HEMOLYTIC ANEMIA

LEARNING OBJECTIVES

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Genetic defect in β and alpha thalassemia

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immune hemolytic anemias

β - THALASAEMIAS

CHARACTERISTIC FEATURES -

Diminished synthesis of β – globin chains - Un – impaired synthesis of α – globin chains - Heterogeneous causative gene mutations

β

+

THALASSAEMIA

MOLECULAR PATHOGENESIS 1. PROMOTOR REGION MUTATION

- Reduced transcription of mRNA by 75% - 80% - 20% - 25% normal β – globin chain synthesis

β

+

THALASSAEMIA

MOLECULAR PATHOGENESIS

2.

ECTOPIC SLIPLICING MUTATION

- Occurs at abnormal sites within intron - Abnormal splicing of mRNA - Normal splicing sites co – exist

β

0

THALASSAEMIA

MOLECULAR PATHOGENESIS 1. CHAIN TERMINATION MUTATION

- Premature termination of mRNA translation

a. NON – SENSE MUTATION:

Within exon; changes amino acid codon to a “stop codon” (UAG, UAA, UGA) ( contd………)

β

0

THALASSAEMIA

MOLECULAR PATHOGENESIS b. FRAME – SHIFT MUTATION:

- Small insertions or deletion, shifts mRNA reading frame - Termination of β globin chain synthesis

β

0

THALASSAEMIA

MOLECULAR PATHOGENESIS 2. SPLICING MUTATION

- Most common mutations in β –thal i) Introns ii) Within exons iii) Normal splice junction

Site of mutation

- Normal splicing of mRNA does not occur at all - Degradation of unspliced mRNA within the nucleus

IMMUNE HAEMOLYTIC ANAEMIA (IHA)

• • Antibody mediated hemolysis Diagnosed by Coombs antiglobulin test a. Direct antiglobulin test (Red cells) - Antibody - Compliment b. Indirect antiglobulin test (serum) - Antibody specificity

WARM ANTIBODY IMMUNE HAEMOLYTIC ANAEMIA

• • • Most common type (48% – 70%) 50% are idiopathic Antibodies : IgG (common) IgA (rare) specificity : Rh system

WARM ANTIBODY IMMUNE HAEMOLYTIC ANAEMIA (CONTD..)

• • • • • • •

MECHANISM OF HAEMOLYSIS

Antibody binds to red cells at 37’ C Antibody coated red cells bind to FC receptors on splenic macrophages Partial phagocytosis Spherocytosis Splenic sequestration/ destruction Moderate splenomegaly is characteristic

COLD AGGLUTININ IMMUNOHAEMOLYTIC ANAEMIA

• • • • Less common (16% - 32%) IgM antibody bind to red cells at 0 – 4 ‘C Compliment fixation to red cell membrane Post – Injection : - Mycoplasma pneumonia - Infectious mononucleosis - Cytomegalovirus - Influenza virus - HIV

COLD AGGLUTININ IMMUNOHAEMOLYTIC ANAEMIA (CONTD…)

• • Extravascular haemolysis Acute, severe I/V haemolysis ( rarely after mycoplasma pneumonae)

DRUG INDUCED IHA

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HAPTEN MODEL

a. Penicillin / cephalosporin type - Drug absorption on red cell membrane - Antibody directed against drug - Large dosage - Prolonged duration ( 1 – 2 weeks) - Haemolysis is extravascular

HAPTEN MODEL (CONTD)

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QUINIDINE TYPE

- Antibody against drug - membrane complex - Very low dose - Short duration - Compliment mediated intravascular haemolysis - Acute onset

CHRONIC CAIHA

• • • • • Idiopathic Associated with lymphoma Compliment mediated E/V haemolysis in spleen/ liver Haemolysis of variable severity Vascular obstruction : - Pallor - Cyanosis Raynaud’s phenomenon