controlled study assessing its impact in the setting of children admitted with acute
pain episodes. Although the primary endpoint of length of stay was not statistically significantly
different between control and test arms, there was an encouraging impact on pain scores and
opiate use which would support ongoing phase III studies. L-citrulline, an arginine precursor, is
in early phase trials under the same rationale.

Since the effects of nitric oxide are largely mediated by cGMP, phosphodiesterase inhibition
would also be expected to promote nitric oxide signalling. Early phase trials are in place as a
presage to investigating the effect of PDE9 inhibition on the frequency of painful crises (PDE9 is
expressed predominantly in haematopoietic cells, by contrast the ubiquitous/smooth muscle
distribution of PDE5, inhibition of which has been associated with an increase in painful crises).
Direct stimulation of guanylate cyclase (e.g. by the experimental agent riociguat, for which
phase II studies are currently in preparation) would be expected to give similar potential
benefits in sickle cell disease.

Preclinical and observational studies highlight the diverse mechanisms that support further
investigation of nitric oxide modulation. For example, PDE9 inhibition and arginine
supplementation both diminish adhesion of leucocytes and red cells to the vascular
endothelium, as well as inhibiting platelet activation. The observation that oral
hydroxycarbamide also acts as a nitric oxide donor raises the possibility of using these
investigational agents in a combinatorial or adjuvant setting; a concept not explored to date in
the management of SCD.

Reducing inflammation/oxidative stress

Inflammation and dysregulation of the innate immune system are also thought to be central to
the pathophysiology of SCD. Statins have broad anti-inflammatory, vaso-active and cell adhesion
effects, and are the subject of phase II trials. The anti-oxidant N-acetylcysteine (NAC) has also
been shown to have vasoactive and anti-inflammatory effects (Nur et al., 2012). A phase III trial
assessing the potential impact of NAC on the frequency of sickle-related pain, including the
frequency and duration of hospital admissions did not show any clinical benefit over placebo,
but findings were confounded by poor compliance. In an adherent subset there was evidence of
reduction of days with painful crises and a trend to reduction in other pain related endpoints in
the NAC treatment arm (Sins et al., 2017). A phase 3 trial with L-Glutamine, another anti-
oxidant, has shown a reduction sickle cell crisis (3 events vs 4 events) and in median incidence
of hospitalisation (2 events vs 3 events) in the treated versus the untreated group. This drug
was licensed for use in the US in 2017 (Niihara et al., 2014; Sins et al., 2017).

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Allosteric effectors of haemoglobin

The agents discussed above all focus on the consequences of SCD in terms of vaso-occlusion,
endothelial dysfunction, inflammation and ischaemia. However, the proximal
pathophysiological mechanism, namely the polymerisation of sickle haemoglobin, may also be
targeted. The investigational drugs GBT440 and Aes-103 stabilise the R-state of haemoglobin,
increasing its oxygen affinity and directly impeding polymerisation. GBT-440 is now in a phase
III trial and has promise as a drug that acts at the onset of the sickling process.

Reducing red blood cell dehydration

Although there is some scientific rationale for drugs which limit red blood cell dehydration, a
recent Cochrane review failed to find evidence to support a role for the agent senicapoc, a
Gardos channel inhibitor which has been widely studied in the context of sickle cell disease
(Nagalla & Ballas, 2016).

Reactivating foetal haemoglobin

This remains an appealing target for investigational drugs, not least since it appears to be one of
the key mechanisms of action of hydroxycarbamide. Alternative inducers of foetal haemoglobin
that continue to attract attention in clinical trials include the histone deacetylase inhibitors,
panobinostat and vorinostat, as well as the immunomodulator agent, pomalidomide, though
these remain in early phase trials (Okam & Ebert, 2012; Okam et al., 2015).

Gene therapy
Gene therapy involves autologous haematopoietic stem cell transplantation, using HSCs that
have been modified ex vivo either to correct or to circumvent the sickle mutation (Hoban et al.,
2016). Although expensive and technically challenging, this is a technique of curative potential
that would not be expected to hold the immunological complications (and possibly the higher
procedure-related mortality) of allogeneic transplantation, currently the only other curative
strategy in sickle cell disease.

Additive gene therapy

Major advances in the understanding of the mechanics of globin gene expression, plus critical
technological breakthroughs, have made gene therapy a more practical future option for the
treatment and potential cure of SCD. Either normal or modified anti-sickling β globin variants
have been used in lentiviral vectors, driven by the β globin promoter and regulatory regions to
ensure high level, erythroid-specific expression once incorporated into the cell. Since
permanent incorporation of the target gene into the patient’s haematopoietic cell genome is
needed, the development of small, effective insulators has been important in enabling a
reduction in off-target effects on the expression of nearby genes.

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Trials of gene therapy for SCD are now active in Europe and North America, though with limited
patient outcome data reported at the time of writing. Data on the first patient treated on the
HGB-205 gene therapy study at 12 months post-drug infusion confirm a therapeutic benefit
with anti-sickling haemoglobin accounting for 51 per cent of all haemoglobin production which
is above the minimum 30 per cent threshold required to have a therapeutic benefit (Cavazzana
et al., 2015; Ribeil et al., 2017).

Genome engineering

The development of targeted nucleases has given researchers the capacity to make small and
precise changes to the sequence of genes (known as gene editing) without the requirement for
the permanent insertion of viral DNA vectors. For conditions arising as consequence of a
recognised point mutation, of which sickle cell anaemia is a prime example, these gene editing
techniques provide the potential scope to make corrective genetic changes.

Although significant technical hurdles remain in the precise editing of haematopoietic stem cells
with long term repopulating potential for autologous transplantation, this remains an area of
active study. Expanding appreciation of the detailed mechanisms of normal expression of the
transcription factor BCL11a, critical for silencing gamma globin expression, also means that
tissue-specific disruption of this gene (with resultant therapeutic increases in haemoglobin F
levels) can also be achieved in sickle cell models. While gene editing is not yet available
clinically, significant steps forward have been made in the last decade in securing a proof of
principle.

Chapter 24: Conclusion

There have been genuine advances in the last decade in highlighting potential new targets for
drug treatment of sickle cell disease, with the focus broadening from gamma globin de-
repression to include a variety of anti-inflammatory, vaso-active and anti-adhesive agents. It is
especially encouraging that several agents (including rivipansel, MST-188 and N-acetylcysteine)
have progressed to phase III studies. Supporting a trials-active culture in the field of major
haemoglobinopathies and ensuring all patients have access to trials will be essential for ongoing
progress.

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 Chapter 25: Overall conclusion
Section A of this document outlines general principles of care for adults with sickle cell disease
(SCD). The acute and chronic complications of SCD are outlined in section B so can either be
read in its entirety or used by clinicians faced with a particular complication. Section C provides
information on more general topics, including reproductive health, and outlines currently
available treatments and briefly introduces possible future treatment options. Additional
resources have been provided in the appendices including an annual review pro forma and
guidance on staffing levels.

The editorial team have spent the past two years updating this edition of the standards but they
will become out of date and we advise readers to use additional sources of information where
indicated. Where clinical trials are available we have incorporated them into the standards but
we have been faced with a lack of high-grade evidence in many areas and have relied on
consensus opinion from the editorial team to provide pragmatic and practical advice.

There is a lack of effective treatment of SCD at present but there are many ongoing clinical trials
involving new pharmaceutical agents and therapeutic advances and we hope these will be
available when the next edition of the standards is published.

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 Appendices
Appendix 1: Medical staffing recommendations ..........................................................................................215

Appendix 2: Psychological therapies.................................................................................................................217

Appendix 3: Benefits advice..................................................................................................................................219

Appendix 4: Annual review pro-forma.............................................................................................................223

Appendix 5: GP outpatient letter ........................................................................................................................229

Appendix 6: Indications for haematopoietic stem cell transplantation (HSCT) in adults with
sickle cell disease...........................................................................................................................237

Appendix 7: Frequently asked questions ........................................................................................................239

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 Appendix 1: Medical staffing recommendations

A workforce survey was led by Dr K. Ryan on behalf of the UK Forum on Haemoglobin Disorders
and can be found at www.haemoglobin.org.uk/library/. The recommendations are summarised
below.

A suggested programmed activity (PA) allocation for lead consultants at Specialist

Haemoglobinopathy Centres (SHCs) is 1.5 programmed activities (Pas) for every 50 patients for
direct clinical duties, made up as:

 Clinics including specialist annual review (2.0 hours /week);

 Ward rounds (1.5 hours/week);
 Day unit attendance and ad hoc consultations, on call (1.0 hour per week); and
 Clinical administration and multidisciplinary team (MDT) meetings (1.5 hours/week).

Other PAs

 0.25 PA for every 50 patients for supporting activities, National Haemoglobinopathy

Registry (NHR) and data collection, audit, teaching, patient liaison, network
participation;
 0.25 PA continuing professional development (CPD) per consultant; and
 1PA for geographical area clinical lead.

Additional programmed activities are also likely to be required for other activities including
specialist training; laboratory work; research; and outreach clinics.

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 Appendix 2: Psychological therapies

Psychological Therapies

Cognitive Behavioural Therapy

Cognitive Behavioural Therapy (CBT) is a gold standard psychological intervention and

comprises two approaches i.e. cognitive and behavioural techniques.

Psychoeducation

Psychoeducational interventions primarily focus on improving knowledge and understanding of

patients about their illness while at the same time providing psychological support.

Other Psychological Therapies

There are other established and emerging psychological therapies, which should also be
considered for people with sickle cell disease (SCD) based on evidence in other conditions.

a. Mindfulness-Based Cognitive Therapy (MBCT) specifically helps people with recurring

depression or chronic pain, by combining mindfulness techniques including meditation,
breathing exercises and stretching, with elements from cognitive therapy to help break negative
thought patterns.

b. Acceptance and Commitment Therapy (ACT) uses acceptance and mindfulness strategies,
together with commitment and behavioural change schemes to help people accept difficulties
that come with their lives to build resilience.

c. Motivational Interviewing is an evidence-based treatment that addresses ambivalence to

behavioural change. This helps to motivate people to stop habits such as smoking and engage in
valued activities, for instance, adhere to medication.

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 Appendix 3: Benefits advice

An individual’s entitlement to benefits is likely to change, along with how benefits are
structured. The information below is correct at the beginning of 2018. The Citizens Advice is an
excellent resource, providing up-to-date information (www.citizensadvice.org.uk/benefits/).
Government information is available from: www.gov.uk/browse/benefits

Personal Independence Payment (PIP)

PIP is the new benefit which replaced Disability Living Allowance (DLA) for those aged 16 to 64
years, who have illnesses, disabilities and mental health conditions and need financial support
in order to pay for the extra help or support they need with everyday activities. It consists of
two components, daily living activities and mobility component. Each component is paid at
either a standard or enhanced rate; depending on the total number of points awarded by a
Department for Work and Pensions (DWP)-appointed Independent Health Professional (IHP), at
a PIP consultation, based on their (the IHP’s) view of the impact an illness, disability or mental
health condition has on the claimant’s ability to do simple daily activities.

Claimants need to answer a total of twelve questions; ten for daily living activities and two for
mobility. They also need to score 8 points in order to get standard rate or 12 points for
enhanced. The IHP awards the points based on a criteria referred to as ‘PIP descriptors’. Further
details about the entire application process, which is in three stages, are available on gov.uk and
Citizens Advice Bureau (CAB) websites. It is highly recommended that all claimants familiarise
themselves with this benefit or seek assistance from a welfare advisor before they start the
application process.

Employment and Support Allowance (ESA)

ESA is a benefit for people who have difficulties working due to an illness, disability or health
condition. Current incapacity benefit claimants are being assessed for a switch over to ESA. Also
note that income-related ESA is being replaced with universal credit (UC) soon, as part of the
welfare reform programme. There are two types of ESA; contribution-based ESA and income-
related ESA. Claimants should, where possible seek advice from CAB, a social worker or a
welfare support advisor before applying for ESA due to its complexity. Those who are not able
to work due to their health and have not made enough national insurance contribution may
qualify for the income-related ESA.

ESA application process is in three stages. A simple mistake with the application process could
lose you benefits. Patients should therefore seek assistance from CAB, social workers or welfare
support workers for step by step guidance through the application process.

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 Appendix 3: Benefits advice

Statutory Sick Pay (SSP)

If you are employed but unable to work due to illness, you can get SSP for 28 weeks. This is paid
by your employer, who may also pay additional sick pay, depending on your contract.

Attendance Allowance (AA)

AA is a benefit for people who are disabled or have care needs, aged 65 or over and are not in
receipt of DLA or PIP. It is paid at two rates. You can get the lower rate if you need frequent care
during the day or night. You get the higher rate if you need frequent care during the day and
night. It is highly advisable that you contact the CAB or an experienced welfare support officer if
you want to apply for AA. The gov.uk and CAB websites publish detail information about this
benefit.

Direct Payment (DP)

This is funding you can access through your local social services to enable you pay for care and
services yourself. This is subject to an assessment by social services of your care needs. NHS
choices publish further information about this. Contact your local social service team for advice
on how to access care through direct payment

Universal credit (UC)

Universal credit is the new benefit introduced to replace 6 existing benefits. It will be a single
monthly payment for people in or out of work. It is being introduced gradually so it is important
for claimants to check when it is going live in their area. The following means-tested benefits
are being replaced by UC:

 Income Support
 Income-based Jobseeker’s Allowance
 Income-related Employment and Support Allowance
 Housing Benefit
 Working Tax Credit
 Child Tax Credit

www.moneyadviceservice.org.uk/en/articles/universal-credit-an-introduction (09/03/2016)

Free NHS Prescription or prepayment prescription certificate

Free prescriptions are generally only available to those on income-based benefits such as
income support, and those suffering from specific health conditions of which sickle cell disease
(SCD) is not one. However, low income patients can apply for exemption from prescription

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 Appendix 3: Benefits advice

charges on the basis of their income. Anyone who is not able to get free prescriptions could
apply for a prepayment certificate which reduces the prescription charge considerably. Link
below for further information on exception.

See www.nhs.uk/NHSEngland/Healthcosts/Pages/Prescriptioncosts.aspx

Local Welfare Assistance Scheme (LWAS)

Crisis loan and community care grant were replaced with LWAS in April 2013. This new system
of emergency support is administered by local authorities who are able to apply qualifying rules
at their discretion. Patients with SCD are able to apply for local welfare assistance scheme for
emergencies through their local authority.

Benefits Cap
Since 2013, if you are aged between16 to 64 years, the total amount of benefits you can get per
week is limited to £350 for a single person and £500 for a couple or lone parent. These figures
could be reduced further in the near future. You can check the money advice service website for
the list of benefits that are included in the cap and for any change in the above amounts.

Local Housing Allowance

This can be claimed by private sector tenants who need assistance with their rent. There are
limits on how much you can claim so check with your local authority for details.

Council Tax Reduction

Council Tax Benefit was abolished in April 2013. This has been replaced by council tax
reduction schemes. It is no longer subject to standard rules across the country. The reduction
you get is now dependent on local rules, set by your council.

Additional benefits
 Equipment for independent living
 Health equipment and hospital travel
 Value added tax (VAT) relief on equipment and services
 Access to work
 Community and public transport
 Disabled Students’ Allowance
 Caring for someone
 Winter fuel payment
 Pension credit

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 Appendix 3: Benefits advice

Sources of further information

 Department for Work and Pensions
 UK Government: www.gov.uk
 UK Legislation: www.legislation.gov.uk
 Citizens Advice Bureau: www.citizensadvice.org.uk/
 Money Advice Service: www.moneyadviceservice.org.uk/
 Child Poverty Action Group: www.cpag.org.uk/
 Turn2us : www.turn2us.org.uk
 NHS Choices: www.nhs.uk/
 NHS England: www.england.nhs.uk/
 Age UK: www.ageuk.org.uk/
 Independent Age: www.independentage.org/
 Disability Rights UK: www.disabilityrightsuk.org/

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 Appendix 4: Annual review pro-forma

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 Annual Review Pro forma

Date of current review: ………/……../……….

Date of last review: ……./……./…….. Name of Reviewer: …………….……………………………………………
Diagnosis: ……………………………………………………………………………………………………………… AFFIX PATIENT LABEL
Height: m Weight: Kg Spleen size: cm
BP / mmHg SaO2 %

Centre changed in this review period: Y N Local Hospital Team: ..........................................................

Number of emergency (A&E or urgent day care) attendances (IN LAST 12 MONTHS):.............................................................
Does the patient have an emergency care plan? Y N
Has the patient had any Red Cell Antibodies? Y N Unknown

Has the patient conceived a child in this review period? Y N

If Yes, outcome: C Section C Section / Live Birth Live Birth ND
Preterm baby less than 36 weeks Spontaneous Miscarriage
Therapeutic Abortion

COMPLICATIONS (past 12 months): DESCRIPTION DATE

Acute chest syndrome ..................................................................................... ……../……./………
Bone Problem ......................................................................................... ……../……./………
(i.e. AVN, Osteopenia, Osteoporosis, Other (specify)
Gallstones ......................................................................................... ……../……./………
Chronic Hepatitis B, C, HIV ......................................................................................... ……../……./………
Hepatic or Splenic sequestration ......................................................................................... ……../……./………
Hyperhaemolysis ......................................................................................... ……../……./………
Leg ulcers ......................................................................................... ……../……./………
Multi organ failure ......................................................................................... ……../……./………
Neurological: Stroke/TIA ......................................................................................... ……../……./………
Osteomyelitis ......................................................................................... ……../……./………
Other Bacteraemia ......................................................................................... ……../……./………
Pneumococcal Infection ......................................................................................... ……../……./………
Parvovirus ......................................................................................... ……../……./………
Priapism ......................................................................................... ……../……./………
Pulmonary Hypertension ......................................................................................... ……../……./………
Renal Failure ......................................................................................... ……../……./………
Sickle Retinopathy ......................................................................................... ……../……./………
Sickle Hepatopathy ......................................................................................... ……../……./………

TRANSFUSION: Has the patient had regular transfusions in this review? Y N

Indication for transfusion: ....................................................................................................................................
Type of transfusion: EBT: Long term EBT Urgent/one off Auto/Manual
Top up: Long term Top up Urgent/one off New Allo-antibody (document on NHR)

INVESTIGATIONS IN THIS REVIEW PERIOD:

Mandatory Others Transfused Patients

ACR ECG Audiology
Bilirubin Echo Bone Profile (Ca)
Creatinine MRI/MRA FSH/LH
Ferritin Ophthalmology GTT
Hb Other Radiology Thyroid
LFT Pulmonary function Testosterone
Microalbuminuria Sleep study Virology
Vitamin D

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 Annual Review Pro forma

VACCINATIONS IN THIS REVIEW PERIOD: SPECIALIST IMAGING:

Influenza Date given: .…../…../……. Cardiac T2*(ms) result: Date given: .…../….../…….
Haemophilus Date given: .…../…../……. ................................................
Pneumovax Date given: .…../…../……. Liver T2* (ms) result: Date given: .…../….../…….
Hep B Date given: .…../…../……. ................................................
Meningitis C Date given: .…../…../……. Liver R2 FerriScan® result: Date given: .…../….../…….
Meningitis B Date given: .…../…../……. ................................................
Men ACWY Date given: .…../…../…….
Meningitis+Hib Date given: .…../…../…….
(Menitorix)
Prevenar Date given: .…../…../…….
Other: Date given: .…../…../…….

IRON CHELATION IN THIS REVIEW PERIOD:

Iron Chelation type:
Deferasirox Deferiprone Desferrioxamine
Combined Desferrioxamine+Deferiprone

MEDICATIONS IN THIS REVIEW PERIOD: OPERATIONS IN THIS REVIEW PERIOD:

Penicillin V Date given: .…../…../……. Adenotonsillectomy Hip replacement
Folic Acid Date given: .…../…../……. Cholecystectomy Orthopaedic
Date given: .…../…../……. Retinal Surgery Splenectomy
ACE Inhibitor Date given: .…../…../……. Other
Hydroxycarbamide Date given: .…../…../……. ....................................................................................
Vitamin D Date given: .…../…../……. Date of operation:
Biphosphonates Date given: .…../…../…….
Other Date given: .…../…../…….

EXAMINATION:

Respiratory symptoms and examination

Symptoms of sleep disordered breathing ................................................................................................................................

Cardiac symptoms and examination .........................................................................................................................................

Leg ulcers and inspection of lower extremities .....................................................................................................................

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 Annual Review Pro forma

DISCUSSION CHECKLIST (tick all that apply and document)

Acute care plan: Emergency department:

Home pain plan:

Chronic pain review: Opiate use

Referral to pain management:

Adherence to medications:

Discussion of infection prevention and need for early treatment:

Review of visual symptoms:

Referral to other specialist services:

Fertility/contraception. Pre-pregnancy counselling:

Priapism:

Discussion of therapeutic options currently available and new information including ongoing trials. Is the
patient eligible for a clinical trial?

Emotional and psychosocial well-being; is psychology referral needed?

Holistic assessment – lifestyle, education, work or welfare issues. Consideration of referral to community
services.

Offer additional information: Include key contact details, NHR information, local patient support groups,
relevant patient information.

Offer patient satisfaction survey (optional)

Any other comments:

Referral for MDT (local or network) discussion if needed.

Management Plan: (Insert acute pain plan action points from consultation)

Date:

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 Appendix 5: GP outpatient letter

To include:

Active problems:

 Active painful episodes:

 Number of hospital admissions, number of A&E, day unit admissions, number of days of pain at home
in last 12 months
 Emergency care plan:
 Chronic pain: Site, severity, review of analgesia
 Pregnancy in last 12/12
 Surgical procedures in last 12/12

Other health concerns:

 Chest pain
 Shortness of breath (at rest or exertion)
 Symptoms of sleep apnoea
 History of urinary tract infections or haematuria
 Leg ulcers
 Visual symptoms
 Priapism

Transfusion history in previous 12/12

Vaccination history

Medications

 If on hydroxycarbamide – dose, is the patient on maximum tolerated dose, when was last increase,
what is HbF%

Examination and Observations:

 Bp and oxygen saturations

 Cardiorespiratory examination, review of lower legs for ulceration, abdominal examination

Investigations (to include)

 Full blood count, renal function, liver function tests, Vitamin D

 Others as appropriate

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 Appendix 5: GP outpatient let Appendix 5: GP outpatient letter

Referrals (may include)

 Psychology
 Benefits officer
 Ophthalmology
 Discussion
 Fertility and contraception
 New treatments and trials

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 Example of GP letter

Dear […]

[X] was reviewed in the sickle clinic for their annual review today.

Active problems:

Active painful episodes: [X] has had two hospital admission in the past year, in April and August
2017. Both lasted three days and were for acute pain. They have pain severe enough to interfere
with activities of daily living approximately twice a month requiring bed rest and analgesia.

Emergency care plan:

Morphine 5mg sc given 2-4 hourly

Chronic pain:

[X] has had chronic pain in the left hip for over six months. There is pain in the groin on
movement and on examination. X-ray was normal and MRI has been ordered today. They will be
reviewed in the orthopaedic clinic.

No pregnancy in last 12/12

Surgical procedures in last 12/12: Laparoscopic cholecystectomy in Jan 2017. Uncomplicated

procedure.

Other health concerns:

No chest pain, shortness of breath or sleep apnoea. No urinary or visual symptoms.

Leg ulcer in left leg previously but this is now healed.

Floaters in left eye for past three months – to be referred to ophthalmology.

Transfusion history in previous 12/12:

2 units simple transfusion prior to surgery in January 2017

Vaccination history:

Hib/Men C, PCV13, Men B, MenACWY given in primary vaccination schedule

Pneumovax (PPV23) given 2015 (due 2020)

Influenza – given Oct 2017-11-11

Hepatitis B – immune October 2017 (HBsAb 120mIU/ml)

Continued…

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 Example of GP letter

Medications:

Folic acid 5mg od (taken 2-3 times per week)

Penicillin V 250mg bd

Analgesia. Paracetamol, Ibuprofen, Dihydrocodeine, taken as required (approx. once a fortnight)

Hydroxycarbamide: Commenced June 2012. 1g daily, maximum tolerated dose. HbF 13%.
Aware of need for contraception

Examination and Observations:

Bp 124/72, Oxygen saturations 99% on air

Cardiorespiratory examination, review of lower legs for ulceration, abdominal examination -

normal

Investigations (to include):

Full blood count, renal function, liver function tests, Vitamin D results

Referrals:

Referred to psychology team for review.

Referred to ophthalmology

Referred to orthopaedic clinic

Discussion:

[X] continues on the Mirena® coil with no plans for pregnancy at present.

Current trials discussed.

Next appointment:

[--/---/----]

Yours sincerely

Cc: Patient; General Practitioner; and local hospital (if appropriate)

Continued…

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 Example of GP letter

Please also read the following general information about the condition which we hope will be
helpful for you and your team, in managing this patient.

Risk from infection in people with sickle cell.

People with these conditions are more at risk from some infections, in particular bacterial
infections, as spleen function is poor. Pneumococcus and Salmonella species are especially
dangerous but any bacterial infection will affect a person with sickle cell more severely than
other people. Steps to reduce the risk are:

1] Having available at all times a supply of Penicillin V. This can be taken EITHER at a dose of
250 mg [one tablet] twice daily every day OR not taken every day but the patient should know
to start taking a treatment dose – 500 mg [2 tablets] FOUR times a day at the first hint of
infection, fever, sore throat, cough, shivers etc. Even if they take it at a preventing, lower dose
they should increase to this larger treatment dose if they develop symptoms. Penicillin allergic
patients should have a supply of Erythromycin 500 mg bd.

We recommend that, if they are not feeling better within 24 hours, they see you or us for further
assessment and consideration of broader spectrum antibiotics. If symptoms are not responding
to usual antibiotics, please refer to us urgently via the Emergency Department especially if
there is any possibility of sepsis.

2] Appropriate vaccination.

Adults with SCD who have not received primary vaccination as part of the national schedule in
the UK should be offered:

 One dose of Hib/Men C and one dose of pneumococcal polysaccharide vaccine (PPV23);
followed by
 One dose of MenACWY conjugate vaccine one month later
 Two primary doses of MenB vaccine one month apart [this can be at the same visits as
the other vaccinations above]
 A single 0.5 ml dose of pneumococcal conjugate vaccine (PCV13) which should be given
at least six months after PPV

Adults with SCD should also be offered

 Pneumococcal polysaccharide vaccination (PPV23) at five yearly intervals

 Annual influenza vaccination.
 Hepatitis B vaccine if they have not previously received it and are non-immune (HBsAb
<100 mIU/ml)

ALSO

3] If there is any suspicion of food poisoning, please refer to us for assessment, stool culture

Continued…

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 Example of GP letter

etc. Salmonella infection must be treated, even if symptoms are mild, or symptoms have settled
but stool culture is positive, as it can become rapidly invasive and very serious.

4] Please advise antimalarial prophylaxis if you are aware s/he is travelling to a malarious
area. People often think that if they have sickle cell disease they are protected against malaria –
this is far from correct, and malaria can be especially dangerous in in these patients.

Managing pain in sickle cell.

Pain is common, but not universal, in people with HbSS and Sβ0 thalassaemia. It is less common
but still sometimes occurs in those with SC or Sβ+ thalassaemia. It can be of varying severity.
Many uncomplicated pain episodes can be managed safety at home, taking oral paracetamol and
ibuprofen, and plentiful fluid. Patients who have significant pain crises will usually have a
supply of graded stronger analgesia: co-codamol, dihydrocodeine, tramadol and / or oral
morphine.

‘Red flag’ symptoms : significant fever, marked pallor, sleepiness, vomiting/diarrhoea so unable
to keep up positive fluid balance, chest pain, breathing problems, any suggestion of limb
weakness, anything UNUSUAL other than familiar limb or back pains. If these occur, with or
without pain, the person must be assessed here at the hospital, and will often need admission
for care of complicated episodes.

Watching for less common complications.

Sickle cell can cause a host of complications, the range getting wider as the person gets older.
Patients will have a comprehensive ‘annual review’ screening for some of the longer term
problems, as well as managing any current symptoms or problems.

*** N.B. Omit if female ***: [However, an acute complication to be watchful for from the start is
priapism. This is a painful penile erection, lasting longer than normal. It can be ‘stuttering’ –
coming and going, sometimes a couple of times a night, or can be ‘fulminant’ – an attack which
starts and will not spontaneously resolve. If your patient has stuttering priapism, please let us
know for an early clinic review. If he has a fulminant attack he should be directed immediately
to the Emergency Department for possible aspiration.]

You and your team in primary care can help by:

a] Repeat prescribing Penicillin V 250 mg bd for those who take it regularly, and 500 mg qds
[give a two week supply] for those who take if only for signs of infection. Please give
Erythromycin 500 mg bd for people who are penicillin allergic.

b] Prescribing oral Paracetamol and ibuprofen when requested, and any other medications
including stronger analgesia, as indicated from clinic letters.

c] Remembering that symptoms which may be trivial in others [e.g. sore throat, fever of 38.0°C
or higher] may warn of significant bacterial infection in those with sickle cell disease: please

Continued…

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 Example of GP letter

give broad spectrum antibiotics early, and refer to us promptly via ED if there is any possibility
of sepsis.

d] Being aware of the side effects of some of the medications he / she may require in the future:
for example hydroxycarbamide [given as a disease modifier as it reduces the frequency and
severity of pain crises] can cause neutropenia and deferiprone, sometimes used to reduce iron
levels in patients on regular transfusions, can cause agranulocytosis, SO anyone on these
medications should be referred immediately to hospital if febrile. Deferasirox is also used to
reduce iron levels in transfused patients, and it can cause indigestion, even upper GI bleeding,
rash, and kidney and liver function abnormalities. If people on desferrioxamine develop acute
abdominal pain we will need to assess them in case of Yersinia bowel infection. Please contact
us immediately if you have any concerns about anyone on these medications.

e] Encouraging / giving annual ‘flu vaccine and other vaccinations as needed

Contact numbers:

[01234 567890]

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 Appendix 6: Indications for haematopoietic stem cell
transplantation (HSCT) in adults with sickle cell disease

Patient Selection

Adapted from (Angelucci et al., 2014)

Indications

 Patients with sickle cell disease (SCD) at high risk for disease-related morbidity or
mortality defined by
 Overt stroke
 Pulmonary hypertension as defined by cardiac catheterisation
 Patients requiring long-term transfusion therapy for other sickle-related complications
 Patients with potentially reversible complications not ameliorated by HC
 Vaso-occlusive crises and/or acute chest syndrome (≥3 hospital admission per year
while on maximal tolerated dose of HC)
 Patients unable to receive transfusion therapy due to alloimmunisation or
hyperhaemolysis

Inclusion criteria

 Aged between 18 and 65 years of age

 Availability of fully HLA-matched or haplo-identical family donor
 Negative B-HCG within 7 days of commencing conditioning
 ECOG score ≤ 2
 Ability to comprehend and sign informed consent

Donors

 6/6 HLA identical family donor

 Haplo-identical donor in the absence of 6/6 family donor
 Fit to receive granulocyte colony-stimulating factor (G-CSF) and give peripheral blood
stem cells as assessed by an independent physician experienced in the medical
assessment of HSCT donors
 Ability to comprehend and willing to sign an informed consent

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 Appendix 6: Indications for haematopoietic stem cell transplantation (HSCT) in adults with
sickle cell disease

Exclusion Criteria

Patients

 DLCO (diffusing capacity of lung for carbon monoxide) <45% predicted

 LVEF (left ventricular ejection fraction) <40% estimated by ECHO
 Uncontrolled bacterial, fungal or viral infections within one month of HSCT
 Active lower limb ulcers
 Active hepatitis B or C or human immunodeficiency virus (HIV) infection
 Liver cirrhosis or organ failure incompatible with survival following HSCT
 Major ABO mismatch if high titre antibodies present
 Failure to comply with adequate iron chelation pre-HSCT
 Pregnant or lactating
 Where haplo-identical donor is the only option available, presence of anti-bodies to
donor HLA antigens

Donors

 Pregnant or lactating
 HIV positive
 Sickle cell disease (SCD)

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 Appendix 7: Frequently asked questions

General questions

I have the sickle cell trait, but can I experience symptoms associated with sickle
cell disorder?

Sickle cell trait means you carry one copy of the sickle cell gene (S) and one copy of the normal
haemoglobin gene (A) so sickle cell trait may be referred to as ‘AS’. Because most of the
haemoglobin in your body is normal, the majority of people do not have symptoms.

There's a slightly higher rate of complications during surgery if you have the trait. However, if
your anaesthetist knows, he or she can make sure you have extra oxygen, which reduces the
changes of complications. Lack of oxygen is one of the known causes of complications in people
with sickle cell trait. So be careful if you're at a high altitude (e.g. at the top of a mountain, long-
haul flights). Other known triggers are high atmospheric pressure environments (such as scuba
diving) and dehydration, so make sure you drink lots of water if you have the trait. Exercise is
also a trigger. If you exercise, let your teacher/coach know you have the trait, and stay hydrated
throughout.

The majority of people with sickle cell trait have no complications associated with this. For
people with trait are often told they can't do sport, and they can't be at altitude, but that's not
true, you just need to take a little extra care.

What is the difference between sickle cell disease and sickle cell anaemia?

Sickle cell disease is an umbrella term that describes a group of inherited major blood disorders
that are characterised by abnormal haemoglobin molecules called haemoglobin S. Sickle cell
anaemia is the commonest and most severe sub-type of sickle cell disease abbreviated as HbSS.
Other sub-types of sickle cell disease include HbS β0 thalassaemia, HbS β+ thalassaemia, HbSC,
Hb SD Punjab, HbSE and HbSO. The other forms of sickle cell disease are usually milder and vary
in terms of the spectrum of the problems they might cause with some patients not being aware
of the diagnosis until it is picked up incidentally on routine testing.

What is the difference between SS and SC genotype?

In the SS genotype an individual inherits two copies of the abnormal haemoglobin S but in the
SC genotype the individual inherits one copy of haemoglobin S and one copy of haemoglobin C
from each parent. The SC genotype tends to be milder although individuals are prone to all the
complications that can occur in the SS genotype. The SC genotype tends to have less frequent
crisis and a higher haemoglobin level with overall milder disease behaviour.

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 Appendix 7: Frequently asked questions

What’s the general life expectancy for people with sickle cell disease?

The general life expectancy for people with sickle cell disease is dependent on a number factors
including the natural behaviour of the disease in a particular individual, other medical problems
unrelated to sickle cell disease as well as the quality and access to appropriate healthcare
facilities and professionals. Historically, early studies from the United States suggested that the
median life expectancy for men and women with the more severe form of sickle cell disease i.e.
sickle cell anaemia was between 42 and 48 years. Interventions such as regular penicillin,
vaccinations, blood transfusion and Hydroxycarbamide as well as availability and access to
specialist care have improved life expectancy. Bone marrow transplantation is potentially
curative. A recent study from London suggested that the median survival for patients with sickle
cell anaemia was closer to 70 years although this cannot be immediately be extrapolated to an
individual’s life expectancy due to the number of factors previously discussed.

Primary care

What is the role for GPs in sickle cell disease care?

It is very important for people with sickle cell disease to maintain their health. General
practitioners (GPs) can help them stay healthy and prevent sickle cell crises. GPs prescribe
penicillin prophylaxis and give immunisations in their surgeries to prevent infections. They can
recommend vitamin supplements such as folic acid, and appropriate analgesia for pain. GPs can
also reinforce self-management of sickle cell disease such as fluid intake and keeping warm,
provide advice about healthy lifestyles including smoking cessation, and travel information
including countries where malaria is prevalent and prophylaxis is needed.

How can my GP help me when I have sickle cell pain?

Many people with sickle cell disease have pain at home and do not go to the hospital. Your GP
can help you manage your pain at home, and advise you of when to go to the hospital. Your GP
can review your analgesia (medication for pain) with you regularly and recommend changes if
necessary, or complementary (additional) therapies including physiotherapy and massage. It is
important to talk to your GP about your pain management even if you are admitted to hospital.

Why should sickle cell patients have all these vaccinations?

Patients with sickle cell disease are more prone to infections for a number of reasons, an
important one being the gradual reduction in size and the function of the spleen. Particular
strains of some bacteria are potentially life threatening due to the risk of complications such as
severe pneumonia, acute chest syndrome and sepsis. A number of vaccinations are available and
although they do not provide universal protection, they reduce the risk of specific infections.
The recommendations as to which vaccinations are most appropriate potentially change over
time. Patients should be advised by their haematologist as to the required vaccinations; these

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 Appendix 7: Frequently asked questions

are either administered in the hospital outpatients or via the GP. Vaccinations are also given to
protect against potential infection transmission in the course of treatment. An example is
vaccination against hepatitis B due to the very small risk of contracting this infection from a
blood transfusion.

What are the long-term effects of these vaccinations on my immune system?

Vaccinations work by stimulating the immune system to produce antibodies that fight infections
and therefore have a protective role. Apart from stimulating the immune system to produce
antibodies, there should be no long-term effects on the immune system.

How can sickle cell disease affect my teeth?

Patients with sickle cell disease are prone to all the problems that other individuals have as
regards their teeth and dental care. There are a number of oral hygiene and dental problems
that occur more frequently in patients with sickle cell disease. These include pain and yellow
discolouration of the tissue of the mouth, delayed tooth growth as well as abnormalities of the
covering of the teeth, poor alignment and sometimes increased dental infections. Some of these
problems are due solely to having sickle cell disease but others relate to dental hygiene as a
whole. Therefore good dental hygiene and regular brushing reduces dental problems, but
importantly early attendance at a dental clinic if any problems arise is highly recommended.

Does all dental treatment have to be done in the hospital?

By no means does all dental treatment have to take place in the hospital. Your dentist should
regularly assess your dental hygiene and early warning signs of any abnormalities of the teeth
or gums. Most non-invasive dental care can be undertaken by a dentist. For more complex
dental work, a discussion is usually had between the dentist and hospital maxillofacial surgeon
as to the suitability, safety and appropriateness of undergoing dental treatment either in the
community or in the hospital, especially if a general anaesthetic is required. Sometimes special
precautions are required to reduce the risk of developing complications after a dental
procedure which will require discussion with your haematologist.

Health and well-being

What is the benefit of going to the outpatient clinic when I am well?

It is very important for people with sickle cell disease to maintain their health.

Sickle cell disease affects people differently, and it is important to look out for early signs of
problems with your spleen, lung, heart, kidneys, liver, eyes and other body organs. This is done
in the clinic, and you may be asked to go to other clinics for additional tests or examinations to
prevent complications later. Also, some patients are on long-term treatment for their sickle cell

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disease such as hydroxycarbamide (previously known as hydroxyurea) or transfusion and

require regular blood tests and monitoring.

What is a psychologist?

A psychologist working in healthcare has professional training and clinical skills to help people
learn and cope much better with life issues and emotional problems. There are many kinds of
psychologists working in healthcare; however they all help by using a variety of methods based
on the best available research, and consider each person’s unique values, characteristics, goals
and circumstances.

Why would a psychologist be needed for sickle cell disease?

Sickle cell disease affects people differently; some do well by their own means, and others need
help. Even those who do well sometimes need some support. Psychologists help people with
sickle cell disease to recognise their daily situations including health problems, stress, and what
they do about their pain and other symptoms. They help to find practical and realistic solutions
to these problems, and better coping methods to live with sickle cell disease.

How can psychology help to deal with sickle cell pain?

There is good research to show that a kind of therapy called cognitive behavioural therapy
(CBT), which includes certain things like relaxation can reduce the frequency, duration and
intensity of pain. There are other methods you can learn to change the way you think about pain
that can help lessen the distress of being in pain.

How can I find a psychologist to help me with sickle cell disease?

That depends. Your hospital and sickle cell team may have a psychologist(s) working with them.
If your hospital does not have a psychologist as part of its sickle cell team, they will be able to
refer you or ask your GP to find a psychologist through, for example, Improving Access to
Psychological Therapies (IAPT) or other psychological services near you.

Do I need to be an inpatient to see a psychologist?

No. In all likelihood, if your hospital has a psychologist available, you will be able to have
support as an outpatient. Most psychologists work with carers and families too; you do not even
need to be a patient in order to find some help, so long as the concern is related to sickle cell
disease. You could also be referred to see a psychologist by your GP.

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How else might a psychologist help me with sickle cell disease?

Sometimes people want to make health-related changes that are not directly related to sickle
cell disease, but are helpful nonetheless. For instance, if you want to quit smoking, psychologists
have strategies to help you quit. Although this is not directly related to sickle cell disease, we
know smoking is especially harmful in sickle cell disease because it increases the chance of
getting a chest crisis, so making a change here will help. Psychologists also work together with
patients, carers and their families in order to improve the experience of the healthcare system.
They can help people deal with disagreements, conflict, and other challenging scenarios that can
arise between patients, families and providers.

What are the main nutritional problems associated with sickle cell disease?

There are many nutritional consequences associated with the main clinical features of sickle cell
disease namely, chronic haemolysis, vaso-occlusion, chronic inflammation and impaired
immune function. Research conducted investigating the role of nutrition in sickle cell disease
provides convincing evidence that sickle cell patients have a high resting energy expenditure
with associated increased cardiac output, high protein turnover, appetite suppression, low body
mass index (BMI) and exercise tolerance and are at risk of ‘protein/ energy-like malnutrition’.
Many complications associated with sickle cell disease therefore have a nutritional
underpinning with under-nutrition identified as a critical feature and a serious complication of
the disease.

Why is good nutrition important in the management of sickle cell disease?

Good nutrition is associated with good clinical outcomes and improved quality of life which is
observed in many people living with long term conditions such as chronic obstructive lung
disease (COPD) and diabetes and it is no different for people living with sickle cell disease.
Without good nutrition, sickle cell patients are at high risk of disease-related malnutrition
resulting from poor appetite and weight loss, frailty, increased risk of infection, weakness,
immobility and muscle loss as well as developing complications of sickle cell disease itself. Good
nutrition is associated with increased recovery from illness, reduced length of hospital stay and
improved functional status in individuals. Timely referral to a dietician can help improve the
overall nutritional intake and nutritional status of sickle cell patients at risk of disease-related
malnutrition.

What is the best nutritional management for patients with sickle cell disease?

Educating sickle cell patients about their condition and the associated nutritional risks is
paramount to supporting the effective nutritional management of the condition. Dehydration,
impaired immune functioning, inflammation, chronic anaemia and fatigue, constipation and low
BMI are the common nutritional problems facing a sickle cell patient so the best nutritional
management would be tailored to effectively management and reduce the incidence and effects

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 Appendix 7: Frequently asked questions

of these problems. Following the national healthy eating guidelines such as the Eat Well Guide
are helpful adjuncts to managing the nutritional status of sickle cell patients

Can we get more information on how diet can improve sickle cell crisis?

A healthy and balanced diet is important as part of the overall care of patients with sickle cell
disease. There are no specific dietary interventions that affect sickle cell crisis, but adequate
nutrition both in terms of quantity and timing of eating might reduce the propensity to develop
a sickle cell crisis. Information on diet in sickle cell disease is available in most clinics where
patients are looked after. In addition, a patient can request a consultation with a dietician either
via the local hospital clinic or via his or her general practitioner. There is a significant amount of
reading material related to diet in sickle cell disease online, but it is important that information
accessed by this means is validated by healthcare professionals who look after patients with
sickle cell disease. This information is usually best accessed from sickle cell disease specific
websites.

Should I take multivitamins or a blood tonic for my anaemia?

Multivitamins and blood tonics are supplements, and their constituents are variable. These are
supposed to be nutritional supplements that help you produce more red blood cells and reduce
your anaemia; however there may be side effects that can be detrimental to your health. It is
very important to show any supplements you intend to take to your doctor for the correct
advice. Do not rely solely on the information provided by people selling these supplements.

Does sickle cell cause my insomnia?

Insomnia is difficulty getting to sleep or staying asleep for long enough to feel refreshed the next
morning. People with sickle cell disease may have hypoxia (low oxygen levels in their blood).
This has something to do with sickle cells that do not carry enough oxygen, and breathing
problems that make it difficult for you to have a good night’s sleep, resulting in insomnia.
Furthermore, when people have sickle cell pain it usually affects their sleep. Some people have
to live with frequent pain and even though it may not affect their daily activities as much, it may
interfere with their sleep. Also, some people worry about their sickle cell disease and this may
disturb their sleep.

Where can I get further information about living with sickle cell disease?

There are many sources of information about living with sickle cell disease. The Sickle Cell
Society, other voluntary organisations, and support groups produce information. Your GP can
provide you with information, and there are NHS websites. You can also ask health
professionals at the hospital where you attend, and community based sickle cell centres.

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Who can I speak to about daily health issues related to my sickle cell disease?

You can speak to health professionals about issues related to you sickle cell disease. Speak to
your GP, specialist doctors or nurses. If you are not feeling well contact these health
professionals immediately to make an appointment, do not wait for your scheduled clinic
appointment, which may be weeks or months away. It is important that health issues related to
sickle cell disease are addressed early to avoid subsequent complications.

How do the voluntary organisations and charities help people with sickle cell
disease?

Voluntary organisations and charities support and represent people with sickle cell disease.
Advocacy is very important, and these organisations and charities facilitate this. They can direct
and assist people with sickle cell disease to access services such as social support, welfare
benefits, and housing. In addition, these organisations may provide small grants to help with the
finances of people with sickle cell disease.

Why am I not entitled to free medication and why is access to any form of welfare
for sickle cell in the UK extremely difficult?

Some groups of people are automatically entitled to free NHS prescriptions, some are not. You
can get free NHS prescriptions if you are: aged 60 years or over; under 16 years; 16-18 years
and in full-time education; pregnant or have had a baby in the previous 12 months and have a
valid maternity exemption certificate. You will not automatically qualify unless you fall into
these groups, or are in receipt of welfare benefits, or medication given in hospital when you are
an inpatient. The system around welfare benefits is complex and can be difficult to understand,
you may be entitlement to some benefits but it is better to seek advice to ensure that you can
claim appropriately.

How should I communicate my medical needs to my employer and what are my

rights?

You are under no obligation to tell your employer about your sickle cell disease if you do not
want to, unless your condition may affect your health and safety in the workplace, you work in
the armed forces or you drive for work. If you do decide to disclose, having an ongoing dialogue
about your condition and medical needs may help to manage the work environment and your
workload, and if you ever need time off for hospital appointments.

Even if you don’t need any support, you may still want to tell them so they’re aware in case
things change in the future. This can help to avoid any misunderstanding if any of your
symptoms – particularly if hidden symptoms such as fatigue start to affect you at work.
Consider arranging an informal chat with your employer, and it always helps to prepare what
you are going to say e.g. the medical treatment you are currently receiving, any support or

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 Appendix 7: Frequently asked questions

reasonable adjustments you may need and a reassurance that you are committed to your job –
having sickle cell disease doesn’t change your skills or experience. It may also be beneficial to
bring in some literature about the condition to raise awareness.

Under the Equality Act 2010 (UK Government, 2010), your employer is required to take
‘reasonable adjustments’ to allow you to continue working. For example, providing a warm,
draught-free work environment, access to drinking water and toilet facilities, and good
accessibility in and around the building will help you continue working without exacerbating
your condition. Further reasonable adjustments include making informed decisions about tasks
you can and cannot do, providing supervision/support to reduce stress, altering your hours of
work or allowing you additional time off.

To find out more about disability and employment you can contact your local job centre and ask
to speak to the Disability Employment Adviser.

Or contact the Disability Rights Commission on 08457 622 633, or 08457 622 644 for the
textphone, or write to them: Freepost, MID02164, Stratford-Upon-Avon CV37 9BR.

If you feel you have been a victim of disability discrimination in the workplace, please contact:
the Equality Advice Support Service discrimination helpline on 0808 800 0082. They can help
you by:

 explaining what the law says and how this applies to you
 explaining how a situation could be resolved
 supporting you to try and resolve issues informally
 if the issues can't be resolved informally, referring you to a conciliation or mediation
service
 if you need or want to seek a legal solution, helping you work out if you're eligible for
civil legal aid or what to do if you plan to represent yourself

Pain management

What is the maximum waiting time for analgesia in A&E departments and why is
there variation?

It is recommended that analgesia is given within 30 minutes of arrival in the Accident and
Emergency (A&E) department. Unfortunately A&E departments are often very busy and this is
not always achieved. If you are having to wait more than 30 minutes for analgesia please make
sure your local sickle team are aware so they can make sure you have a clear care plan and they
can support A&E to meet the national standard.

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 Appendix 7: Frequently asked questions

Why has my opioid dose been reduced recently?

Opioids have lots of side effects and doctors try to give the smallest effective dose for the
minimum amount of time. There are lots of reasons why your dose has been reduced and you
should discuss this with your doctor or nurse specialist. You may have developed side effects
(e.g. sleepiness or low oxygen levels) on your previous dose, your doctors may be trying to
gradually decrease your dose of opioid, or they may have introduced a different pain killer.

Why do I not get IV fluids when I am on the wards?

If you are able to take fluids orally then you will not be given intravenous (IV) fluids. You will be
prescribed IV fluids if you are not able to drink, for example if you are vomiting.

Why is my doctor recommending gabapentin?

Gabapentin is used for the treatment of neuropathic (nerve-related) pain, and may be offered if
your pain is sharp, burning or shooting. It is usually used together with opiates.

Why are analgesic patches used?

Transdermal patches such as fentanyl can be used for both acute and chronic pain control and
they slowly releases a small, regular amount of pain killer. Some patients find that lidocaine
patches, used in addition to other therapy, can provide effective analgesia where pain is very
localised.

Disease complications

When do I know I am having an asthmatic attack and an acute chest syndrome?

It can sometimes be quite difficult for an individual patient to distinguish the two conditions, an
asthma attack can range from mild to life-threatening while an acute chest syndrome is also
potentially life-threatening and requires immediate medical attention. They both have some
symptoms in common including shortness of breath. It is important that a patient recognises
that they are unwell and immediately seeks urgent medical attention with the team managing
his or her sickle cell disease.

Is priapism caused by sexual activity?

Priapism is a prolonged, painful erection lasting more than a few hours and essentially is a form
of sickle cell crisis that is localised to the penis. Although in most cases this is not associated
with normal sexual function or desire, occasionally patients do report that priapism develops
during sex. Having sex can be physically demanding and this might trigger a sickle cell crisis
including an episode of priapism.

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Why am I at risk of fevers and blood infections (sepsis)?

Patients with sickle cell disease have an increased propensity to infections, most importantly
due to the reduction in the size and function of the spleen therefore compromising its function
in fighting certain types of bacteria and as part of the immune system. This reduced capacity of
the spleen predisposes to infections which sometimes can be life threatening especially in cases
of severe pneumonia or sepsis. It is for this reason that patients are routinely vaccinated on a
regular basis as well as prescribed oral antibiotics to take as a preventive measure, although
none of the interventions completely remove the risk of severe infection.

What should I do if I have a fever?

It is important to seek prompt medical care if you notice a high fever. It is always helpful to
document the exact temperature using a thermometer. Subsequently this should be followed by
direct contact with your local haematology team depending on the access arrangements during
and outside working ours. If there is any difficulty or delay in accessing your local haematology
team, then it is advisable to attend the Accident and Emergency Department of your local
hospital where further investigations and in most cases appropriate antibiotics will be
commenced and possible admission, which might also reduce the risk of developing a crises.

What should I do if I notice blurred vision or something floating across my vision?

It is advisable to seek medical help as soon as possible. This would ideally be at an eye casualty
otherwise reporting to your local Accident and Emergency Department will prompt a referral
either to an eye casualty, or ophthalmology clinic dependant on the severity of the symptoms
and findings on the initial examination.

There is not enough information being given about sickle retinopathy. Why?

Sickle related eye disease is complex and needs input by eye specialists who are able to
recognise and advise and undertake appropriate management. For patients, it is important that
they have regular optician reviews as the first signs of sickle retinopathy might well be picked
up at this stage. It is also important that should a patient develop blurring of vision or any other
significant visual abnormalities, they should report to the nearest emergency eye unit or his or
her local team responsible for his or her sickle cell disease. Sickle retinopathy tends to be a
slowly developing process with most patients who are not monitored carefully being unaware
until a major complication of the retinopathy occurs. The advice is to have regular optician
reviews or attend clinics arranged by the local sickle cell disease team.

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How do I prevent avascular necrosis and how do I manage it?

Avascular necrosis (AVN) which most commonly affects the hips but can affect the knees, the
ankles, the shoulders or elbows is a chronic degenerative condition related to sickle cell disease.
It is somewhat similar to a chronic form of arthritis. The measures that are put in place to
manage and prevent progression of arthritis are also helpful in this condition. Maintaining good
posture, regular exercise and an optimal body mass index are very helpful in reducing the onset
and slowing down the progression of AVN. In terms of its management appropriate pain relief is
usually the first line, but sometimes differing from that used in managing an acute sickle cell
crisis. Appropriate advice should be sought from a patient’s GP and local sickle cell disease team
who might refer the patient to an orthopaedic surgeon. Sometimes in addition to the above
measures, physiotherapy is recommended; a proportion of patients will need some form of
surgical intervention to manage the AVN.

Surgery

Why do I need to have a transfusion before surgery if I never needed one before?

Surgery confers a number of risks on patients with sickle cell disease, including an increased
risk of a sickle cell crisis either during surgery or afterwards. Not only is it important for a
surgeon to discuss your condition with your haematologist prior to undertaking any form of
surgery, but in certain cases a transfusion might be recommended to allow surgery to proceed
safely. This transfusion can either be in the form of a top-up or in some cases an exchange blood
transfusion. In many cases, simply increasing the haemoglobin with a transfusion reduces the
risk of sickling and developing a crisis around the time of surgery. Overall outcomes following
surgery have been shown to improve following a transfusion; protocols and guidance are
provided dependant on how severely the patient is affected by sickle cell disease and the nature
and potential risks associated with the surgery.

Should I insist the surgeon contacts a haematologist before my operation?

Yes, as appropriate advice and potential intervention will reduce the risks of surgery in patients
with sickle cell disease.

Treatment

Does hydroxycarbamide cause leukaemia?

Hydroxycarbamide has been used in sickle cell disease for over 20 years and a careful follow-up
of patients over many years has shown that there is no increased risk of leukaemia in patients
with sickle cell disease taking hydroxycarbamide as part of their treatment. Hydroxycarbamide
is used in a number of other blood conditions some of which are forms of leukaemia while

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others are pre-leukaemic blood disorders. In those with pre-leukaemic blood disorders, as there
is already a propensity to develop leukaemia, a proportion of patients on hydroxycarbamide for
these conditions will go on to develop leukaemia while on hydroxycarbamide. This is definitely
not the case when hydroxycarbamide is used in sickle cell disease; there are several thousands
of patients followed up over many years to support this finding.

Will hydroxycarbamide make me infertile?

In general for men, hydroxycarbamide does not prevent a man from making a woman pregnant
or fathering children. Sperm count and function might be reduced while taking
hydroxycarbamide. In most cases these abnormalities are corrected after hydroxycarbamide
has been stopped for 2-3 months. In a few cases, the sperm count and function has not returned
to normal after this period. It is recommended that a sperm sample is taken and stored before
commencing hydroxycarbamide. It is strongly recommended that contraception is used when
taking hydroxycarbamide because the drug can potentially be harmful to a developing foetus.

In women pregnancy should be avoided when a woman or her partner is taking

hydroxycarbamide due to the potential risk of foetal abnormalities. The drug should also be
stopped immediately if you become pregnant.

What is the risk of contracting HIV or hepatitis from a transfusion?

It is extremely rare for someone to develop a viral infection from a blood transfusion in the UK,
as the blood services undertake strict testing processes to detect contaminated blood. For
example it is estimated that;

1. The risk of getting hepatitis B is about 1 in 1.3 million

2. The risk of getting hepatitis C is about 1 in 28 million
3. The risk of getting HIV is about 1 in 6.5 million

It is reassuring to know that there has been no recorded case of an individual developing any of
the viral infections above from a transfusion since 2005.

Will a blood transfusion start a sickle cell crisis?

Blood transfusions are very safe procedures with a very low risk of side effects. They do not
directly start a sickle cell crisis, although a rare reaction to a transfusion could precipitate a
sickle cell crisis.

What will happen if I don’t take my iron chelation?

Excess iron from transfusions accumulates in a number of organs including the liver, pancreas,
joints and heart. Unfortunately the body does not have the capacity to excrete the excess iron

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that is absorbed. Iron chelating drugs act efficiently to remove excess iron form the body either
due to an inherent tendency to absorb iron or that which accumulates through blood
transfusions. The ultimate outcome of failure to adhere to iron chelation therapy is progressive
damage to vital organs due to the accumulation of iron, which in some cases is irreversible. This
can lead to liver disease, diabetes, arthritis, infertility and heart disease including the risk of
early death.

Can I have a transplant if I have a sibling as a donor?

Yes, if a sibling is a compatible match with you. At the time of preparation of these standards of
care, bone marrow transplantation for adults with sickle cell disease is not routinely
commissioned or funded by NHS England, although this might change in the future.

What is a bone marrow/stem cell transplant and would I be eligible for the
procedure?

In an individual with a sickle cell disease (SCD), the bone marrow produces red blood cells that
contain haemoglobin S, which leads to the complications of SCD. The transplant process
involves eradicating the patient’s stem cells, the patient’s immune system, using strong
medicines like chemotherapy. The stem cells are then replaced with a matched donor’s stem
cells using a transfusion through an IV tube. The new bone marrow then produces red blood
cells that are healthy as they do not contain haemoglobin S.

In the UK, funding for stem cell transplants is available where it can be shown that the potential
benefits outweigh the risks. Patients are at higher risk of catching life-threatening infections due
to chemotherapy and the immunosuppressants taken to avoid risk of graft-versus-host-disease
(GVHD), which is when the donor cells attack the host cells. GVHD that does not respond to
treatment can lead to organ damage or even death. A further risk is graft failure (when the
donated bone marrow fails to take). Each risk has a 5-10% chance of occurring. Transplants are
generally safer in children than in adults because their immune systems and other body tissues
are better able to regenerate and recover quickly from toxic treatments.

To be considered for the treatment, the following criteria must be met:

 The recipient must be healthy enough to survive the process, and not have severe organ
damage.
 There must be a matched donor. The donor will ideally be a healthy sibling who is a
cell/tissue match. There is about a 1 in 4 chance that a sibling will have matching tissue
and be a suitable donor.

Research into a cure for SCD is ongoing in the UK and abroad. For example, there is a new type
of stem cell transplant being developed, whereby chemotherapy is not needed, reducing the
risks involved. However, recipients still require immunosuppressants.

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If you would like to find out more about the treatments available to you in line with your
medical need and history, please speak to your consultant.

I have heard of new drugs in other countries, why are these not available in the
UK?

As at the time of preparing these standards, a number of new drugs have shown encouraging
results in the context of well-designed clinical trials. These new drugs are likely to be used on
their own or with hydroxycarbamide. Drug trial results are validated and published, then
assessed by the various licensing and funding regulatory bodies, including the European
Medicines Agency (EMA), the National Institute for Health and Care Excellence (NICE) and NHS
England. Once approved for use and funded, they will be available to patients in the UK.

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