Transcript β - THALASAEMIAS

HEMOLYTIC ANEMIA
LEARNING OBJECTIVES
• Genetic defect in β and alpha
thalassemia
• 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
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β
THALASSAEMIA
MOLECULAR PATHOGENESIS
2. ECTOPIC SLIPLICING MUTATION
- Occurs at abnormal sites within intron
- Abnormal splicing of mRNA
- Normal splicing sites co – exist
0
β
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………)
0
β
THALASSAEMIA
MOLECULAR PATHOGENESIS
b. FRAME – SHIFT MUTATION:
- Small insertions or deletion, shifts mRNA
reading frame
- Termination of β globin chain synthesis
0
β
THALASSAEMIA
MOLECULAR PATHOGENESIS
2. SPLICING MUTATION
- Most common mutations in β –thal
i) Introns
Site
ii) Within exons
of
mutation
iii) Normal splice junction
- 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
• 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)
• 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