Write a short note on haemolytic anaemia.

Definition

Haemolytic anaemia results from premature destruction of red cells (normal lifespan 120 days) at a rate exceeding the marrow's compensatory capacity — the marrow can increase output six- to eightfold, so compensated haemolysis without anaemia is possible.

Classification

Intrinsic (hereditary) — a defect in the red cell itself:

• Membrane: hereditary spherocytosis (autosomal dominant; spectrin/ankyrin defect), hereditary elliptocytosis
• Enzyme: G6PD deficiency (X-linked; the commonest enzymopathy worldwide), pyruvate kinase deficiency
• Haemoglobin: sickle cell disease, thalassaemias, unstable haemoglobins
• Acquired intrinsic exception: paroxysmal nocturnal haemoglobinuria (see below)

Extrinsic (acquired) — the red cell is normal but the environment is hostile:

• Immune: autoimmune haemolytic anaemia (warm and cold types), alloimmune (haemolytic transfusion reaction, haemolytic disease of the newborn), drug-induced
• Microangiopathic (MAHA): DIC, TTP, HUS, malignant hypertension, prosthetic valve haemolysis, HELLP syndrome
• Infection: malaria (a major cause in India), clostridial sepsis, babesiosis
• Chemical and physical: snake and spider venom, lead, copper (Wilson's disease), burns
• Hypersplenism; liver disease (spur cell anaemia)

Clinical Features

• Anaemia — fatigue, pallor, dyspnoea.
• Jaundice — unconjugated (acholuric); the urine is normal in colour in extravascular haemolysis.
• Splenomegaly — in extravascular haemolysis (spherocytosis, thalassaemia, autoimmune haemolysis).
• Dark urine — haemoglobinuria in intravascular haemolysis (red-brown urine), and urobilinogen excess.
• Pigment (bilirubin) gallstones — a common late complication.
• Leg ulcers and frontal bossing with skeletal changes from marrow expansion in chronic congenital haemolysis.
• Aplastic crisis — abrupt fall in haemoglobin with reticulocytopenia, classically due to parvovirus B19 infection.
• Family history and ethnic background — essential for hereditary causes.

Investigations

Step 1 — confirm haemolysis:

• Raised reticulocyte count — the hallmark of marrow response
• Raised unconjugated bilirubin; raised LDH
• Low or absent haptoglobin (binds free haemoglobin — the most sensitive marker of intravascular haemolysis)
• Haemoglobinuria and haemosiderinuria in intravascular haemolysis
• Raised urinary urobilinogen

Step 2 — determine the cause:

• Peripheral smear — the key test: spherocytes (hereditary spherocytosis, autoimmune), schistocytes/fragments (microangiopathy — DIC, TTP, HUS, prosthetic valve), sickle cells, target cells (thalassaemia), bite cells and blister cells with Heinz bodies (G6PD deficiency), malarial parasites, agglutination (cold agglutinin disease).
• Direct antiglobulin (Coombs) test — the single most important discriminator: POSITIVE indicates immune haemolysis; NEGATIVE points to a non-immune cause.
• Haemoglobin electrophoresis/HPLC for haemoglobinopathy; G6PD assay (perform after the acute episode, since reticulocytes have higher enzyme levels and give a falsely normal result); osmotic fragility and EMA binding test for spherocytosis.
• Flow cytometry for CD55 and CD59 for paroxysmal nocturnal haemoglobinuria.
• Coagulation profile, renal function, blood cultures, malaria smear and rapid test, ANA, and viral serology as directed.

Paroxysmal Nocturnal Haemoglobinuria (PNH)

An acquired clonal stem cell disorder caused by a somatic PIG-A gene mutation, leading to deficiency of GPI-anchored complement regulatory proteins CD55 and CD59 on blood cells, and consequent complement-mediated intravascular haemolysis.

Clinical triad: intravascular haemolysis (dark urine, classically most marked on waking — hence "nocturnal"), thrombosis at unusual sites (hepatic, portal, cerebral veins) — the leading cause of death, and marrow failure with cytopenias (it overlaps with aplastic anaemia and myelodysplasia).

Diagnosis: flow cytometry demonstrating CD55/CD59-deficient cells (FLAER assay) — the definitive test, replacing the older Ham's acid haemolysis and sucrose lysis tests.

Management: complement inhibition with eculizumab or ravulizumab (with meningococcal vaccination before starting, as complement blockade markedly increases meningococcal risk), anticoagulation for thrombosis, iron and folate supplementation, transfusion support, and allogeneic stem cell transplantation as the only curative option.

Management of Haemolytic Anaemia

• Treat the underlying cause — stop the offending drug, treat infection (antimalarials), manage the underlying autoimmune or malignant disease.
• Autoimmune haemolytic anaemia: corticosteroids first-line for warm AIHA; rituximab, splenectomy, and other immunosuppressants for refractory disease. Cold agglutinin disease responds poorly to steroids — keep the patient warm and use rituximab; treat any underlying lymphoproliferative disorder or *Mycoplasma* infection.
• G6PD deficiency: avoid oxidant drugs — primaquine, dapsone, nitrofurantoin, sulphonamides, quinolones, and fava beans; supportive care during a crisis.
• Folic acid supplementation for all chronic haemolytic states (increased marrow turnover).
• Transfusion for symptomatic severe anaemia — with careful cross-matching, which may be difficult in autoimmune haemolysis.
• Splenectomy — effective in hereditary spherocytosis and selected autoimmune cases; vaccinate against encapsulated organisms (pneumococcus, meningococcus, Haemophilus) at least 2 weeks beforehand and give lifelong penicillin prophylaxis.
• Iron chelation for transfusion-dependent patients; avoid iron supplementation unless deficiency is proven, since iron overload is the greater risk.