A 30-year-old woman develops thrombocytopenia and microangiopathic haemolytic anaemia 5 days after starting ticlopidine. ADAMTS13 activity is <10% of normal. Which mechanism is primarily responsible for this complication?
- A Direct platelet membrane binding of ticlopidine metabolites forming drug-dependent antibodies (immune-mediated thrombocytopenia)
- B Complement-mediated platelet destruction via terminal MAC deposition on platelets (C-TMA)
- C Drug-induced autoantibody formation inhibiting ADAMTS13, the metalloprotease that cleaves ultra-large von Willebrand factor multimers, causing platelet microthrombi in the microcirculation (drug-induced TTP) ✓
- D Ticlopidine-induced P2Y12 receptor downregulation causing platelet-endothelial adhesion through GPIb-vWF pathway
Explanation
Ticlopidine (and less commonly clopidogrel) can rarely cause drug-induced thrombotic thrombocytopenic purpura (iTTP) through formation of an immune inhibitor against ADAMTS13, the VWF-cleaving metalloprotease. Without ADAMTS13 activity, ultra-large vWF (ULvWF) multimers accumulate on endothelial surfaces, capturing and activating platelets, forming platelet-rich microthrombi in the microvasculature — causing MAHA, thrombocytopenia, and end-organ ischaemia (renal, CNS). This requires urgent plasma exchange. Classic immune thrombocytopenia (ITP) does not cause MAHA. Complement-mediated TMA (C-TMA) involves complement pathway dysregulation. ADAMTS13 <10% with drug exposure is diagnostic of drug-induced TTP.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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