A patient with paroxysmal nocturnal hemoglobinuria (PNH) is at highest risk for which serious complication, and what is the molecular basis linking the GPI-anchor deficiency to this complication?

• A Venous thrombosis (especially Budd-Chiari, portal, and cerebral veins); complement-activated PNH platelets lacking CD59/CD55 undergo persistent sublytic MAC-induced activation, releasing microparticles that trigger the coagulation cascade ✓
• B Iron deficiency anemia; loss of GPI-linked transferrin receptor on PNH clones impairs iron uptake into erythroblasts
• C Autoimmune hemolytic anemia; absence of DAF causes IgG deposition on RBCs, activating classical complement pathway
• D Myelodysplastic syndrome; PIGA mutations directly impair erythroid differentiation by disrupting erythropoietin receptor signaling

Explanation

PNH arises from somatic PIGA mutations in a stem cell, impairing GPI-anchor synthesis and abolishing GPI-linked complement regulatory proteins CD55 (DAF) and CD59 (MIRL) from cell surfaces. Without CD59, the membrane attack complex (MAC) is not inhibited on PNH cells. Complement-activated PNH platelets undergo sublytic MAC activation, leading to platelet microparticle release, platelet P-selectin expression, and activation of the prothrombinase complex. Additionally, free hemoglobin from hemolysis scavenges NO, causing vascular smooth muscle constriction and platelet aggregation. The result is a hypercoagulable state, particularly affecting hepatic, portal, mesenteric, and cerebral veins (Budd-Chiari syndrome is a hallmark).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.