Clopidogrel-associated Thrombotic Thrombocytopenic Purpura Research Articles

Ticlopidine‐associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Ticlopidine‐associated <scp>ADAMTS</scp>13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (<scp>SONAR</scp>)

Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR)

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Clopidogrel-associated thrombotic thrombocytopenic purpura

Clopidogrel-associated thrombotic thrombocytopenic purpura

Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A Twenty Year Review

Abstract▪2226▪This icon denotes a clinically relevant abstract Objective:Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome, with our group having identified the thienopyridines ticlopidine and clopidogrel as the most common drugs associated with TTP in Food and Drug Administration (FDA) databases. We review clinical, epidemiologic, laboratory, and drug safety findings for thienopyridine-associated TTP, including the first reported cases with prasugrel, a thienopyridine approved in 2009. Methods:Data sources included FDA’s Adverse Event Reports database, pharmaceutical manufacturers, package inserts, physician surveys, phase III reports, insurance databases, and an epidemiologic study (1989–2011). Causality was assessed with the World Health Organization scale. Results:Since 2002, FDA received reports of 10 ticlopidine-, 140 clopidogrel-, and nine prasugrel-associated TTP cases, including four, 11, and 9 cases respectively, in the first year of marketing of each agent. Surveys of hematologists by our group identified 32 ticlopidine- and ten clopidogrel-associated TTP cases. Thienopyridines were administered for > two weeks for 90% of 93 ticlopidine-associated cases, 26% of 35 cases clopidogrel-associated cases, and none of nine prasugrel-associated cases. In the Phase III setting, one of 2,932 ticlopidine-, none of 27,961 clopidogrel-, and none of 1,769 prasugrel-treated patients developed TTP. Insurance databases identified three clopidogrel-associated TTP case among 15.3 million individuals. Ticlopidine- (n=30) versus clopidogrel-associated TTP patients (n=8) presented with severe ADAMTS13-deficiency (80% versus 0%) and neutralizing auto-antibodies to ADAMTS13 (100% versus 0%) and had higher survival rates following therapeutic plasma exchange (87% versus 50%) (p<0.05). Greater than 95% of ticlopidine-associated TTP cases were assessed as having a probable causal relationship versus none of the clopidogrel- or prasugrel-associated TTP cases. TTP is described in a Black Box warning for ticlopidine (1998, incidence of 1 in 2,000) and as a warning for clopidogrel (2000; 12 per million) and prasugrel (2010; no incidence reported) Conclusion:TTP is associated with all thienopyridines, although causal relationships remain under active investigations. Disclosures:Armstrong:LeadHorse Technologies Inc.: Employment.

Finishing the Picture: Clopidogrel Is Indeed the Most Common Drug Associated with Thrombotic Thrombocytopenic Purpura (TTP) In FDA Databases: Its Mechanism, Laboratory Findings, Clinical Features, and Epidemiology Differ From That Associated with Ticlopidine

AbstractAbstract 1527In 1998, 60 persons developed TTP between two and 12 weeks after initiation of ticlopidine therapy. We predicted that a newer thienopyridine, clopidogrel, upon FDA approval in 1999, would be associated with TTP. Cleveland Clinic physicians predicted that because of different metabolites, TTP following clopidogrel would not occur. We initiated an intensive 11-year multifaceted prospective pharmacovigilance program to characterize all clopidogrel-associated TTP instances and to evaluate epidemiologic, clinical and laboratory findings. In 1999, 11 cases of TTP occurred within 0 to 14 days following clopidogrel-initiation from queries of medical directors of plasma exchange centers in Houston, Chicago, Boston, Indiana, North Carolina, Baltimore, and Cincinnati- none of which were reported to the FDA. Since then, FDA's MedWatch database identified clopidogrel as the most common drug associated with reported TTP cases (n=197). (Table 1) Case reporting to the FDA decreased by 90% following toxicity description in Direct-To-Consumer advertisements beginning in 2006. Epidemiologic estimates suggest that 1 TTP occurs among 15,000 to 80,000 clopidogrel-treated persons (estimation efforts), versus rates of 1 TTP per 1,600 to 5,000 ticlopidine users (based on data obtained from interventional cardiology laboratories and plasmapheresis centers). Antibodies to ADAMTS-13 were evaluated for two of the first 11 patients with clopidogrel-associated TTP- both had antibodies to ADAMTS13- and developed spontaneous TTP relapses. After evaluating an additional 24 clopidogrel-associated TTP cases, these cases were recharacterized as idiopathic TTP patients (they were the only clopidogrel-associated TTP individuals exposed to a thienopyridine who had spontaneous relapses and the only clopidogrel-associated TTP patients to have detectable antibodies to ADAMTS13 and severe ADAMTS13 deficiency). Epidemiologic studies funded by clopidogrel's manufacturer reported that TTP occurrence rates did not increase following 1999 FDA approval of clopidogrel and there was no statistical association of clopidogrel with TTP. Pharmacovigilance studies of plasmaphersis centers and national referral laboratories in Japan and Canada identified 20 individuals who developed TTP within two weeks of clopidogrel initiation. Several clinicians reported again that the association of clopidogrel with TTP likely represented an epi-phenomenon. Five published case reports described TTP developing shortly after clopidogrel initiation- none had ADAMTS13 antibodies or deficient ADAMTS13 activity levels. Laboratory studies reported that antibodies to ADAMTS-13 were identified in 100% of 30 ticlopidine-associated TTP patients and 0% of eight clopidogrel-associated TTP patients and severe ADAMTS13-deficiency occurred in 80% of ticlopidine patients and 0% of clopidogrel patients (p<0.05 for each). These laboratory findings for clopidogrel-associated TTP supported the hypothesis that the association of clopidogrel with TTP represented a causal relationship. Clinical studies indicated that ticlopidine- versus clopidogrel-associated TTP differed with respect to platelet counts < 20,000/mm3 (84% versus 60%; p< 0.05) and onset within two to 12 weeks of drug initiation (90% versus 26%, p<0.05). We conclude that: instances of TTP following clopidogrel therapy occurred; clinical and laboratory characteristics of TTP following clopidogrel initiation differed from those reported with ticlopidine; and clopidogrel is the most common drug currently associated with TTP in the MedWatch database. Without this pharmacovigilance effort, the association of clopidogrel with TTP would have gone unnoticed. With this effort, we identified clopidogrel as the most common drug associated with TTP, as a proximate cause of TTP in rare instances, and reported that clinical and laboratory findings, prognosis, and therapeutic approaches differed between clopidogrel- and ticlopidine-associated TTP.Table 1:Epidemiology of Ticlopidine and Clopidogrel associated TTPTotal cases 1999-2009Cases since 2002EpidemiologyClopidogrel induced TTP MA1971401 per 1,600 to 1 per 5000 casesTiclopidine induced TTP87101 per 15,000 to 1 per 80,000 casesFigure 1 FDA reports of Thienopyridine-associated TTP by yearFigure 2 Following Ticlopidine and Clopidogrel over time Disclosures:Bennett:Pfizer: Consultancy.

Ticlopidine- and Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura (TTP): Final Results from the Surveillance Epidemiology and Risk Factor-TTP Study Group.

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 CharacteristicsOnsetPlatelet Count <20,000 (%)Creatinine ≤2 mg/dl (%)Neurologic Symptoms (%)Mortality With TPE/Without TPE (%)Relapseticlopidine10%* <2 weeks; 90% 2-12 weeks84*28*2815/44Occasionalclopidogrel74%*≤2 weeks; 26% > 2 weeks60*55*3228/33RareEpidemiology, Pharmacovigilance & Basic ScienceIncidence (cases per treated patients)SafetyADAMTS13 Activity (%)ADAMTS13 Antibodies (%)ticlopidine1:1,600“Black Box” warning<10*90*clopidogrel1:100,000package insert warning50–100*10**p < 0.05

Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura: A Report From the SERF-TTP Research Group and the RADAR Project

We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Clopidogrel-associated thrombotic thrombocytopenic purpura: A case report and brief review

In 1991, Page and colleagues published a report of four cases of thrombotic thrombocytopenic purpura (TTP) attributed to treatment with the platelet ADP receptor antagonist, ticlodipine. Since then, ticlodipine has been established as an immunemediated cause of TTP with an incidence of approximately 0.02-0.06%. Due to its unfavorable side-effect profile, the use of ticlodipine has been mostly discontinued in the United States and replaced by clopidogrel. Both agents are thienopyridine-derivatives which differ only by a carboxymethyl moiety. In spite of their structural resemblance, no case of TTP was reported in phase III trials of clopidogrel with 19,185 patients. However, reports of clopidogrel-associated TTP have emerged since the FDA approved the drug in 1998, including a seminal publication of eleven cases. Five of these cases passed an independently conducted causality assessment. Despite the identification of additional clopidogrel-associated cases by pharmacologic surveillance, skepticism remains regarding whether clopidogrel actually causes TTP. Here we report a case of clopidogrelassociated TTP and briefly review proposed mechanisms of drug-induced TTP.

Clopidogrel-associated thrombotic thrombocytopenic purpura presenting with coronary artery thrombosis

Clopidogrel-associated thrombotic thrombocytopenic purpura presenting with coronary artery thrombosis

ADAMTS13 Levels Support Hypothesis of Distinct Mechanistic Pathways for Early Versus Late-Onset of Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura (TTP).

Background: Ticlopidine and clopidogrel, thienopyridine derivatives used for cerebrovascular events and coronary artery syndromes, are the first and third most common causes of drug-related TTP reported to the FDA. Ticlopine-associated TTP has been characterized as having later onset, having higher relapse rates, and being more responsive to plasmapheresis—findings associated with ADAMTS13-deficiency. Based on a limited number of ADAMTS13 measurements, Moake (NEJM 2002) and Bennett (NEJM 2000) speculated that antibody-mediated ADAMTS13-deficiency appeared to be the cause of both ticlopidine- and clopidogrel-associated TTP.Methods: Clinical and ADAMTS13 laboratory data for TTP associated with ticlopidine (n=116 and 12 cases, respectively) and clopidogrel (n= 46 and 7 cases, respectively) were reviewed.Results: Clinical Evaluation: Mortality of ticlopidine-associated TTP was 34.5%. Mortality of clopidogrel-associated TTP was 22.2%. Overall moretlaity rate was 31%. Among 162 thienopyridine-associated TTP cases, late-onset TTP (89% of the cases) occurred after > 5 days of thienopyridine use and was 4-times more common with ticlopidine than clopidogrel. Early onset TTP (11% of the cases) occurred within 5-days of thienopyridine initiation and was 4-times less common with ticlopidine than clopidogrel. Laboratory Evaluation: Among 12-ticlopidine and 7-clopidogrel-associated TTP patients, laboratory assays prior to plasmapheresis identified severe ADAMTS13 deficiency 3.3-fold more often with ticlopidine (92% versus 29%, p < 0.01) and presence of inhibitory autoantibody almost 3-fold more common with ticlopidine (83% vs 30%) than clopidogrel. Among thienopyridine-associated TTP cases, patients with severe ADAMTS13-deficiency (<5% of normal) experienced higher relapses rates (15% versus 0%).Conclusions: Contrary to previously proposed mechanistic hypotheses, thienopyridine-associated TTP appears to manifest as an ADAMTS13-deficiency mediated syndrome (primarily with > 5 days of ticlopidine) that has occasional relapses and an ADAMTS13-normal syndrome (primarily with < 5 days of clopidogrel) that is not associated with relapse. Although in the same drug class, the metabolites of ticlopidine and clopidogrel are different, which may account for the distinct mechanistic pathways. Immunologically mediated ADAMTS13 -deficient TTP, like ticlopidine-associated TTP, may result from immunogenic exposures that occurred 1 to 2 weeks prior to syndrome onset. In contrast, ADAMTS13-normal TTP cases, like clopidogrel-associated TTP, may result from recent exposure that occurred within 5 days prior to TTP onset leading to direct endothelial cell injury.

Pathogenesis of Thrombotic Thrombocytopenic Purpura: ADAMTS13 Deficiency and Beyond

Thrombotic thrombocytopenic purpura (TTP) is characterized by the systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. Recently, vWF protease (ADAMTS13) activity was found to be severely deficient in hereditary TTP as well as acquired idiopathic TTP. Homozygous or compound heterozygous mutations of ADAMTS13 gene were demonstrated in hereditary TTP. Autoantibodies against ADAMTS13 were present in majority of patients with idiopathic TTP and ticlopidine- and clopidogrel-associated TTP. The deficiency of ADAMTS13 leaves unchecked the hyperadhesive vWF unfolded under high shear stress in the microvessels, resulting in the formation of platelet thrombi, which in turn causes TTP. ADAMTS13 activity is usually normal in hemolytic uremic syndrome. Approximately 0 to 67% of idiopathic TTP patients reported may not be severely deficient of ADAMTS13. Therefore, acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13, and also induce platelet aggregation either dependent on or independent of vWF, and/or vascular injury, to account for variable clinical and laboratory presentations. Plasma samples from TTP patients have been shown to induce endothelial cell apoptosis and activation. Platelet aggregating factors independent of vWF purified from the plasma of a subset of TTP patients have been reported and shown to be inhibited by normal plasma and immunoglobulin G purified from normal plasma. Defective fibrinolysis and abnormal natural coagulation inhibitors may enhance the thrombi formation in the microcirculation.

Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration.

Since the 1999 identification of clopidogrel-associated thrombotic thrombocytopenic purpura (TTP) through independent active surveillance, subsequent cases have been identified by pharmaceutical suppliers of clopidogrel and the Food and Drug Administration (FDA). For cases of clopidogrel-associated TTP reported between 1998 to 2002, we evaluated the quality and timeliness of data from 3 reporting systems-independent active surveillance (n=13), pharmaceutical suppliers (n=24), and the FDA (n=13)-and identified prognostic factors associated with mortality. This study assessed the completeness of information on TTP diagnosis, treatment response, and causality from the 3 reporting systems. In addition, predictors of mortality were identified through classification tree analysis. Completeness, timeliness, and certainty of diagnosis were best for cases obtained by active surveillance, intermediate for cases reported to the pharmaceutical supplier, and poorest for cases reported directly to the FDA. Clopidogrel had been used for </=2 weeks by 65%. The survival rate for patients with clopidogrel-associated TTP was 71.2%. Receipt of therapeutic plasma exchange within 3 days of onset of TTP increased the likelihood of survival (100% versus 27.3%, P<0.001). Compared with reports submitted by suppliers or the FDA, reports obtained through active surveillance provided timelier and more complete information. Clopidogrel-associated TTP often occurs within 2 weeks of drug initiation, occasionally relapses, and has a high mortality if not treated promptly.

Active pharmacovigilance efforts compared to the FDA's medwatch drug surveillance program for the detection of ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura Mark J. Ricciardi, Charles J. Davidson, Kristin Knox, Charles L. Bennett. Northwestern University Medical School, Chicago, IL

Active pharmacovigilance efforts compared to the FDA's medwatch drug surveillance program for the detection of ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura Mark J. Ricciardi, Charles J. Davidson, Kristin Knox, Charles L. Bennett. Northwestern University Medical School, Chicago, IL