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

Abstract

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.

Keywords

thrombotic thrombocytopenic purpura - ticlopidine - clopidogrel - prasugrel - adverse event

• References

• 1 Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program) 2004; (1) 407-423
• 2 Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med 1998; 128 (7) 541-544
• 3 Bennett CL, Connors JM, Carwile JM , et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342 (24) 1773-1777
• 4 Bennett CL, Davidson CJ, Raisch DW, Weinberg PD, Bennett RH, Feldman MD. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999; 159 (21) 2524-2528
• 5 Bennett CL, Davidson CJ, Green D, Weinberg PD, Feldman MD. Ticlopidine and TTP after coronary stenting. JAMA 1999; 282 (18) 1717-1719 , author reply 1718–1719
• 6 Zakarija A, Bandarenko N, Pandey DK , et al. Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration. Stroke 2004; 35 (2) 533-537
• 7 Evens AM, Kwaan HC, Kaufman DB, Bennett CL. TTP/HUS occurring in a simultaneous pancreas/kidney transplant recipient after clopidogrel treatment: evidence of a nonimmunological etiology. Transplantation 2002; 74 (6) 885-887
• 8 Bennett CL, Kim B, Zakarija A , et al. Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007; 50 (12) 1138-1143
• 9 Bennett CL, Kiss JE, Weinberg PD , et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 1998; 352 (9133) 1036-1037
• 10 Mauro M, Zlatopolskiy A, Raife TJ, Laurence J. Thienopyridine-linked thrombotic microangiopathy: association with endothelial cell apoptosis and activation of MAP kinase signalling cascades. Br J Haematol 2004; 124 (2) 200-210
• 11 Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med 2000; 132 (10) 794-799
• 12 Effient [package insert]. Eli Lilly and Company, Indianapolis, IN; September 2011. Available at: http://pi.lilly.com/us/effient.pdf . Accessed June 26, 2011
• 13 Zakarija A, Kwaan HC, Moake JL , et al. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008). Kidney Int Suppl 2009; (112) S20-S24
• 14 Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA 1999; 281 (9) 806-810
• 15 Patel TN, Kreindel M, Lincoff AM. Use of ticlopidine and cilostazol after intracoronary drug-eluting stent placement in a patient with previous clopidogrel-induced thrombotic thrombocytopenic purpura: a case report. J Invasive Cardiol 2006; 18 (7) E211-E213
• 16 Yusuf S, Zhao F, Mehta SR , et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (7) 494-502
• 17 Wysowksi DK, Bacsanyi J. Blood dycrasias and hematologic reactions in ticlopidine users. JAMA 1996; 276 (12) 952
• 18 Diener HC, Bogousslavsky J, Brass LM , et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364 (9431) 331-337
• 19 Bhatt DL, Topol EJ. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance Executive Committee. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2004; 148 (2) 263-268
• 20 Gent M, Blakely JA, Easton JD , et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1 (8649) 1215-1220
• 21 Gorelick PB, Richardson D, Kelly M , et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289 (22) 2947-2957
• 22 Hass WK, Easton JD, Adams Jr HP , et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321 (8) 501-507
• 23 Miller DP, Kaye JA, Shea K , et al. Incidence of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Epidemiology 2004; 15 (2) 208-215
• 24 Schech SD, Brinker A, Shatin D, Burgess M. New-onset and idiopathic thrombotic thrombocytopenic purpura: incidence, diagnostic validity, and potential risk factors. Am J Hematol 2006; 81 (9) 657-663
• 25 Tripodi A, Chantarangkul V, Böhm M , et al. Measurement of von Willebrand factor cleaving protease (ADAMTS-13): results of an international collaborative study involving 11 methods testing the same set of coded plasmas. J Thromb Haemost 2004; 2 (9) 1601-1609
• 26 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339 (22) 1585-1594
• 27 Majhail NS, Lichtin AE. Clopidogrel and thrombotic thrombocytopenic purpura: no clear case for causality. Cleve Clin J Med 2003; 70 (5) 466-470
• 28 Qureshi ZP, Armstrong J, Bennett C. Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a twenty year review. Presented at: 53rd Annual Meeting and Exposition of American Society of Hematology; December 11, 2011; San Diego, CA
• 29 World Health Organization. Safety monitoring of medicinal products: guidelines for setting up and running a pharmacovigilance centre. 2010. Available at: http://apps.who.int/medicinedocs/en/d/Jh2934e/ . Accessed December 12, 2010
• 30 Page Y, Tardy B, Zeni F, Comtet C, Terrana R, Bertrand JC. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet 1991; 337 (8744) 774-776
• 31 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038) 1329-1339
• 32 Bennett CL, Connors JM, Carwile JM , et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342 (24) 1773-1777
• 33 Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998; 129 (5) 394-405
• 34 Plavix [package insert]. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater, NJ; December 2011. Available at: http://products.sanofi.us/PLAVIX/PLAVIX.html . Accessed January 5, 2012
• 35 Zakarija A, Bennett C. Drug-induced thrombotic microangiopathy. Semin Thromb Hemost 2005; 31 (6) 681-690
• 36 Furlan M, Robles R, Galbusera M , et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339 (22) 1578-1584
• 37 Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103 (11) 4043-4049
• 38 Vesely SK, George JN, Lämmle B , et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003; 102 (1) 60-68
• 39 Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001; 98 (6) 1765-1772
• 40 Moake J. Thrombotic microangiopathies: multimers, metalloprotease, and beyond. Clin Transl Sci 2009; 2 (5) 366-373
• 41 Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001; 14 (2) 437-454
• 42 Section USC. § 201.80 (e) (21 CFR 201.80 (e)). Electronic Code of Federal Regulations Website. Available at: http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&tpl=/ecfrbrowse/Title21/21cfr201_main_02.tpl . Accessed June 26, 2011