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Thalassemia
By: Dr shafiq
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Contents
• Introduction
• Types
• Diagnosis
• Complications and management
• Take home message
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1. Introduction
THALASSEMIA

1930s: from Greek thalassa ‘sea’

(because the diseases were first
known around the Mediterranean)
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Thalassaemias are group of the

haemoglobin
disorders in which the
production of normal haemoglobin is
partly or completely suppressed as a result
of the defective synthesis of one or more
globin chains
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Thalassemia is inherited
by autosomal
recessive
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Normal hemoglobin
• Embryonic Hb: 3rd to 10th week ofpregnancy
ζ2ε2, α2ε2, ζ2γ2 tetramers

• Fetal Hb α2γ2

• Adult Hb
98% HbA α2β2, 2% HbA2 α2δ2
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Chromosomes 11

Chromosomes 16
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Epidemiology
5 in every 100 people are thalassaemia carriers
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• β-Thalassaemia major is an inherited blood

disorder presenting with anaemia at 4 – 6
months of age.

• The carrier rates of α-thalassaemia and

Haemoglobin E (HbE) are 1.8-7.5% and 5-46%
respectively

• Interaction between a β-thalassaemia carrier

with a HbE carrier may result in the birth of a
patient with HbE/β-thalassaemia or
thalassaemia intermedia with variable clinical
severity
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2. Types
-Silent Carrier
-Trait (Minor)
-Hemoglobin H Disease
α
THALASSEMIA

(Intermediate)
-Major (Hemoglobin Bart’s)
-Hemoglobin Constant Spring

- Trait (Minor)
β - Intermedia
- Major (Cooley anemia)
Alpha Thalassemia
• Deficient/absent alpha subunits
▫ Excess beta subunits
▫ Excess gamma subunits newborns

• Encoding genes on chromosome 16

• Each cell has 4 copies of the alpha globin gene

▫ Each gene responsible for ¼ production of alpha
globin
• Possible mutation states: GENE

▫ Loss of ONE gene  silent carrier CHROM

OSOME
PROTEIN
CELL
▫ Loss of TWO genes  thalassemia minor (trait) DNA

▫ Loss of THREE genes  Hemoglobin H disease

Accumulation of beta chains
Association of beta chains in groups of 4  Hemoglobin H

▫ Hb constant spring similar to HbH but no microcytosis

▫ Loss of FOUR genes  Hemoglobin Barts

NO alpha chains produced ∴ only gamma chains present
Association of 4 gamma chains  Hemoglobin Barts
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β/γ β/γ

β/γ
β/γ
Beta Thalassemia
• Encoding genes on chromosome 11

• Each cell contains 2 copies of beta globin gene

• Suppression of gene more likely than deletion

▫ β0 refers to the complete absence of production of β -
globin on the affected allele

▫ β+ refers to alleles with some residual production of ‚

β -globin (around 10%)

▫ β++ ;the reduction in β -globin production is very mild

β-Thalassaemia
An absence or deficiency of β-chain synthesis of adult HbA

β Chain synthesis

Hb-A α2β2

γ and δ chain
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• Loss of ONE gene  thalassemia minor (trait)

▫ ↑HbA2
▫ HbA normal
▫ HbF normal

• Loss of BOTH genes

▫ Thalassemia intermedia β+ β+ or β0 β+
▫ Thalassemia major β0β0
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HbE α2βE2
• Haemoglobin E disorder is the most common
structural variant resembling thalassemia
disorders

• HbE results from a mutation (GA) at codon 26 of

the ‚ β -globin gene

• HbE/ β thalassemia
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3. Diagnosis
• Clinical features
▫ History
▫ Physical examinations

• Lab investigations

• Screening family members

Clinical Outcomes of α
Thalassemia
• Silent carriers
• Asymptomatic

• Alpha Thalassemia minor (trait)

• No anemia
• Microcytosis

• Alpha Thalassemia intermedia (Hemoglobin H)

• Anemia and microcytosis
• Bone deformities
• Splenomegaly
• Hemoglobin Constant Spring
• Similar to HbH but no microcytosis
• Anemia
• Growth delay

• Alpha Thalassemia major

• Hb Bart’s
• Fatal hydrops fetalis
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Pathophysiology of beta thalassemia

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Beta thalassemia
intermedia
“Too haematologically severe to be
called minor, but too mild to be called
major”
Rietti-Greppi-Micheli [1995]
Partial or lack of HbA synthesis ↓MCHC &
MCH Hypochromia & microcytosis

Normal

Thalassaemia
Inadequate production + ineffective
erythropoiesis + haemolysis Anaemia
↑Haemolysis ↑demands of phagocytic
function  hyperplasia of phagocytes
Hepatosplenomegaly
To compensate anaemia extramedullary
haemopoiesis in liver, spleen & brain
Organomegaly
↑Erythropoiesis marrow expansion & thinning
of cortex of skull bone Thalassaemia facies
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Algorithm for screening of thalassaemia in

Malaysia

FBP, Hb
Analysis
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The red blood cells here are normal, happy RBC's. They have a zone of central
pallor about 1/3 the size of the RBC. The RBC's demonstrate minimal variation in
size (anisocytosis) and shape (poikilocytosis). A few small fuzzy blue platelets are
seen. In the center of the field are a band neutrophil on the left and
asegmented neutrophil on the right.
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The RBC's here appear smaller than normal and have an increased zone of central
pallor. This is indicative of a hypochromic (less hemoglobin in each RBC) and
microcytic (smaller size of each RBC) anemia. There is also increased anisocytosis
(variation in RBC size) and poikilocytosis (variation in RBC shape).
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Schistocytes
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basophilic stippling
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5. Complications and management

• Complications of disease

• Complications of treatment
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Management
Baseline investigations
•Full blood count, Peripheral blood film
•Hb analysis by electrophoresis / High Performance Liquid
Chromatography (HPLC)

• Serum ferritin.
• Red cell phenotyping (ideal) before first transfusion.

•DNA analysis (ideal)

• Liver function test.

•Infection screen: HIV, Hepatitis B & C, VDRL screen (before

first transfusion).
• HLA typing (for all patient with unaffected siblings)
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Transfusiondependent
thalassemia
Regular maintenance blood
transfusion and iron chelation
therapy is the mainstay of treatment
in this patient
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β Thalassemia
major
When to start blood transfusion?

•After completing blood investigations for

confirmation of diagnosis.

•Hb < 7g/dl on 2 occasions > 2 weeks apart (in

absence other factors e.g. infection).

•Hb > 7g/dl in β+-thalassaemia major/severe forms

of HbE-β-thalassaemia if impaired growth, severe
bone changes, enlarging liver and spleen.
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Transfusion targets?

•Maintain pre transfusion Hb level at 9 -10 g/dl.

• Keep mean post-transfusion Hb at 13.5-15.5g/dl.

• Keep mean Hb 12 - 12.5 g/dl.

•The above targets allow for normal physical activity and

growth, abolishes chronic hypoxaemia, reduce
compensatory marrow hyperplasia which causes
irreversible facial bone changes and para-spinal masses.
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Transfusion interval?

•Usually 4 weekly interval (usual rate of Hb

decline is at 1g/dl/week).

• Interval varies from individual patients (range: 2

- 6 weekly).

Transfusion volume?

•Volume: 15 - 20mls/kg (maximum) packed red

cells (PRBC).
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• In the presence of cardiac failure or Hb < 5g/dl,

use lower volume PRBC (< 5ml/kg) at slow
infusion rate over > 4 hours with IV Frusemide 1
mg/kg (20 mg maximum dose).

• It is recommended for patients to use

leucodepleted (pre-storage, post storage or
bedside leucocyte filters) PRBC < 2 weeks old.

• Leucodepletion would minimize non-haemolytic

febrile reactions and alloimmunization by
removing white cells contaminating PRBC.
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Example
• Beta thalassemia major
• Wt 16 kg
• Hb 4

Calculations:
Total PC: (12-4)(16)(3.5) = 448 cc
1st tx 5cc/kg = (5)(16) =80 cc
2nd tx 10cc/kg= (10)(16) = 160 cc
Balance 384- 80 -160=208 cc
Max possible tx 20cc/kg = 320 cc
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α Thalassemia (HbH
disease)
• Transfuse only if Hb persistently < 7g/dl and/or
symptomatic.
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Iron chelation therapy

• DFO: Desferrioxamine (Desferal®)

• DFP: Deferiprone (Ferriprox®/Kelfer®)

• DFX: Deferasirox (Exjade®)

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DFO: Desferrioxamine (Desferal®)

When to start? • Usually when the child is > 2 - 3 years old.
• When serum ferritin reaches 1000 μg/L.
• Usually after 10 – 20 blood transfusions.

Dosage, route •Average daily dose is 20 – 40mg/kg/day.

•By subcutaneous (s.c.) continuous infusion using a
portable pump over 8-10 hours daily, 5 - 7 nights a week.
Complications • Local skin reaction
• Yersinia infection
• Ocular/auditory toxicity
• Skeletal lesion i.e. vertebral growth retardation
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DFP DFX
•An alternative if iron chelation is • Can also be used for transfusional
ineffective or inadequate despite iron overload in patients 2 years or
optimal Desferal® use, or if older
Desferal® use
is contraindicated. • Expensive.

•Deferiprone is given 75 – 100 •The dose is 20-30 mg/kg/day in

mg/kg/day in 3 divided doses. liquid dispersible tablet, taken once
daily.
•Can also be used in combination
with Desferal®, using a lower dose of •There are risks of transient skin rash,
50mg/kg/day. GI disturbance and a reversible rise in
serum creatinine.
•Risks of GI disturbance, arthritis and
rare occurrence of idiopathic
agranulocytosis.

•Stop if neutropenic
(<1,500/mm³).
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12.5mg:
Rm40/pill
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• Endocrine: growth retardation,

impaired glucose tolerance,
pubertal delay, hypothyroidism,
hypoparathyroidism and diabetes
mellitus.

• Cardiac: arrhythmias, pericarditis,

cardiac failure.

• Hepatic: liver cirrhosis (especially

if with Hepatitis B/C infection).
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Algorithm to start iron chelation therapy - CPG

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Splenectomy
Indications
•Blood consumption volume of pure RBC > 1.5X
normal or >200-220 mls/kg/year in those > 5
years of age to maintain average haemoglobin
levels.

•Evidence of hypersplenism.
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Example of calculation
(volume pure RBC/kg/yr)
▫ Wt 16 kg
▫ Average HCT of pack RBC given 50-55% (0.55)

•Total PC transfused in a yr
(300cc)(12)=3600cc

•Annual blood requirement/kg

3600cc/16kg=225cc/kg/yr

•Annual pure red cells requirement/kg

(225)(0.55)=123.75cc/kg/yr
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Note:
•Give pneumococcal and HIB vaccinations 4-6 weeks
prior to splenectomy.

•Meningococcal vaccine required in endemic areas.

• Penicillin prophylaxis for life after splenectomy.

•Low dose aspirin (75 mg daily) if thrombocytosis >

800,000/mm³ after splenectomy.
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Hemophilus influenza
Streptococcus pneumoniae

Neisseria meningitidis
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Patient monitoring
Assessment and ix
Blood tx HbsAg, anti HCV, Anti HIV 6 monthly

Growth Wt, Ht 3-6 monthly

Iron overload Serum ferritin 3 monthly

Pt > 10 y/o:
ECG, ECHO annually
LIC MRI 1-2 yearly
Cardiac MRI T2 1-2 yearly
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Assessment and ix
Drug toxicity 1) DFO: auditory/ophtalmology annually
2) DFP: FBC weekly, ALT 3monthly
3) DFX: RFT, LFT, Urine protein monthly,
auditory/ophtalmology annually

Complications 1) Growth failure

(especially in DM, hypothyroidism, delayed puberty, bone disorder,
>10 yrs old)
2) Delayed puberty, hypogonadism
Tanner staging 6 monthly
LH, FSH, estradiol/testosterone

3)Hypothyroidism : TFT

4) DM: FBS, OGTT

5) Osteoporosis/osteopenia
Serum Ca, PO4, ALP, Xray, DEXA scan
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Assessment and ix
Complications (cont.) 6)Hypoparathyroidism: PTH

7)Hypoadrenalism
Baseline morning cortisol
ACTH stimulation test
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Management of complications cont.

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Diet and supplements

•Oral folate at minimum 1 mg daily

•Low dose Vitamin C at 3 mg/kg augments iron excretion for those on

Desferral only. Dose: <10 yrs, 50mg daily; >10yrs, 100mg daily given
only on desferral days

•Avoid iron rich food such as red meat and iron fortified cereals or
milk.

•Tea may help decrease intestinal iron absorption.

•Dairy products are recommended as they are rich in calcium.

•Vitamin E as antioxidant.
•Calcium and zinc.
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Bone marrow transplantation

•Potential curative option when there is an HLA-compatible
sibling donor.

•Results from matched unrelated donor or unrelated cord blood

transplant are still inferior with higher morbidity, mortality and
rejection rates.

•Classification of patients into Pesaro risk groups based on the

presence of 3 risk factors: hepatomegaly > 2cm, irregular
iron chelation and presence of liver fibrosis.

•Best results if performed at the earliest age possible in Class 1

patients.
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Algorithm for management

of transfusion dependent
thalassemia - cpg
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5. Take home messages

• What is thalassemia?

• Genetic transmission and variations

• Family screening

• Patient education and compliance

• Complications
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References:
1. Pediatric Protocol 3rd ed
2. Illustrated Textbook of Pediatrics of 3rd ed
3. Nelson Essential of Pediatrics 6th ed
4. Malaysian CPG Management of Transfusion Dependent Thalassemia
November 2009
5. Guidelines for the Clinical Management of Thalassemia 2nd Revised
ed by Thalassemia International Federation 2008
6. www.mytalasemia.net.my
7. Molecular basis of thalassemia by Chris Chan, Louis Chiu, Lok Tin Liu
and Janet Lui
8. http://library.med.utah.edu/WebPath
9. CDC