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Thalassaemia:
Pathogenesis and Lab Diagnosis
Dr. M Sadequel Islam Talukder
MBBS, M Phil (Pathology), MACP
Assistant Professor
Department of Pathology
Dinajpur Medical College
Presentation at Seminar on observation of World Thalassaemia Day 2009
Presentation: 10 May 2009, Dinajpur Medical College
Pathogenesis
Genetically determined
Heterogenous group of disorder
Reduced synthesis of one or more types of
normal haemoglobin polypeptide chain
Reduced haemoglobin involving affected chain
Normal Haemoglobin
• HbA - α2β2
• HbA2 - α2δ2
• HbF – α2γ2
Each goblin chain have separate genetic control
α –thalassaemia affect α-chain synthesis
β –thalassaemia affect β -chain synthesis
β-Thalassaemia
An absence or deficiency of β-chain synthesis of adult HbA
β Chain synthesis
Hb-A
γ and δ chain
Hb-A = α2β2
On the basis of synthetic ability β-genes are
designated as
• β gene – can synthesize normal amount of β-chain
• β+ gene – can synthesize reduced amount of β-chain
• β0 gene – cannot synthesize β-chain
• β-thalassaemia major
– Mutation of normal β-gene β0-gene  absence
HbA  increased HA2 and HbF
– genotype – β0β0
• β-thalassaemia intermedia
–
–
–
–
↑HbA2
↑HbF
↓HbA
Genotype β+ β+ or β0 β
• β-thalassaemia minor
– ↑HbA2
– HbA normal
– HbF normal
Pathophysiology of β-Thalassaemia
Various mutation in β-gene
Complete or partial absence of β-chain
Decreased adult HbA
α-chain synthesis remain normal
Free complementary α-chain – unstable and
precipitate within normoblasts as insoluble inclusions
Cell membrane damage & impaired DNA synthesis
apoptosis i.e. ineffective erythropoeisis
70-80% marrow normoblasts undergo apoptosis
Inclusion bearing red cells undergo
sequestration & destruction in spleen
Partial or lack of HbA synthesis ↓MCHC & MCH
Hypochromia & microcytosis
Normal
Thalassaemia
Reticulocytes undergo intramedullary death
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
α-Thassaemia
An absence or deficiency of α-chain synthesis
due to delation of α-genes.
Pathogenesis of α-Thalassaemia
• In normal individual HbA, HbA2 and HbF
need α-chain for their formation.
• 4 genes of α-chain, each pair on short arm of
chromosome 16 present with genotype
α,α/α,α.
• In α-thalassaemia, delation of α-genes
reduction or absence of synthesis of α-chain
depending on number of α-gene delation.
• ↓α-chain synthesis free γ-chain in the fetus & βchain in infant of 6 months, and continue in the
rest of life.
• Complementary 4γ and 4β are aggregated 
Hb Bart (4γ ) and HbH (4β ), respectively.
Variants of α-Thalassaemia
• Silent carrier
–
–
–
–
Delation of single α-gene
Genotype α/αα
Asymptomatic
Absence of RBC abnormality
• Thalasaemia trait
–
–
–
–
Delation of 2 α-genes
Genotype --/αα
Asymptometic, minimal or no anaemia
Minimal RBC abnormalities
• Hb H disease
–
–
–
–
Delation of 3 α-genes
Genotype --/- α
75% reduction of α-chain
25% α-chain synthesis small amount of HbF,
HbA, & HbA2
– Fetus can survive
– Severe anaemia
– Severe RBC abnormalites
• Hydrops fetalis
–
–
–
–
Delation of all α-genes
Genotype --/-Absence of α-chain synthsis
Only Hb Bart (γ4) is produced (High affinity for O2
and can not dissociate O2 to tissue)
Inheritance
Laboratory Diagnosis of Thalassaemia
Laboratory Findings
•
•
•
•
•
•
•
•
Hb concentration – Decreased
ESR – Mild increased
WBC – Neutrophilic leucocytosis or normal
RBC count – Markedly decreased
PCV – Markedly decreased
MCV, MCH, MCHC – reduced
Reticulocyte count – Increased
Platelet count – May be increased
Peripheral Blood Film
Normal
Morphology of PBF
• RBC
– Marked anisocytosis,
polikilocytosis,
microcytosis,
frequent target cells,
basophilic stippling,
fragmented cells or
schistocytosis,
polychromatic
macrocytes and
nucleated cells
• WBC
– Whin normal or
neutrophilic
leucocytosis
• Platelets
– Normal or increased
Thalassaemia slides
Haemoglobin Electrophoresis
• Different types of haemoglobins contain
different surface charge which determine the
elecrtrophoretic mobility and gives a specific
bands on the electrophoretic papers when
haemolysate is undergone eletrophoresis.
• HbF, HbA, HbA2, HbC, HbE, HbD, HbS, HbH
and Hb Bart can be measured accurately by
electrophoresis
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