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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

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Thalassaemia pathogenesis and lab diagnosis l.jpg

Thalassaemia:Pathogenesis and Lab Diagnosis

Dr. M Sadequel Islam TalukderMBBS, M Phil (Pathology), MACPAssistant ProfessorDepartment of PathologyDinajpur Medical College

Presentation at Seminar on observation of World Thalassaemia Day 2009

Presentation: 10 May 2009, Dinajpur Medical College


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Pathogenesis

Genetically determined

Heterogenous group of disorder

Reduced synthesis of one or more types of normal haemoglobin polypeptide chain

Reduced haemoglobin involving affected chain


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Normal Haemoglobin

  • HbA - α2β2

  • HbA2 - α2δ2

  • HbF – α2γ2


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Each goblin chain have separate genetic control

α –thalassaemia affect α-chain synthesis

β –thalassaemia affect β-chain synthesis


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β-Thalassaemia

β Chain synthesis

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

Hb-A

γ and δ chain

Hb-A = α2β2


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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


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  • 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 β0β

  • β-thalassaemia minor

    • ↑HbA2

    • HbA normal

    • HbF normal


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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


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70-80% marrow normoblasts undergo apoptosis

Inclusion bearing red cells undergo sequestration & destruction in spleen


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Partial or lack of HbA synthesis ↓MCHC & MCH Hypochromia & microcytosis

Normal

Thalassaemia


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Reticulocytes undergo intramedullary death

Inadequate production + ineffective erythropoiesis + haemolysis Anaemia


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↑Haemolysis ↑demands of phagocytic function  hyperplasia of phagocytes Hepatosplenomegaly

To compensate anaemia extramedullary haemopoiesis in liver, spleen & brain Organomegaly


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↑Erythropoiesismarrow expansion & thinning of cortex of skull bone Thalassaemia facies


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α-Thassaemia

An absence or deficiency of α-chain synthesis due to delation of α-genes.


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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.


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  • ↓α-chain synthesis free γ-chain in the fetus & β-chain 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.


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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


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  • 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)


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Inheritance


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Laboratory Diagnosis of Thalassaemia


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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


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Peripheral Blood Film

Normal


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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

Morphology of PBF


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Thalassaemia slides


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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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Thanks


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