Haemolytic Anaemia — Viva

Q1: Define haemolytic anaemia and classify it along its two principal axes (2 min)

Haemolytic anaemia is anaemia caused by premature destruction of red blood cells (lifespan shortened from the normal ~120 days) at a rate that exceeds marrow compensation. Two axes: (1) site of destruction — extravascular (splenic/hepatic macrophages; spherocytes; bilirubin unconjugated; the commoner pattern) vs intravascular (rupture within the circulation; haemoglobinaemia, haemoglobinuria, haemosiderinuria, absent haptoglobin); (2) origin — inherited/corpuscular (membrane — hereditary spherocytosis; enzyme — G6PD, pyruvate kinase; haemoglobin — sickle, thalassaemia) vs acquired/extracorpuscular (immune — warm AIHA, cold agglutinin, PCH; non-immune — MAHA, PNH, infection, mechanical, burns, Wilson).^[1][2]

Q2: Walk through the biochemical signature and the role of the direct Coombs test (3 min)

The signature: reticulocytes raised (corrected count / production index raised; the single marker of an adequate marrow response), LDH raised, unconjugated bilirubin raised, haptoglobin low or absent (a level of 25 mg/dL or less is 83 percent sensitive and 96 percent specific for haemolysis; normal haptoglobin makes significant intravascular haemolysis unlikely). In intravascular forms add haemoglobinaemia, haemoglobinuria (positive dipstick blood with no red cells), haemosiderinuria, and methaemalbumin. The direct antiglobulin (Coombs) test (DAT) is the master discriminator: positive = immune (warm AIHA — IgG +/- C3d; cold agglutinin — C3d-dominant (IgG usually negative); PCH — Donath-Landsteiner positive; drug-induced; haemolytic disease of newborn); negative = non-immune (HS, G6PD, PNH, MAHA, sickle, thalassaemia).^[1][2][3]

Q3: Distinguish warm AIHA from cold agglutinin disease in mechanism and treatment (3 min)

Warm AIHA — IgG1/IgG3 antibody optimally reactive at 37 °C (often anti-Rh) coats the red cell; splenic macrophages phagocytose via Fc-gamma receptors (extravascular); film shows spherocytes; DAT positive IgG +/- C3d. Treatment: high-dose prednisolone first-line (taper slowly over 6–12 months), rituximab or splenectomy second-line. Cold agglutinin disease — IgM pentamer binds in the cold extremities (anti-I, anti-i), fixes classical complement (C1q → C3b); on rewarming IgM dissociates leaving C3b, and liver macrophages of the mononuclear phagocytic system clear the C3b-opsonised cell (extravascular but liver-based); DAT strongly positive for C3d (IgG usually negative — weakly positive in up to 20 percent); cold agglutinin titre raised. Clinical: acrocyanosis, Raynaud-type, livedo on cold exposure. Treatment: keep warm (blood warmer for transfusions), rituximab first-line, sutimlimab (anti-C1s) approved 2022; steroids and splenectomy are INEFFECTIVE because destruction is complement- and liver-mediated.^[4][5][6]

Q4: Outline the G6PD deficiency story and its key pitfalls (2 min)

X-linked recessive enzyme defect (commonest human enzyme defect, ~400 million worldwide); G6PD maintains glutathione in the reduced (GSH) form, protecting red cells from oxidative damage. Without GSH, oxidant stress denatures haemoglobin into Heinz bodies; the spleen bites them out producing bite cells; this triggers acute intravascular haemolysis with haemoglobinuria (cola urine) after a trigger. Triggers: fava beans, sulphonamides, primaquine, dapsone, rasburicase, naphthalene, methylene blue, infection. Two pitfalls: (1) the G6PD assay is falsely normal during an acute attack because the oldest, most deficient cells are lysed first — repeat after the acute episode resolves; (2) methylene blue for methaemoglobinaemia is contraindicated in G6PD deficiency (it is itself an oxidant). Treatment is trigger avoidance + supportive care.^[7]

Q5: What is PNH, and how has its prognosis changed? (2 min)

Paroxysmal nocturnal haemoglobinuria — an acquired PIG-A mutation in a haematopoietic stem cell abolishes the GPI anchor, so the complement-regulatory proteins CD55 (DAF) and CD59 (MIRL) are absent from red cells, allowing uncontrolled complement-mediated intravascular lysis. Classic triad: haemolytic anaemia, pancytopenia, and thrombosis at unusual sites (hepatic, portal, cerebral venous sinus). Diagnosis: FLAER / CD55-CD59 flow cytometry on granulocytes; DAT negative. Previously poor prognosis (median survival about 10 years, from thrombosis and marrow failure). Eculizumab (anti-C5) — Hillmen, NEJM 2006 — transformed survival to near-normal; ravulizumab (every 8 weeks) and crovalimab are newer long-acting anti-C5 agents. Meningococcal vaccination and penicillin prophylaxis are mandatory because complement blockade raises encapsulated-infection risk. Bone marrow transplant is the only cure.^[8][9][10]

Q6: Describe the pre- and post-splenectomy bundle and OPSI management (2 min)

Before elective splenectomy (at least 2 weeks before; optimal 4–6 weeks): vaccinate against encapsulated organisms — pneumococcal (PCV13 +/- PPSV23 or PCV20), meningococcal ACWY + B, and annual influenza (additional Hib is no longer recommended in the UK). If emergency splenectomy, vaccinate at least 2 weeks post-op. After splenectomy: antibiotic prophylaxis with phenoxymethylpenicillin 250 mg twice daily (Green Book: prophylaxis advisable, usually phenoxymethyl penicillin; lifelong for continued high risk), a patient-held standby antibiotic, a spleen alert card / medical ID, and counselling that any fever is a medical emergency. OPSI — overwhelming post-splenectomy infection — classically from Streptococcus pneumoniae (also Hib, meningococcus, capnocytophaga from dog bites); septicaemia with case-fatality of 40–54 percent even with treatment. Management: immediate empirical IV antibiotics per local OPSI protocol — do NOT wait for cultures.^[11][12]

References12ShowHide

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