Paroxysmal nocturnal hemoglobinuria (PNH) results from somatic mutation in the PIGA gene, causing deficiency of GPI-anchored proteins CD55 and CD59. Which complement pathway is primarily uncontrolled, leading to intravascular hemolysis?

• A Classical pathway activated by IgM antibodies against RBC antigens
• B Lectin pathway activated by mannose residues on abnormal RBCs
• C Terminal complement pathway activated exclusively by lectin pathway
• D Alternative pathway with spontaneous C3 tickover amplified on the RBC surface without regulatory protein inhibition ✓

Explanation

PNH RBCs lack GPI-anchored complement regulatory proteins: CD55 (decay-accelerating factor, inhibits C3 convertase) and CD59 (protectin, inhibits MAC formation). Normally, the complement alternative pathway undergoes continuous low-level C3 'tickover' activation, which is controlled on normal RBCs by CD55 and CD59. In PNH, the absence of these regulators allows unrestricted alternative pathway amplification, MAC formation, and intravascular lysis, particularly during acidosis (sleep, as nocturnal CO2 retention mildly acidifies blood).

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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