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Semin Thromb Hemost 2012; 38(08): 845-853
DOI: 10.1055/s-0032-1328894
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Sony Jacob
1   South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, South Carolina
2   WJB Dorn VA Medical Center, Columbia, South Carolina
,
Brianne L. Dunn
1   South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, South Carolina
2   WJB Dorn VA Medical Center, Columbia, South Carolina
,
Zaina P. Qureshi
1   South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, South Carolina
,
Nicholas Bandarenko
3   Duke University Medical Center, Durham, North Carolina
,
Hau C. Kwaan
4   Northwestern University Feinberg School of Medicine, Chicago, Illinois
,
Dilip K. Pandey
5   University of Illinois Medical Center at Chicago, Chicago, Illinois
,
June M. McKoy
4   Northwestern University Feinberg School of Medicine, Chicago, Illinois
,
Sara E. Barnato
4   Northwestern University Feinberg School of Medicine, Chicago, Illinois
,
Jeffrey L. Winters
6   Mayo Clinic, Rochester Minnesota
,
John F. Cursio
7   Rush University Medical Center, Chicago, Illinois
,
Ivy Weiss
4   Northwestern University Feinberg School of Medicine, Chicago, Illinois
,
Thomas J. Raife
8   University of Iowa, Iowa City, Iowa
,
Patricia M. Carey
9   Hoxworth Blood Center, University of Cincinnati, Cincinnati, Ohio
,
Ravindra Sarode
10   University of Texas Southwestern, Dallas, Texas
,
Joseph E. Kiss
11   The Institute for Transfusion Medicine and the University of Pittsburgh, Pittsburgh, Pennsylvania
,
Constance Danielson
12   Indiana University School of Medicine, Indianapolis, Indiana
,
Thomas L. Ortel
3   Duke University Medical Center, Durham, North Carolina
,
William F. Clark
13   London Health Sciences Centre, London, Ontario, Canada
,
Gail Rock
14   Canadian Apheresis Group, Ottawa, Ontario, Canada
,
Masanori Matsumoto
15   Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan
,
Yoshihiro Fujimura
15   Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan
,
X. Long Zheng
16   Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Hao Chen
17   eHealthMe, Madison, Wisconsin
,
Fei Chen
17   eHealthMe, Madison, Wisconsin
,
John M. Armstrong
18   Lead Horse Technologies, Junction City, Kansas
,
Dennis W. Raisch
19   College of Pharmacy, University of New Mexico, Albuquerque, New Mexico
,
Charles L. Bennett
1   South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, South Carolina
2   WJB Dorn VA Medical Center, Columbia, South Carolina
20   Arnold School of Public Health of the University of South Carolina, Columbia, South Carolina
21   Hollings Cancer Center of the Medical University of South Carolina, Charleston, South Carolina
› Author Affiliations
Further Information

Publication History

Publication Date:
30 October 2012 (online)

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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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 3 Bennett CL, Connors JM, Carwile JM , et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342 (24) 1773-1777
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 9 Bennett CL, Kiss JE, Weinberg PD , et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 1998; 352 (9133) 1036-1037
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMed
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 17 Wysowksi DK, Bacsanyi J. Blood dycrasias and hematologic reactions in ticlopidine users. JAMA 1996; 276 (12) 952
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Gent M, Blakely JA, Easton JD , et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1 (8649) 1215-1220
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 23 Miller DP, Kaye JA, Shea K , et al. Incidence of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Epidemiology 2004; 15 (2) 208-215
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 27 Majhail NS, Lichtin AE. Clopidogrel and thrombotic thrombocytopenic purpura: no clear case for causality. Cleve Clin J Med 2003; 70 (5) 466-470
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMed
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 32 Bennett CL, Connors JM, Carwile JM , et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342 (24) 1773-1777
    CrossrefPubMedSearch in Google Scholar
  • 33 Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998; 129 (5) 394-405
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMed
  • 35 Zakarija A, Bennett C. Drug-induced thrombotic microangiopathy. Semin Thromb Hemost 2005; 31 (6) 681-690
    Thieme ConnectPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 40 Moake J. Thrombotic microangiopathies: multimers, metalloprotease, and beyond. Clin Transl Sci 2009; 2 (5) 366-373
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMed