A 35-year-old woman has haemolytic anaemia, thrombocytopenia, and repeated episodes of dark urine at night. Flow cytometry of peripheral blood shows >50% loss of CD55 and CD59 on red blood cells and granulocytes. The diagnosis is paroxysmal nocturnal haemoglobinuria (PNH). What is the MECHANISM of haemolysis and current standard of care?
- A Anti-GPI antibody destruction; treatment is rituximab
- B Auto-immune warm haemolysis; treat with steroids
- C GPI anchor deficiency (PIGA mutation) causing complement-mediated intravascular haemolysis; treatment is eculizumab (anti-C5) or iptacopan (anti-factor B) ✓
- D Direct anti-red cell antibody from complement activation; IVIG is first-line
Explanation
PNH is caused by a somatic PIGA gene mutation in haematopoietic stem cells, leading to deficiency of GPI-anchored complement regulatory proteins CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis). Without these, complement C3b opsonisation leads to intravascular haemolysis via terminal complement (C5b-9, membrane attack complex). Eculizumab (anti-C5 monoclonal antibody) inhibits terminal complement and is the standard treatment, reducing haemolysis, thrombosis risk, and improving quality of life (TRIUMPH and SHEPHERD trials). Iptacopan (anti-factor B) is a newer oral proximal complement inhibitor approved for PNH with residual anaemia on anti-C5 therapy.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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