A 35-year-old woman develops thrombocytopenia and microangiopathic hemolytic anemia 5 days after initiating heparin therapy. ELISA is positive for anti-PF4/heparin antibodies. What is the pathomechanism of thrombosis (paradoxical thrombosis with thrombocytopenia) in heparin-induced thrombocytopenia type II (HIT)?

• A Heparin directly binds thrombin, causing paradoxical fibrinogen consumption and platelet aggregation
• B IgG antibodies against PF4-heparin complex bind platelet FcγRIIa (CD32a), causing platelet activation, degranulation, procoagulant microparticle release, and thrombocytopenia simultaneously ✓
• C PF4 autoantibodies activate monocytes via TLR4, producing TNF-alpha-mediated endothelial injury and fibrin thrombus formation
• D Complement-mediated RBC and platelet destruction with secondary monocyte activation and coagulation cascade amplification

Explanation

In HIT type II, heparin binds platelet factor 4 (PF4) released from platelets, forming large immunogenic PF4-heparin complexes that stimulate IgG antibody formation (days 5–14). These IgG antibodies bind PF4-heparin complexes on the platelet surface; the Fc portion of the IgG then crosslinks platelet FcγRIIa (CD32a) receptors, directly activating platelets — releasing more PF4 (amplification loop), generating thrombin, and producing procoagulant microparticles. Endothelial FcγRIIa activation also contributes. The net result is massive thrombin generation, venous or arterial thrombosis, and platelet consumption (thrombocytopenia). Heparin must be stopped and a direct thrombin inhibitor (argatroban) substituted.

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

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