Ticlopidine- and Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura (TTP): Final Results from the Surveillance Epidemiology and Risk Factor-TTP Study Group.
Authors: Richey Elizabeth A. , Bennett Charles L. , Kwaan Hau C. , Zakarija Anaadriana , Banderanko Nicholas , Pandey Dilip K. , McKoy June M. , Yarnold Paul R. , Raisch Dennis W. , Winters Jeffrey L. , Raife Thomas J. , Cursio John F. , Fisher Matthew J. , Ortel Thomas L. , Tallman Martin S. , Matsumoto Masanori , Fujimura Yoshihiro , Moake Joel L. 
Published: April 2020

Thrombotic thrombocytopenic purpura (TTP) is a microvascular occlusive disorder characterized by systemic aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. Between 30% and 80% of TTP cases are associated with ADAMTS13 deficiency. Thienopyridine-derivative anti-platelet agents, ticlopidine and clopidogrel, are the drugs most commonly associated with TTP. The structures differ only by a carboxymethyl side-chain and have no common metabolites. Since 2002, our R01 research project has focused on evaluating thienopyridine-associated TTP. Herein, we present the final results. Clinical and laboratory data were obtained from case reports, the FDA’s MedWatch program, a Japanese national reference laboratory for ADAMTS13 assays, and apheresis centers at Duke University, University of North Carolina, Northwestern University, and the Mayo Clinic. Epidemiologic data for rate estimation for thienopyridine-associated TTP among persons who receive cardiac stents were obtained from international cardiology laboratories. Pharmacovigilance information was obtained from package inserts for the drugs. Most thienopyridine-associated TTP cases are associated with two weeks or more of ticlopidine rather than clopidogrel, are immune-mediated involving neutralizing antibodies to ADAMTS13, resolve with therapeutic plasma exchange (TPE), and have spontaneous relapses. Less frequently, cases are associated with clopidogrel, occur within days of drug initiation, may be a direct result of endothelial cell damage, are less responsive to TPE, and are less likely to recur. Thienopyridine-associated TTP patients with severe deficiency of ADAMTS13 activity have a different profile than those with normal ADAMTS13 levels. Among thienopyridine-associated TTP patients who have ADAMTS13 deficiency, TPE is usually performed for a few days and patients recover without detectable organ damage. In contrast, among thienopyridine-associated TTP patients who do not have ADAMTS13 deficiency, several weeks of TPE is required for recovery, and 30% mortality rates have been reported. Despite similar chemical structures, ticlopidine- and clopidogrel-associated TTP probably occur by different mechanisms and have different clinical presentations and expected outcomes.

Clinical Characteristics Onset Platelet Count &lt;20,000 (%) Creatinine ≤2 mg/dl (%) Neurologic Symptoms (%) Mortality With TPE/Without TPE (%) Relapse *p &lt; 0.05 ticlopidine 10%* &lt;2 weeks; 90% 2-12 weeks 84* 28* 28 15/44 Occasional clopidogrel 74%*≤2 weeks; 26% &gt; 2 weeks 60* 55* 32 28/33 Rare Epidemiology, Pharmacovigilance & Basic Science Incidence (cases per treated patients) Safety ADAMTS13 Activity (%) ADAMTS13 Antibodies (%) ticlopidine 1:1,600 “Black Box” warning &lt;10* 90* clopidogrel 1:100,000 package insert warning 50–100* 10*