Ticlopidine-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>)

Deficient ADAMTS13 Activity in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura (TTP) in Populations From Japan in 2012: Validation of Findings Initially Reported in the United States in 1998 and 2000.

AbstractAbstract 2203 Background:Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods:We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008.Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results:Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and USMatsumoto (n= 186)Bennett (n=22)Bennett (n= 98)Tsai (n=7)Steinhubl (n=19)SourcePLOS One 2011This paperArch Int Med 1999Ann Int Med 2000JAMA 1999CountryJapanJapanUSUSUSEtiologyIdiopathicTiclopidineTiclopidineTiclopidineTiclopidine% female55.1%45.5%46.6%70.0%30.0%Median Age (yrs)54 (8 mos-87)69 (41-89)64.2 (11.1= SD)57 (42-89)62 (38-75)Plt < 20k/mm3100.0%96.0%71.9%100.0%89.4%Hgb < 9 g/dlNA72.7%26,9%42.3%66.7%Cr > 2.0 mg/dl75.8%31.2%30.1%NA47.0%Neuro abn79.0%63.6%73.1%70.0%73.7%Median days ticlopidine (range)NA27.5 (14-36)21 (7-112)21 (14-56)21 (14-28)% w/ coronary stentNot applicable13.6%42.3%57.1%100.0%% w/ other CAD indicationNA31.2%0.0%14.3%0.0%% CVA preventionNot applicable55.8%57.7%14.3%0.0%Survival84.3%91.0%84.9%100.0%78.9%% TPENA63.6%74.2%100.0%68.4%Survival w/o TPENot available75.0%42.1%NA33.3%Survival w/ TPE83.9%100.0%81.7%100.0%100.0%% w/ ADAMTS13:AC deficiency (<5%)100.0%100.0%100.0%83.3%NA% with ADAMTS13 inhibitors97.8%100.0%100.0%100.0%NA Conclusions:These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures:Ortel:Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

The Alternate Complement Pathway in Thrombotic Thrombocytopenic Purpura

AbstractAbstract 3342The thrombotic microangiopathies (TMA) thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) involve progressive microvascular thrombi, endothelial cell (EC) injury, vascular ischemia, and severe end-organ damage. Acquired TTP is often associated with autoantibody-mediated suppression of the ADAMTS13 vWF cleaving protease, causing vWF multimer accumulation and platelet aggregation. aHUS is associated with dysregulation of the alternate complement pathway through mutation in and/or autoantibodies against, complement regulatory proteins. It is responsive to the anti-C5 mAb eculizumab. TTP, by contrast, usually responds to plasma exchange, but in the refractory setting there are few effective treatments. We hypothesized that dysregulation of the alternate complement pathway represents a susceptibility factor for EC injury in at least a subset of TTP patients. Our objective was to identify the degree of complement dysregulation in acute TTP vs. other TMAs in vivo, and correlate these data with (1) the ability of plasma from acute TTP and aHUS patients to induce apoptotic injury in primary human microvascular EC in vitro and (2) the potential of eculizumab to block this injury.Plasmas from acute TMA patients (TTP n=12, malignancy-associated aHUS n=6, ticlopidine-associated TTP n=4, systemic Degos disease n=1), and healthy controls (n=4) were collected at time of presentation. Samples were assayed for terminal complement components sC5b-9 (MAC, membrane attack complex) and C5a by ELISA. Genomic DNA was isolated from these plasmas and amplified by standard DNA PCR, followed by semi-nested PCR using primers designed around the exon sequences of complement factor H (CFH), complement factor I (CFI) and MCP (CD46) known to be mutated in 60–80% of aHUS cases. Amplicons were sequenced and correlated with a database of previously reported mutations and SNPs with varying degrees of functional significance in the complement regulatory pathway. In our in vitro model for plasma-mediated EC injury, primary human dermal microvascular ECs were starved in medium lacking EC growth factors and then incubated for 18–24 hours with 1–2% plasma (v/v) in the presence or absence of pharmacologic levels of anti-C5 mAb (100–250μg/ml). Apoptosis was assessed by ELISA-based quantification of cytoplasmic histone-associated DNA fragments from cell lysate and propidium iodide labeling with construction of DNA histograms and assessment of A0 peaks by flow cytometry.We found significantly elevated plasma levels of C5a in all subsets of patients with TMAs compared to control plasma (42.8 ng/ml +/− 6.2 vs. 32 ng/ml +/− 6.8; p=0.014). We also found markedly elevated levels sC5b-9 in these TMAs compared to controls (1852.0 ng/ml +/− 1169.8 vs 598.8 +/− 338.7; p=0.012). Little variation was seen in TTP vs. aHUS and other TMAs, regardless of ADAMTS13 status. Complement mutations in CFH and CFI were identified in 14 (66.7%) of TMA patients: 41.6% TTP, 60% malignancy-aHUS, 100% ticlopidine TTP. In terms of interference with TMA plasma-induced MVEC apoptosis in vitro, EC injury was blocked by anti-C5 mAb eculizumab in 8 of 19 cases (5 TTP, 2 aHUS, 1 Degos). Correlation of sensitivity to plasma-mediated EC apoptosis and blockade with eculizumab with levels of terminal complement components, presence of complement regulatory factor mutations, levels of ADAMTS13 activity, and anti-ADAMTS13 antibody titers are underway.We conclude that dysregulation of the alternate complement pathway may represent a susceptibility factor in the pathophysiology of many TMAs, not only aHUS. Blockade of C5 may offer a therapeutic avenue for some patients with refractory TTP. Indeed, in a recent report our group noted the rescue of a patient with classic TTP, including ADAMTS13 activity <5% and anti-ADAMTS13 IgG, refractory to plasma exchange and a variety of immune suppressive regimens, utilizing eculizumab (Chapin J, et al. Brit J Hematol, 2012). Defining this subset, and the potential for clinical response to anti-C5 therapy, will involve exploration of other complement and complement regulatory factor mutations and autoantibodies. Disclosures:Off Label Use: Eculizumab is not FDA approved for use in the treatment of TTP. Laurence:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

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.

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.

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.

Are There Two Distinct Mechanistic Pathways That Explain the Varying Clinical Presentations, Laboratory Findings, and Outcomes of Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura (TTP)?.

Introduction: The antiplatelet agents ticlopidine and clopidogrel are thienopyridine derivatives that are commonly used for secondary prevention of cerebrovascular events, prevention of coronary artery stent thrombosis, and for treatment of acute coronary syndrome. While these chemically related agents are the first and third most common causes of drug-associated TTP respectively, clinical presentations, laboratory findings, and outcomes suggest that there may be two distinct mechanistic pathways.Methods: Clinical and laboratory data for 60 cases of ticlopidine-associated TTP and 35 cases of clopidogrel associated TTP were reviewed.Results: Type 1 thienopyridine-associated TTP, characterized by onset of disease > 5 days after drug initiation, occurred in 98% of the ticlopidine patients versus 63% of the clopidogrel patients. Laboratory studies identified severe deficiency of ADAMTS13 activity and the presence of IgG inhibitors in 7 ticlopidine (Tsai, et al.; Annals of Internal Medicine, 2000) and 2 clopidogrel (Bennett, et al.; NEJM, 2000) patients. Survival was 68% in the ticlopidine patients versus 91% in the clopidogrel patients. Type 2 thienopyridine-associated TTP, consisting of TTP onset within 5 days of drug initiation, occurred in 2% of the ticlopidine patients versus 37% of the clopidogrel patients. Laboratory studies failed to identify deficient ADAMTS13 activity or the presence of IgG inhibitors in 1 clopidogrel patient (Zheng, et al.; Blood, 2004). Survival was 0% in the ticlopidine patients versus 38% in the clopidogrel patients.Conclusion: The proposed type 1 and type 2 thienopyridine-associated TTP may be distinguished on the basis of clinical presentation, ADAMTS13 levels, and outcome. Type 1 thienopyridine-associated TTP—characterized as occurring after > 5 days of thienopyridine treatment, severely deficient ADAMTS13 activity and presence of IgG inhibitors, and high survival rates with plasmapheresis—is more likely to occur in patients receiving ticlopidine. Type 2 thienopyridine-associated TTP—characterized as occurring within 5 days of thienopyridine therapy initiation, normal ADAMTS13 activity and undetectable IgG inhibitors, and poor survival rates despite plasmapheresis—is more likely to occur in patients receiving clopidogrel. Additional confirmatory studies on larger numbers of patients are needed.

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

Thrombotic thrombocytopenic purpura (TTP) affects 1 in 1600 to 1 in 5000 patients who receive ticlopidine, but little is known about the pathogenesis of this complication. To investigate whether von Willebrand factor (vWF), which has been associated with idiopathic TTP, is involved in the pathogenesis of ticlopidine-associated TTP. Case series. Three tertiary care, university-affiliated medical centers. Seven patients who developed TTP 2 to 7 weeks after initiation of ticlopidine therapy. Controls were 7 consecutive patients without thrombocytopenia who had been receiving ticlopidine for 3 to 5 weeks and 10 randomly selected hospitalized patients. Platelet-bound vWF in patients' EDTA-anticoagulated whole blood samples; vWF proteinase activity in patients' plasma samples; inhibitory activity of IgG isolated from patients' plasma samples against the proteinase from the controls' plasma samples; and vWF multimeric patterns in patients' EDTA-anticoagulated plasma samples. Binding of vWF to single platelets was increased in the three patients tested during the most thrombocytopenic phase of TTP episodes. Initial plasma samples from all seven patients lacked the largest vWF multimers and were severely deficient in vWF metalloproteinase. IgG molecules, isolated from plasma samples of five patients, inhibited metalloproteinase in plasma samples from the controls. In patients examined, these abnormalities resolved upon the remission that accompanied plasma exchange and discontinuation of ticlopidine therapy. In the patients who developed ticlopidine-associated TTP, autoantibodies to the vWF metalloproteinase were formed; this led to the same type of vWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF multimers in vivo caused binding of vWF to platelets, systemic platelet thrombosis, and TTP.

Mechanisms of Thrombotic Thrombocytopenic Purpura (TTP), a Complication Associated with the Drug Ticlopidine

Summaries for Patients16 May 2000Mechanisms of Thrombotic Thrombocytopenic Purpura (TTP), a Complication Associated with the Drug TiclopidineSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-10-200005160-00039 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Ticlopidine is a drug that acts on platelets, the tiny cells in the bloodstream that help blood to clot. Ticlopidine is therefore sometimes used to reduce the risk for strokes by preventing clotting in patients whose arteries leading to the brain are greatly narrowed. It is also used to prevent clots from blocking cardiac stents (tunnel-like devices that are sometimes used to open narrowed blood vessels in the heart), thus cutting down the risk of heart attacks. Thrombotic thrombocytopenic purpura (TTP) is a medical condition that can occur ... Author, Article, and Disclosure InformationAffiliations: The summary below is from the full report titled “Antibody Inhibitors to von Willebrand Factor Metalloproteinase and Increased Binding of von Willebrand Factor to Platelets in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura.” It is in the 16 May 2000 issue of Annals of Internal Medicine (volume 132, pages 794-799). The authors are H.-M. Tsai, L. Rice, R. Sarode, T.W. Chow, and J.L. Moake.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAntibody Inhibitors to von Willebrand Factor Metalloproteinase and Increased Binding of von Willebrand Factor to Platelets in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura Han-Mou Tsai , Lawrence Rice , Ravindra Sarode , Thomas W. Chow , and Joel L. Moake Metrics 16 May 2000Volume 132, Issue 10Page: 794KeywordsDrugsKidneysMedical conditionsMetalloproteasesMyocardial infarctionPlateletsStent implantationStrokeThrombosisThrombotic thrombocytopenic purpura Issue Published: 16 May 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.Loading ...

Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention.

One of the most unusual causes of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease, is ticlopidine hydrochloride, an antiplatelet agent used to prevent strokes in high-risk populations or following coronary artery stent placement. Recently, Hoffman-LaRoche Pharmaceuticals, following reports of 20 deaths from ticlopidine-associated TTP, updated the information about the hematologic adverse effects of the drug. To review our recent findings on ticlopidine-associated hematologic toxic effects, which served as the impetus for the revised warnings, and to discuss the implications of these findings. Data were obtained from the Food and Drug Administration's MedWatch program, published phase 3 clinical trials and case reports, hematologists, and plasmapheresis centers. No cases of TTP have been reported in phase 3 ticlopidine trials. In contrast, postmarketing surveillance has identified serious adverse drug reactions to ticlopidine, resulting in 259 deaths, with TTP accounting for 40 of these deaths. Detailed information was available on 98 cases of ticlopidine-associated TTP. Compared with 42 patients in the coronary artery stent setting, 56 patients with ticlopidine-associated TTP in the stroke prevention setting were more likely to be women (62.5% vs 28.6%; P = .01). Before the onset of TTP in patients receiving stroke prevention therapy and patients with stent placement, ticlopidine had been used for less than 2 weeks in 5.4% and 2.4%, between 2 and 3 weeks in 17.9% and 21.4%, between 3 and 4 weeks in 30.4% and 38.1%, and between 4 and 12 weeks in 46.4% and 38.1%, respectively. Death occurred in almost 60% of all patients not receiving plasmapheresis compared with 21.9% of patients receiving plasmapheresis for stroke prevention and 14.3% of patients receiving plasmapheresis in the stent setting. Use of ticlopidine requires frequent physician visits and laboratory tests for at least 3 months in the stroke prevention setting, while, with short-term use in the coronary artery stent setting, adverse events are less likely to occur. These factors, as well as competition from clopidogrel bisulfate, a new antiplatelet agent, potentially limit the feasibility of ticlopidine as a stroke prevention agent, while having less impact on its use following coronary artery stent placement.

Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura

Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases.

Thrombotic thrombocytopenic purpura, a life-threatening multisystem disease, has been infrequently associated with use of ticlopidine, a platelet anti-aggregating agent. To review 60 cases of ticlopidine-associated thrombotic thrombocytopenic purpura. Medical records, published case reports, and case reports submitted to the U.S. Food and Drug Administration. Instances of ticlopidine-associated thrombotic thrombocytopenic purpura were identified. Ticlopidine had been prescribed for less than 1 month in 80% of the patients, and normal platelet counts had been found within 2 weeks of the onset of thrombotic thrombocytopenic purpura in most patients. Mortality rates were higher among patients who were not treated with plasmapheresis than among those who underwent plasmapheresis (50% compared with 24%; P < 0.05). Ticlopidine use may be associated with the development of thrombotic thrombocytopenic purpura, usually within 1 month of initiation of therapy. The onset of ticlopidine-associated thrombotic thrombocytopenic purpura is difficult to predict, despite close monitoring of platelet counts.