Definition
- Haemolytic anaemias = anaemias which result from an increase in the rate of premature RBC destruction
- Normal mean red cell life is 120 days (falls to <15 days in haemolytic anaemias)
- Can be classified by:
1) Site: Extravascular haemolysis vs Intravascular haemolysis
2) Causative Factor: Intrinsic vs Extrinsic
Extravascular vs Intravascular – Mechanisms
1) Extravascular:
- Involves macrophages of the reticulo-endothelial system (especially in bone marrow, liver and spleen).
- Haem is broken down to protoporphyrin (-> bilirubin), iron (bound to transferrin) and carbon monoxide
- Globin chains are broken down to amino acids, which are re-utilized for protein synthesis.
- Because of erythropoietic hyperplasia and anatomical extension of bone marrow, RBC destruction may be increased several-fold before the patient becomes anaemic (“compensated haemolytic disease”). The normal BM, after full expansion, is able to produce RBC at 6- 8 times the normal rate (-> marked reticulocytosis)
2) Intravascular:
- Involves breakdown of RBC within blood vessels (always pathological)
- Free Hb is released which rapidly saturates plasma haptoglobins, and the excess is filtered by glomerulus
- If the rate of haemolysis saturates the renal tubular reabsorptive capacity, free Hb enters urine and, as iron is released, the renal tubules become loaded with haemosiderin
Pathological causes include:-
a) Mismatched blood transfusion (usually ABO)
b) G6PD deficiency with oxidant stress
c) Red cell fragmentation syndromes
d) Some autoimmune haemolytic anaemias
e) Some drug- and infection-induced haemolytic anaemias
f) Paroxysmal nocturnal haemoglobinuria
g) March haemoglobinuria
h) Unstable Hb
Intrinsic vs Extrinsic – Mechanisms
1. Intrinsic defect (hereditary)
Membrane synthesis:
a) Hereditary spherocytosis*
b) Hereditary elliptocytosis (milder picture, caused by defects in spectrin self-association)
c) South-East Asian ovalocytosis (red cell membrane protein defect [band 3], protects against malaria)
Metabolism:
a) G6PD deficiency (à susceptibility to oxidant stress by infections, drugs and fava beans)
b) Pyruvate kinase deficiency (autosomal recessive, autohaemolysis increased but uncorrected by glucose)
c) Triose phosphate isomerase deficiency (rare!)
Haemoglobin synthesis:
a) HbS
b) HbC
c) Unstable
2. Acquired (environmental change)
Immune:
a) Autoimmune (positive Coombs test!):
a) Warm Ab type (idiopathic or secondary to SLE, CLL etc.)
b) Cold Ab type (idiopathic or secondary to infections [e.g. paroxysmal cold haemoglobinuria])
b) Alloimmune:
[Ab produced by one individual reacts with RBCs of another]
a) Haemolytic transfusion reactions (due to ABO-incompatible blood)
b) Haemolytic disease of newborn
c) Marrow or solid organ transplantation (production of red cells Ab in recipient by donor lymphocytes transferred in allograft)
c) Drugs
a) Ab directed against a drug-RBC membrane complex (e.g. penicillin, ampicillin)
b) Deposition of complement via drug-protein-Ab complex onto RBC surface (e.g. quinidine, rifampicin)
c) True autoimmune HA in which role of drug is unclear (e.g. methyldopa, fludarabine)
[NB: in each case, the opsonized cells are destroyed in the reticulo-endothelial system]
Red cell fragmentation syndromes:
a) Artificial heart valves or arterial grafts (via physical damage)
b) Microangiopathic e.g. TTP, HUS, DIC, meningococcal sepsis (via RBCs passing through fibrin strands deposited in vessels)
March haemoglobinuria:
- Damage to RBCs between the small bones of the feet
- Usually during prolonged marching or running
Infections:
a) Malaria (extravascular and intravascular lysis)
b) Clostridium perfringens (due to toxin production and intravascular lysis)
c) Neisseria meningitidis (à septicaemia à microangiopathic HA)
d) Mononucleosis (due to autoantibody formation)
Chemical and physical agents:
a) Drugs (e.g. dapsone, via intravascular lysis [oxidative])
b) Chemicals (e.g. chlorate)
c) Burns (via direct damage of RBCs)
d) Snake bites
