Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura

Background: Thrombotic thrombocytopenic purpura (TTP) affects 1 in 1600 to 1 in 5000 patients who receive ticlopidine, but little is known about the p athogenesis of this complication. Objective: To investigate whether von Willebrand factor (VWF), which has be en associated with idiopathic TTP, is involved in the pathogenesis of ticlo pidine-associated TTP. Design: Case series. Setting: Three tertiary care, university-affiliated medical centers. Patients: Seven patients who developed TTP 2 to 7 weeks after initiation of ticlopidine therapy. Controls were 7 consecutive patients without thromboc ytopenia who had been receiving ticlopidine for 3 to 5 weeks and 10 randoml y selected hospitalized patients. Measurements: Platelet-bound vWF in patients' EDTA-anticoagulated whole blo od samples; vWF proteinase activity in patients' plasma samples; inhibitory activity of IgG isolated from patients' plasma samples against the protein ase from the controls' plasma samples; and vWF multimeric patterns in patie nts' EDTA-anticoagulated plasma samples. Results: Binding of vWF to single platelets was increased in the three pati ents tested during the most thrombocytopenic phase of TTP episodes. Initial plasma samples from al I seven patients lacked the largest vWF multimers a nd were severely deficient in vWF metalloproteinase. IgG molecules, isolate d from plasma samples of five patients, inhibited metalloproteinase in plas ma samples from the controls. In patients examined, these abnormalities res olved upon the remission that accompanied plasma exchange and discontinuati on of ticlopidine therapy. Conclusion: In the patients who developed ticlopidine-associated TTP, autoa ntibodies to the vWF metalloproteinase were formed; this led to the same ty pe of VWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF mul timers in vivo caused binding of vWF to platelets, systemic platelet thromb osis, and TTP.