Handbook of Oral Anticoagulation 2nd Edition

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Handbook of
Oral Anticoagulation
Second edition

Editors
Gregory YH Lip
University of Birmingham
Birmingham, UK

Eduard Shantsila
University of Birmingham
Birmingham, UK

Contributors
Deirdre A Lane
University of Birmingham
Birmingham, UK

Chee W Khoo
Specialist Registrar in Cardiology
West Midlands Deanery, UK

Kok Hoon Tay

Specialist Registrar in Cardiology
West Midlands Deanery, UK

Suresh Krishnamoorthy
Specialist Registrar in Cardiology
East Midlands Deanery, UK

Stavros Apostolakis
University of Birmingham
Birmingham, UK
Published by Springer Healthcare Ltd, 236 Gray’s Inn Road, London, WC1X 8HB, UK.

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© 2013 Springer Healthcare, a part of Springer Science+Business Media.

First edition, 2010

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ISBN 978 1 908517 58 6

eISBN 978 1 908517 96 8

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Designer: Joe Harvey
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Printed in Great Britain by Latimer Trend
 Contents
Author biographies vii

1 The coagulation pathway and approaches

to anticoagulation 1
Kok Hoon Tay, Eduard Shantsila, Gregory YH Lip

A brief overview of the coagulation pathway  1

The coagulation cascade  2
Approaches to anticoagulation  4
References5

2 Common clinical indications for anticoagulation 7

Suresh Krishnamoorthy, Chee W Khoo, Eduard Shantsila, Gregory YH Lip

Venous thromboembolism  7
Atrial fibrillation  17
Anticoagulation in other medical conditions  22
Conclusions  26
References26

3 Vitamin K antagonists and their limitations 33

Chee W Khoo, Eduard Shantsila, Gregory YH Lip

Pharmacology of warfarin 33
Pharmacogenetics of warfarin 34
Interactions of warfarin with other drugs and food 35
Commencement of anticoagulation 36
Monitoring of warfarin therapy 37
Conclusions39
References40

4 Hemorrhage risks, patient perspectives, and

quality-of-life issues 41
Kok-Hoon Tay, Stavros Apostolakis, Deirdre A Lane, Gregory YH Lip

Warfarin and risk of hemorrhage 43

Risk factors for hemorrhage 44

v
vi • co n te nts

Physician barriers to use of warfarin 46

Patient barriers to use of warfarin 47
Quality of life in atrial fibrillation 47
Conclusions49
References49

5 New oral anticoagulants 53

Direct thrombin inhibitors 53
Factor Xa inhibitors 64
Other novel factor Xa inhibitors 79
Other warfarin analogs 82
References 83

6 Future directions 87
Eduard Shantsila, Gregory YH Lip
Author biographies
Editors
Professor Gregory YH Lip is Professor of Cardiovascular Medicine at
the University of Birmingham, and Visiting Professor of Haemostasis,
Thrombosis, and Vascular Sciences in the School of Life and Health
Sciences at the University of Aston in Birmingham, UK.
Professor Lip is a member of the scientific documents committee of
the European Heart Rhythm Association (EHRA), and serves on the board
of the Working Group on Hypertension of the Heart of the European
Society of Cardiology (ESC). He is also a member of the Working Groups
of Thrombosis and Cardiovascular Pharmacology of the ESC.
Professor Lip has acted as Clinical Adviser for the UK National
Institute for Health and Clinical Excellence (NICE) guidelines on atrial
fibrillation (AF) management. He was on the writing committee for
the 8th American College of Chest Physicians (ACCP) Antithrombotic
Therapy Guidelines for Atrial Fibrillation, as well as various guidelines
and/or position statements from the EHRA, including the EHRA state-
ment on defining endpoints for AF management, and the EHRA guide-
lines for antithrombotic therapy during ablation. He was also on the
writing committee for the 2010 ESC Guidelines on Atrial Fibrillation
and was Deputy Editor for the 9th ACCP guidelines on antithrombotic
therapy for AF.
Professor Lip is involved at senior editorial level for several major
international journals, including Journal of Human Hypertension (Editor-
in-Chief), Thrombosis and Haemostasis (Editor-in-Chief [Clinical Studies]
designate), Thrombosis Research (Associate Editor), Europace (Associate
Editor), and Circulation (Guest Editor). He has published and lectured
extensively on thrombosis and antithrombotic disease in cardiovascular
disease.

v ii
viii • Aut h o r b i o g ra p h i e s

Dr Eduard Shantsila is a Postdoctorate Research Fellow at the University

of Birmingham Centre for Cardiovascular Science, City Hospital,
Birmingham, UK, where he leads a research group working on a number
of research projects that investigate endothelial damage/recovery and
monocyte characteristics including their role in thrombosis in patients with
acute coronary syndromes, heart failure, and systemic atherosclerosis.
Dr Shantsila worked in the Republican Research and Practical Centre
‘Cardiology,’ Minsk, Belarus, as a researcher and a cardiologist from 1998
and completed his PhD thesis in 2002 in Minsk, Belarus and another
PhD thesis in 2012 in Birmingham, United Kingdom. From 2005 to 2008
he was a head of the Department of Urgent Cardiology in this centre,
where he was actively involved in research work on the problems of car-
diovascular diagnostics, endothelial dysfunction, and thrombosis. He is
a member of the Working Group of Thrombosis of the ESC. Dr Shantsila
has published extensively on these topics, and is a peer reviewer of major
journals in thrombosis.

Contributors
Dr Stavros Apostolakis is an Honorary Lecturer in the School of Clinical
and Experimental Medicine, University of Birmingham. He graduated
from Medical School, University of Crete in 1999. He completed his PhD
research in the same institution in 2007. He practiced medicine in Greece
until October 2011. He was elected Senior Lecturer in Medicine at the
Democritus University of Thrace, Greece in 2010. In the same year he
was awarded the European Association of Cardiology Atherothrombosis
Research Grant. His main research interests are genetic epidemiology,
inflammation and coronary artery disease and atrial fibrillation.

Dr Deirdre A Lane is a Lecturer in Cardiovascular Health in the School of

Clinical and Experimental Medicine at the University of Birmingham, UK.
She received her Bachelor of Science with honors from the University of
Liverpool in 1995 and her PhD from the University of Birmingham in 2000.
 Au t h o r b i o g ra p h i e s • i x

Dr Lane is currently the principal investigator on a randomized con-

trolled trial (TREAT-ISCRTN93952605) comparing intensive education
with usual care in AF patients newly referred for oral anticoagulation,
to examine the impact of education on patients’ knowledge and percep-
tions of AF and its treatment, and international normalized ratio (INR)
control. In addition, she is involved in refining the risk stratification of
AF patients; she is a co-author of both the CHA 2DS2-VASc stroke risk
stratification schema and HAS-BLED bleeding risk schema. She is also a
panelist on the 9th edition of the American College of Chest Physicians
guidelines on Antithrombotic Therapy and Prevention of Thrombosis
and a member of the European Heart Rhythm Association Task Force
on bleeding risk assessment in atrial fibrillation.
Dr Lane has published her work widely in journals such as Stroke,
Chest, Thrombosis and Haemostasis, Psychosomatic Medicine, Journal of
Psychosomatic Research, and Heart.

Dr Chee W Khoo is a Specialist Registrar in Cardiology and the West

Midlands Deanery, UK. He graduated from University of Aberdeen.
After successfully obtaining the MRCP. He worked at the University of
Birmingham as Teaching Fellow and Cardiology Research Fellow from
2007 to 2011. His research interests are atrial fibrillation in pacemaker
populations and thrombogenesis. He has published numerous articles in
peer reviewed journals and also presented in national and international
conferences, which include the British Cardiac Society annual conference,
American College of Cardiology Conference, Heart Rhythm Congress,
and the Asia–Pacific Cardio Rhythm Congress.

Dr Kok Hoon Tay is a Specialist Registrar in Cardiology and the West

Midlands Deanery, UK and Dr Suresh Krishnamoorthy is a Specialist
Registrar in Cardiology and the East Midlands Deanery, UK. They are both
interested in the epidemiology and pathophysiology of thromboembo-
lism – and the use of antithrombotic therapy – in cardiovascular disease.
 Chapter 1

The coagulation pathway and

approaches to anticoagulation
Kok Hoon Tay, Eduard Shantsila, Gregory YH Lip

A brief overview of the coagulation pathway

Intact endothelium is smooth, lacks thrombogenic proteins on its surface,
and protects circulating blood from exposure to subendothelial proteins
such as collagen. As a result, blood constituents flow freely without
adhering to endothelial structures. However, when the endothelium is
damaged and its integrity is disrupted, subendothelial structures come
into contact with the constituents of blood (including coagulation factors
and platelets), and this triggers an intricate process responsible for platelet
attraction and deposition and, simultaneously, the coagulation cascade.
The coagulation cascade comprises two principal elements:
• the tissue factor (extrinsic) pathway; and
• the contact activation (intrinsic) pathway.
Both pathways ultimately lead to the formation of an insoluble fibrin clot.
Each involves a series of reactions in which inactive enzyme precursors
are transformed into their active forms, which catalyze the subsequent
reactions of the cascade.
The fundamental role of the coagulation system is to facilitate hemo-
stasis when there is hemorrhage due to blood vessel injury. Physiologically,
a self-maintained balance of procoagulant and anticoagulant factors/
regulators provides a negative feedback system for the prevention of
excessive coagulation or hemorrhagic diathesis.

G. Y. H. Lip and E. Shantsila (eds.), Handbook of Oral Anticoagulation, 1

DOI: 10.1007/978-1-908517-96-8_1,  Springer Healthcare 2013
2 • Hand b o o k o f Oral A nt icoagu lat io n

The coagulation cascade

The tissue factor (extrinsic) pathway
When the coagulation cascade is activated, tissue factor (TF), which is
normally located in subendothelial tissue, comes into contact with circu-
lating factor VII and forms an activated complex (TF–VIIa) in the pres-
ence of Ca2+ (Figure 1.1) [1]. TF–VIIa catalyses the conversion of factor X
into factor Xa and, following binding of activated factor Va, initiates
formation of the serum protease thrombin. Thrombin is formed from

Coagulation pathways

Contact activation Tissue factor

(intrinsic) pathway (extrinsic) pathway

Damaged surface Trauma

TFPI

XII XIIa
TF

XI XIa TF-VIIa VII

IX IXa VIIIa VIII

Antithrombin
X X
Xa
Prothrombin (II) Thrombin (IIa) Common
Va pathway
V
Fibrinogen (I) Fibrin (Ia)

XIIIa XIII

Cross-linked
Activated fibrin clot
Protein C

Protein S

Protein C + Thrombomodulin

Figure 1.1 Coagulation pathways. TFPI, Tissue factor pathway inhibitor.

 T h e coag u l at i o n pat h way a n d a p p r oac h e s to a n t i coag u l at i o n • 3

prothrombin via a complex reaction in which factors Xa and Va cleave

prothrombin fragments 1 and 2 in the presence of Ca2+. Subsequently,
thrombin cleaves fibrinopeptides A and B from fibrinogen, resulting in
the formation of insoluble fibrin.

The contact activation (intrinsic) pathway

The contact activation (intrinsic) pathway begins with the formation
of a complex made up of Hageman factor (factor XII), prekallikrein,
high-molecular-weight kininogen (HMWK), and collagen. Given that
the absence of factor XII, prekallikrein, or HMWK does not induce a
clinically apparent pathology [2], the physiological role of this complex is
unclear and it is assumed to have only a minor function in clot formation.
Damage to the endothelial surface triggers formation of factor XIa
from factor XI via factor XIIa. Next, in the presence of Ca2+ factor XIa
catalyses the conversion of factor IX to IXa, which then triggers the
conversion of factor VIII to VIIIa. Factors IXa and VIIIa form a catalytic
complex and efficiently activate factor X. Activation of factor X marks
the convergence of the tissue factor and contact activation pathways into
a common pathway, which is responsible for the formation of a fibrin
mesh on the damaged vessel wall.

Regulation of the coagulation cascade

The ‘protagonist’ of the coagulation cascade is thrombin, which has a
master role in regulating the coagulation pathway. Generation of thrombin
subsequently activates circulating platelets bound to von Willebrand factor
and factor VIIIa.
To avert excessive clotting, multiple elements of a negative feedback
system maintain the coagulation cascade in a balanced state. Activated
protein C (coupled with protein S) and thrombomodulin limit the exces-
sive generation of factors Va, Xa, VIIIa, and IXa, thus both protein C and
protein S act as naturally occurring anticoagulants. Antithrombin, a potent
inhibitor of the coagulation cascade, inhibits thrombin and several other
clotting factors involved in the cascade. Another mechanism that keeps
platelet activation and coagulation under control is mediated by a TF
pathway inhibitor, which has its primary role as a restrictor of TF activity.
4 • Hand b o o k o f Oral A nt icoagu lat io n

Conclusions
The coagulation cascade is an intricate process without which hemorrhage
clotting would occur uncontrollably whenever there is tissue insult.

Approaches to anticoagulation
Eduard Shantsila, Gregory YH Lip

In a large number of disorders there is a raised risk of thrombosis, the

pathological development of blood clots that interfere with the circulation.
Common examples include:
• venous thromboembolism, encompassing both deep vein
thrombosis and pulmonary embolism;
• atrial fibrillation;
• acute coronary syndromes;
• valve disease and endocarditis; and
• conditions associated with a raised risk of ischemic stroke.
The coagulation cascade is a major target for thromboprophylactic
medications. Anticoagulation can be achieved by inhibition of different
factors of coagulation. For example, warfarin, discussed in Chapter 3,
reduces the functional level of factors II (prothrombin), VII, IX, and X
by preventing the γ-carboxylation of these vitamin K-dependent factors.
However, a disadvantage of warfarin and other vitamin K antagonists is
that they are associated with a raised risk of hemorrhage, as described
in Chapter 4, together with the fact that their effect fluctuates in any
one patient and necessitates frequent monitoring.
Another route exploited for anticoagulation is the use of heparin to
increase the inhibitory action of antithrombin. Heparin preparations are
the mainstay of anticoagulation in many clinical settings, as reviewed
in Chapter 2. However, unlike warfarin, heparin preparations require
parenteral administration.
The ideal anticoagulant would be an oral preparation that has a more
predictable therapeutic action and which requires significantly less moni-
toring than warfarin. Consequently, the development of a number of alter-
native oral anticoagulants is of great interest. Modern novel anticoagulant
development has focused on the synthesis of selective inhibitors of specific
 T h e coag u l at i o n pat h way a n d a p p r oac h e s to a n t i coag u l at i o n • 5

coagulation factors, which preferably act independently of cofactors. Novel

oral anticoagulants targeting inhibition of factor Xa and thrombin (factor
IIa) have now been incorporated into clinical practice, as discussed in
Chapter 5. These factors are the final elements of the coagulation cascade
and their inhibition blocks both the intrinsic (plasma) and the extrinsic
(tissue) coagulation cascades.

References
1 Mann KG, Nesheim ME, Church WR, et al. Surface-dependent reactions of the vitamin K
dependent enzyme complexes. Blood. 1990;76:1-16.
2 Badimon L, Badimon JJ. The pathophysiology of thrombus. In: Blann A, Lip GYH, Turpie AGG (eds),
Thrombosis in Clinical Practice. London: Taylor & Francis; 2005:1-16.
 Chapter 2

Common clinical indications

for anticoagulation
Suresh Krishnamoorthy, Chee W Khoo, Eduard Shantsila,
Gregory YH Lip

As discussed in Chapter 1, an anticoagulant is a substance that pos-

sesses the properties to limit clot formation and therefore can be used
therapeutically to prevent or treat thrombotic disorders. In this chapter
we discuss the common clinical conditions in which anticoagulation
should be considered and the evidence available to justify the use of an
appropriate antithrombotic therapy in these clinical settings.

Venous thromboembolism
Epidemiology
Venous thromboembolism (VTE) encompasses both deep vein thrombosis
(DVT) and pulmonary embolism (PE). It is a common disorder with an
incidence of 7.1 per 1000 person-years in developed countries [1,2]. VTE
is more common in males and in black populations, and the incidence
increases with aging. Furthermore, up to a fifth of patients with previous
VTE have recurrences of VTE in the following 5 years [3].
PE, a life-threatening presentation of VTE, has a reported incidence
of 6 cases per 10,000 person-years [4]. Notably, around 80% of cases
of PE occur without any clinical signs [5]. It is also estimated that 1 in
every 100 inpatient deaths is related to PE, making it one of the most
common causes of preventable hospital mortality [6].

G. Y. H. Lip and E. Shantsila (eds.), Handbook of Oral Anticoagulation, 7

DOI: 10.1007/978-1-908517-96-8_2,  Springer Healthcare 2013
8 • Hand b o o k o f Oral A nt icoagu lat io n

Given that patients with VTE have a substantially increased risk of

morbidity and mortality because of its complications (life-threatening
PE and post-thrombotic syndrome) [7], when its presence is suspected
patients should be carefully considered to ensure timely diagnosis and
initiation of treatment. Common conditions associated with VTE are
shown in Table 2.1. The imbalance between the activated coagulation
cascade (both intrinsic and extrinsic pathways) and the fibrinolytic
system is another predisposing feature that increases the risk of VTE.
It is worth mentioning that venous thrombi differ in site of formation
and are rich in red cells compared with arterial thrombi, which are mainly
platelet rich. Consequently, the antithrombotic effects of anticoagulants
may vary substantially depending on thrombus location and these agents
require a specific regimen for the clinical settings of venous thrombosis
(eg, VTE) and arterial thrombosis (eg, acute coronary syndromes).

Anticoagulation in the prevention of

venous thromboembolism
The incidence of VTE can be reduced significantly using prophylactic regi-
mens in high-risk patients. Appropriate prophylaxis has been found to be
cost-effective compared with the cost of managing established VTE cases [8].
Various prophylactic measures have been recommended in the pre-
vention of VTE, including injections of low-dose unfractionated heparin
(UFH), adjusted-dose UFH, low-molecular-weight heparin (LMWH), oral
warfarin, external pneumatic compression, or gradient elastic stockings

Common conditions associated with venous thromboembolism

Post-trauma
•• Post-surgical patients (major surgery lasting >30 min, orthopedic surgeries)
•• Previous deep vein thrombosis/pulmonary embolism
•• Prolonged immobilization (bed rest, paralysis of legs or plaster casts, long flights)
•• Malignancy
•• Obesity
•• Pregnancy, use of oral contraceptive pills
•• Advanced age
•• Other conditions: antithrombin III deficiency, protein C and S deficiency (eg, varicose
veins, thrombocytosis, polycythemia rubra vera, systemic lupus erythematosus, nephritic
syndrome, stroke and debilitating infections)

Table 2.1 Common conditions associated with venous thromboembolism.