Haemolytic Anaemia

Anaemia resulting from premature red cell destruction exceeding the bone marrow's compensatory capacity, classified by whether the defect is intrinsic (within the red cell) or extrinsic (external factors), and by whether destruction is intravascular or extravascular, which determines the clinical and laboratory picture.

Classification

• Intrinsic (hereditary): membrane defects (hereditary spherocytosis, elliptocytosis), enzyme defects (G6PD deficiency, pyruvate kinase deficiency), haemoglobinopathies (sickle cell disease, thalassaemia).
• Extrinsic (acquired): immune-mediated (autoimmune haemolytic anaemia, alloimmune --- haemolytic transfusion reaction, haemolytic disease of the newborn), mechanical (microangiopathic haemolytic anaemia from TTP/HUS/DIC, prosthetic heart valves, march haemolysis), infective (malaria, Clostridium perfringens sepsis), and acquired membrane disorders (paroxysmal nocturnal haemoglobinuria).
• Intravascular haemolysis: destruction within the circulation (mechanical, complement-mediated, severe G6PD crisis), releasing free haemoglobin causing haemoglobinuria and haemoglobinaemia, with marked haptoglobin depletion.
• Extravascular haemolysis: destruction by the reticuloendothelial system, predominantly the spleen (most autoimmune haemolytic anaemia, hereditary spherocytosis), producing jaundice and splenomegaly without haemoglobinuria.

• Pallor and fatigue from anaemia, of variable onset depending on chronicity.
• Jaundice (unconjugated hyperbilirubinaemia) and scleral icterus.
• Splenomegaly, particularly with extravascular/chronic haemolysis.
• Dark urine: in intravascular haemolysis this is haemoglobinuria (urine dipstick positive for blood with no red cells on microscopy); distinguish from the dark urine of conjugated hyperbilirubinaemia in hepatobiliary disease.
• Gallstones (pigment stones) from chronic elevated bilirubin turnover.
• Acute haemolytic crises: fever, rigors, back/flank pain, dark urine, sudden haemoglobin drop, occasionally precipitated by infection, drugs or transfusion reaction.
• Leg ulcers (chronic haemolytic states, particularly sickle cell disease and some membranopathies).
• Features of the underlying cause: fatigue and cold-induced symptoms in cold agglutinin disease, recent drug exposure, prosthetic valve, malaria endemic travel.

• Full blood count with reticulocyte count: reticulocytosis is the expected compensatory response; an inappropriately low reticulocyte count in the presence of other haemolysis markers suggests concurrent marrow suppression (parvovirus B19 aplastic crisis in chronic haemolytic states, folate deficiency exhausted by high turnover).
• Blood film: spherocytes (hereditary spherocytosis, autoimmune haemolytic anaemia), schistocytes (microangiopathic haemolysis), bite/blister cells (G6PD deficiency), sickle cells, agglutination (cold agglutinin disease).
• Haemolysis markers: elevated LDH, elevated unconjugated bilirubin, reduced/absent haptoglobin (most sensitive for intravascular haemolysis).
• Direct antiglobulin (Coombs) test: positive in immune-mediated haemolysis (distinguishing IgG-mediated warm autoimmune haemolytic anaemia from complement/IgM-mediated cold agglutinin disease by the pattern of positivity), negative in hereditary and mechanical causes.
• Urinalysis for haemoglobinuria and urobilinogen.
• Targeted testing by suspected cause: G6PD assay (ideally after the acute episode, since reticulocytes have higher enzyme activity and can mask deficiency), osmotic fragility/EMA binding test for hereditary spherocytosis, haemoglobin electrophoresis, flow cytometry for paroxysmal nocturnal haemoglobinuria, ADAMTS13 activity for suspected TTP.

• Treat the underlying cause specifically, detailed under each condition.
• Folic acid supplementation in chronic haemolysis given increased erythropoietic demand.
• Transfusion for severe or symptomatic anaemia, with caution in autoimmune haemolytic anaemia where crossmatching may be difficult (transfuse "least incompatible" blood urgently if life-threatening rather than delaying).
• Avoid identified precipitants (oxidant drugs in G6PD deficiency, cold exposure in cold agglutinin disease).
• Splenectomy considered for select chronic haemolytic conditions refractory to medical management (hereditary spherocytosis, some autoimmune haemolytic anaemia), with pre-splenectomy vaccination and post-splenectomy antibiotic prophylaxis.
• Monitor for and manage complications: gallstones, iron overload from chronic transfusion, folate depletion, aplastic crisis.
• Genetic counselling for hereditary causes.