Thalassaemias are group of the
disordersin which the
production of normal haemoglobin is
partly or completely suppressed as a result
of the defective synthesis of one or more
Thalassemia is inherited
5 in every 100 people are thalassaemia carriers
• 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%
• 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
- Silent Carrier
- Trait (Minor)
- Hemoglobin H Disease
- Major (Hemoglobin Bart’s)
- Hemoglobin Constant Spring
- Trait (Minor)
- Major (Cooley anemia)
• 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
• Possible mutation states:
▫ Loss of ONE gene silent carrier
▫ Loss of TWO genes thalassemia minor (trait)
▫ 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
• 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
An absence or deficiency of β-chain synthesis of adult HbA
β Chain synthesis
γ and δ chain
• Loss of ONE gene thalassemia minor (trait)
▫ HbA normal
▫ HbF normal
• Loss of BOTH genes
▫ Thalassemia intermedia β+ β+ or β0 β+
▫ Thalassemia major β0β0
• Haemoglobin E disorder is the most common
structural variant resembling thalassemia
• HbE results from a mutation (GA) at codon 26 of
the ‚ β -globin gene
• HbE/ β thalassemia
• Clinical features
▫ Physical examinations
• Lab investigations
• Screening family members
Clinical Outcomes of α Thalassemia
• Silent carriers
• Alpha Thalassemia minor (trait)
• No anemia
• Alpha Thalassemia intermedia (Hemoglobin H)
• Anemia and microcytosis
• Bone deformities
• Hemoglobin Constant Spring
• Similar to HbH but no microcytosis
• Growth delay
• Alpha Thalassemia major
• Hb Bart’s
• Fatal hydrops fetalis
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.
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).
5. Complications and management
• Complications of disease
• Complications of treatment
• Full blood count, Peripheral blood film
• Hb analysis by electrophoresis / High Performance Liquid
• Serum ferritin.
• Red cell phenotyping (ideal) before first transfusion.
• DNA analysis (ideal)
• Liver function test.
• Infection screen: HIV, Hepatitis B & C, VDRL screen (before
• HLA typing (for all patient with unaffected siblings)
Regular maintenance blood
transfusion and iron chelation
therapy is the mainstay of treatment
in this patient
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.
• 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.
• Usually 4 weekly interval (usual rate of Hb
decline is at 1g/dl/week).
• Interval varies from individual patients (range: 2
- 6 weekly).
• Volume: 15 - 20mls/kg (maximum) packed red
• 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.
• Beta thalassemia major
• Wt 16 kg
• Hb 4
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
α Thalassemia (HbH disease)
• Transfuse only if Hb persistently < 7g/dl and/or
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
• An alternative if iron chelation is
ineffective or inadequate despite
optimal Desferal® use, or if
• Deferiprone is given 75 – 100
mg/kg/day in 3 divided doses.
• Can also be used in combination
with Desferal®, using a lower dose of
• Risks of GI disturbance, arthritis and
rare occurrence of idiopathic
• Stop if neutropenic
• Can also be used for transfusional
iron overload in patients 2 years or
• The dose is 20-30 mg/kg/day in
liquid dispersible tablet, taken once
• There are risks of transient skin rash,
GI disturbance and a reversible rise in
Algorithm to start iron chelation therapy - CPG
• 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
• Evidence of hypersplenism.
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
• Annual blood requirement/kg
• Annual pure red cells requirement/kg
• 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.
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
• Tea may help decrease intestinal iron absorption.
• Dairy products are recommended as they are rich in calcium.
• Vitamin E as antioxidant.
• Calcium and zinc.
Bone marrow transplantation
• Potential curative option when there is an HLA-compatible
• Results from matched unrelated donor or unrelated cord blood
transplant are still inferior with higher morbidity, mortality and
• 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
Algorithm for management
of transfusion dependent
thalassemia - cpg
5. Take home messages
• What is thalassemia?
• Genetic transmission and variations
• Family screening
• Patient education and compliance
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
5. Guidelines for the Clinical Management of Thalassemia 2nd Revised
ed by Thalassemia International Federation 2008
7. Molecular basis of thalassemia by Chris Chan, Louis Chiu, Lok Tin Liu
and Janet Lui