Thrombotic Thrombocytopenic Purpura Associated with Clopidogrel
Charles L. Bennett, M.D., Ph.D., Jean M. Connors, M.D., John M. Carwile, M.D., Joel L. Moake, M.D., William R. Bell, M.D., Ph.D., Stefano R. Tarantolo, M.D., Leo J. McCarthy, M.D., Ravindra Sarode, M.D., Amy J. Hatfield, Pharm.D., Marc D. Feldman, M.D., Charles J. Davidson, M.D., and Han-Mou Tsai, M.D.
Background The antiplatelet drug clopidogrel is a new thienopyridinederivative whose mechanism of action and chemical structureare similar to those of ticlopidine. The estimated incidenceof ticlopidine-associated thrombotic thrombocytopenic purpurais 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associatedcases were observed among 20,000 closely monitored patientstreated in phase 3 clinical trials and cohort studies. Becauseof the association between ticlopidine use and thrombotic thrombocytopenicpurpura and other adverse effects, clopidogrel has largely replacedticlopidine in clinical practice. More than 3 million patientshave received clopidogrel. We report the clinical and laboratoryfindings in 11 patients in whom thrombotic thrombocytopenicpurpura developed during or soon after treatment with clopidogrel.
Methods The 11 patients were identified by active surveillanceby the medical directors of blood banks (3 patients), hematologists(6), and the manufacturers of clopidogrel (2).
Results Ten of the 11 patients received clopidogrel for 14 daysor less before the onset of thrombotic thrombocytopenic purpura.Although 10 of the 11 patients had a response to plasma exchange,2 required 20 or more exchanges before clinical improvementoccurred, and 2 had relapses while not receiving clopidogrel.One patient died despite undergoing plasma exchange soon afterdiagnosis.
Conclusions Thrombotic thrombocytopenic purpura can occur afterthe initiation of clopidogrel therapy, often within the firsttwo weeks of treatment. Physicians should be aware of the possibilityof this syndrome when initiating clopidogrel treatment.
Source Information
From the Veterans Affairs Chicago Healthcare System, Lakeside Division (C.L.B.), and the Divisions of Hematology–Oncology (C.L.B.) and Cardiology (C.J.D.), Department of Medicine, the Robert H. Lurie Comprehensive Cancer Center (C.L.B.), and the Institute for Health Services Research and Policy Studies (C.L.B.), Northwestern University — both in Chicago; the Hematology Division, Department of Medicine, Harvard Medical School, and Clinical Laboratories, Department of Pathology, Brigham and Women's Hospital — both in Boston (J.M. Connors); the Division of Hematology–Oncology, Department of Medicine, Baylor College of Medicine, Houston (J.M. Carwile, J.L.M.); the Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (W.R.B.); the Division of Hematology–Oncology, Department of Medicine, University of Nebraska Medical Center at Omaha, Omaha (S.R.T.); the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis (L.J.M.); the Department of Pathology, University Hospitals of Cleveland, and Case Western Reserve University, Cleveland (R.S.); the Mission St. Joseph's Health System, Asheville, N.C., and the University of North Carolina–Chapel Hill School of Pharmacy, Chapel Hill (A.J.H.); the Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio (M.D.F.); and the Division of Hematology, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, N.Y. (H.-M.T.). Another author was Elizabeth L. Michalets, Pharm.D. (University of North Carolina–Chapel Hill School of Pharmacy, Chapel Hill).
Address reprint requests to Dr. Bennett at the VA Chicago Healthcare System, Lakeside Division, Chicago, IL 60611, or at cbenne{at}nwu.edu.
Fauler, J.
(2009). Clinical pharmacology of antithrombotic drugs in coronary artery disease. Ther Adv Cardiovasc Dis
3: 465-478
[Abstract]
Verstuyft, C., Simon, T., Kim, R. B.
(2009). Personalized medicine and antiplatelet therapy: ready for prime time?. Eur Heart J
30: 1943-1963
[Full Text]
Scott, D. M., Norwood, R. M, Parra, D.
(2009). P2Y12 Inhibitors in Cardiovascular Disease: Focus on Prasugrel. The Annals of Pharmacotherapy
43: 64-76
[Abstract][Full Text]
Patrono, C., Baigent, C., Hirsh, J., Roth, G.
(2008). Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 199S-233S
[Abstract][Full Text]
Harrington, R. A., Becker, R. C., Cannon, C. P., Gutterman, D., Lincoff, A. M., Popma, J. J., Steg, G., Guyatt, G. H., Goodman, S. G.
(2008). Antithrombotic Therapy for Non-ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 670S-707S
[Abstract][Full Text]
Becker, R. C., Meade, T. W., Berger, P. B., Ezekowitz, M., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H., Mark, D. B., Harrington, R. A.
(2008). The Primary and Secondary Prevention of Coronary Artery Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 776S-814S
[Abstract][Full Text]
Fougerat, A., Gayral, S., Gourdy, P., Schambourg, A., Ruckle, T., Schwarz, M. K., Rommel, C., Hirsch, E., Arnal, J.-F., Salles, J.-P., Perret, B., Breton-Douillon, M., Wymann, M. P., Laffargue, M.
(2008). Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-{gamma} Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes. Circulation
117: 1310-1317
[Abstract][Full Text]
Bennett, C. L., Kim, B., Zakarija, A., Bandarenko, N., Pandey, D. K., Buffie, C. G., McKoy, J. M., Tevar, A. D., Cursio, J. F., Yarnold, P. R., Kwaan, H. C., De Masi, D., Sarode, R., Raife, T. J., Kiss, J. E., Raisch, D. W., Davidson, C., Sadler, J. E., Ortel, T. L., Zheng, X. L., Kato, S., Matsumoto, M., Uemura, M., Fujimura, Y.
(2007). 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
50: 1138-1143
[Abstract][Full Text]
Desch, K. C., Motto, D. G.
(2007). Thrombotic Thrombocytopenic Purpura in Humans and Mice. Arterioscler. Thromb. Vasc. Bio.
27: 1901-1908
[Abstract][Full Text]
Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol
50: e1-e157
[Full Text]
Aster, R. H., Bougie, D. W.
(2007). Drug-Induced Immune Thrombocytopenia. NEJM
357: 580-587
[Full Text]
Bennett, C. L., Nebeker, J. R., Yarnold, P. R., Tigue, C. C., Dorr, D. A., McKoy, J. M., Edwards, B. J., Hurdle, J. F., West, D. P., Lau, D. T., Angelotta, C., Weitzman, S. A., Belknap, S. M., Djulbegovic, B., Tallman, M. S., Kuzel, T. M., Benson, A. B., Evens, A., Trifilio, S. M., Courtney, D. M., Raisch, D. W.
(2007). Evaluation of Serious Adverse Drug Reactions: A Proactive Pharmacovigilance Program (RADAR) vs Safety Activities Conducted by the Food and Drug Administration and Pharmaceutical Manufacturers. Arch Intern Med
167: 1041-1049
[Abstract][Full Text]
George, J. N.
(2007). Evaluation and Management of Patients With Thrombotic Thrombocytopenic Purpura. J Intensive Care Med
22: 82-91
[Abstract]
Kocabay, G, Okcular, I, Akkaya, V, Guler, K.
(2006). Suicide attempt with clopidogrel. Hum Exp Toxicol
25: 731-734
[Abstract]
Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
(2006). Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.. Circulation
113: e409-e449
[Abstract][Full Text]
Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
(2006). Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.. Stroke
37: 577-617
[Abstract][Full Text]
Sadler, J. E.
(2006). Thrombotic Thrombocytopenic Purpura: A Moving Target. ASH Education Book
2006: 415-420
[Abstract][Full Text]
Walsh, S J, Spence, M S, Crossman, D, Adgey, A A J
(2005). Clopidogrel in non-ST segment elevation acute coronary syndromes: an overview of the submission by the British Cardiac Society and the Royal College of Physicians of London to the National Institute for Clinical Excellence, and beyond. Heart
91: 1135-1140
[Abstract][Full Text]
Jamieson, D. G., Parekh, A., Ezekowitz, M. D.
(2005). Review of Antiplatelet Therapy in Secondary Prevention of Cerebrovascular Events: A Need for Direct Comparisons Between Antiplatelet Agents. J CARDIOVASC PHARMACOL THER
10: 153-161
[Abstract]
Levy, G. G., Motto, D. G., Ginsburg, D.
(2005). ADAMTS13 turns 3. Blood
106: 11-17
[Abstract][Full Text]
Bennett, C. L., Nebeker, J. R., Lyons, E. A., Samore, M. H., Feldman, M. D., McKoy, J. M., Carson, K. R., Belknap, S. M., Trifilio, S. M., Schumock, G. T., Yarnold, P. R., Davidson, C. J., Evens, A. M., Kuzel, T. M., Parada, J. P., Cournoyer, D., West, D. P., Sartor, O., Tallman, M. S., Raisch, D. W.
(2005). The Research on Adverse Drug Events and Reports (RADAR) Project. JAMA
293: 2131-2140
[Abstract][Full Text]
Andreotti, F., Becker, R. C.
(2005). Atherothrombotic Disorders: New Insights From Hematology. Circulation
111: 1855-1863
[Full Text]
Schleinitz, M. D., Heidenreich, P. A.
(2005). A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone. ANN INTERN MED
142: 251-259
[Abstract][Full Text]
von Mach, M-A, Eich, A, Weilemann, L S, Munzel, T
(2005). Subacute coronary stent thrombosis in a patient developing clopidogrel associated thrombotic thrombocytopenic purpura. Heart
91: e14-e14
[Abstract][Full Text]
Matthai, W. H. Jr
(2005). Thrombocytopenia in Cardiovascular Patients: Diagnosis and Management. Chest
127: 46S-52S
[Abstract][Full Text]
Cattaneo, M.
(2004). Aspirin and Clopidogrel: Efficacy, Safety, and the Issue of Drug Resistance. Arterioscler. Thromb. Vasc. Bio.
24: 1980-1987
[Abstract][Full Text]
Trontell, A.
(2004). Expecting the Unexpected -- Drug Safety, Pharmacovigilance, and the Prepared Mind. NEJM
351: 1385-1387
[Full Text]
Andersohn, F, Hagmann, F G, Garbe, E
(2004). Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome associated with clopidogrel: report of two new cases. Heart
90: e57-e57
[Abstract][Full Text]
Patrono, C., Coller, B., FitzGerald, G. A., Hirsh, J., Roth, G.
(2004). Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
126: 234S-264S
[Abstract][Full Text]
Popma, J. J., Berger, P., Ohman, E. M., Harrington, R. A., Grines, C., Weitz, J. I.
(2004). Antithrombotic Therapy During Percutaneous Coronary Intervention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
126: 576S-599S
[Abstract][Full Text]
Sundram, F, Roberts, P, Kennedy, B, Pavord, S
(2004). Thrombotic thrombocytopenic purpura associated with statin treatment. Postgrad. Med. J.
80: 551-552
[Abstract][Full Text]
Akcay, A., Kanbay, M., Agca, E., Sezer, S., Ozdemir, F. N.
(2004). Neutropenia due to clopidogrel in a patient with end-stage renal disease. The Annals of Pharmacotherapy
38: 1538-1539
[Full Text]
Haj, M., Dasani, H, Kundu, S, Mohite, U, Collins, P W
(2004). Acquired haemophilia A may be associated with clopidogrel. BMJ
329: 323-323
[Full Text]
Zakarija, A., Bandarenko, N., Pandey, D. K., Auerbach, A., Raisch, D. W., Kim, B., Kwaan, H. C., McKoy, J. M., Schmitt, B. P., Davidson, C. J., Yarnold, P. R., Gorelick, P. B., Bennett, C. L.
(2004). Clopidogrel-Associated TTP: An Update of Pharmacovigilance Efforts Conducted by Independent Researchers, Pharmaceutical Suppliers, and the Food and Drug Administration. Stroke
35: 533-537
[Abstract][Full Text]
Colwell, J. A., Nesto, R. W.
(2003). The Platelet in Diabetes: Focus on prevention of ischemic events. Diabetes Care
26: 2181-2188
[Abstract][Full Text]
Vesely, S. K., George, J. N., Lammle, B., Studt, J.-D., Alberio, L., El-Harake, M. A., Raskob, G. E.
(2003). ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood
102: 60-68
[Abstract][Full Text]
Jneid, H., Bhatt, D. L., Corti, R., Badimon, J. J., Fuster, V., Francis, G. S.
(2003). Aspirin and Clopidogrel in Acute Coronary Syndromes: Therapeutic Insights From the CURE Study. Arch Intern Med
163: 1145-1153
[Abstract][Full Text]
Wolf, I., Mouallem, M., Rath, S., Farfel, Z.
(2003). Clopidogrel-Induced Systemic Inflammatory Response Syndrome. Mayo Clin Proc.
78: 618-620
[Abstract]
Nurden, A. T., Nurden, P.
(2003). Advantages of Fast-Acting ADP Receptor Blockade in Ischemic Heart Disease. Arterioscler. Thromb. Vasc. Bio.
23: 158-159
[Full Text]
DeLoughery, T. G.
(2002). Thrombocytopenia in Critical Care Patients. J Intensive Care Med
17: 267-282
[Abstract]
Spiera, R. F., Berman, R. S., Werner, A. J., Spiera, H.
(2002). Ticlopidine-Induced Lupus: A Report of 4 Cases. Arch Intern Med
162: 2240-2243
[Abstract][Full Text]
Sadler, J. E.
(2002). A new name in thrombosis, ADAMTS13. Proc. Natl. Acad. Sci. USA
99: 11552-11554
[Full Text]
Moake, J. L.
(2002). Thrombotic Microangiopathies. NEJM
347: 589-600
[Full Text]
Gaspoz, J.-M., Coxson, P. G., Goldman, P. A., Williams, L. W., Kuntz, K. M., Hunink, M.G. M., Goldman, L.
(2002). Cost Effectiveness of Aspirin, Clopidogrel, or Both for Secondary Prevention of Coronary Heart Disease. NEJM
346: 1800-1806
[Abstract][Full Text]
Bhatt, D. L., Bertrand, M. E., Berger, P. B., L'Allier, P. L., Moussa, I., Moses, J. W., Dangas, G., Taniuchi, M., Lasala, J. M., Holmes, D. R., Ellis, S. G., Topol, E. J.
(2002). Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol
39: 9-14
[Abstract][Full Text]
George, J. N., Sadler, J. E., Lammle, B.
(2002). Platelets: Thrombotic Thrombocytopenic Purpura. ASH Education Book
2002: 315-334
[Abstract][Full Text]
Mannucci, P. M., Canciani, M. T., Forza, I., Lussana, F., Lattuada, A., Rossi, E.
(2001). Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood
98: 2730-2735
[Abstract][Full Text]
Veyradier, A., Obert, B., Houllier, A., Meyer, D., Girma, J.-P.
(2001). Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood
98: 1765-1772
[Abstract][Full Text]
Sarrot-Reynauld, F., Bouillet, L., Bourrain, J.-L.
(2001). Severe Hypersensitivity Associated with Clopidogrel. ANN INTERN MED
135: 305-306
[Full Text]
Groeneveld, P. W, Hlatky, M. A
(2001). Clopidogrel reduced recurrent ischaemic events in patients with previous cardiac surgery more than aspirin. Evid. Based Med.
6: 114-114
[Full Text]
Schuhlen, H., Kastrati, A., Pache, J.u., Dirschinger, J., Schomig, A.
(2001). Incidence of thrombotic occlusion and major adverse cardiac events between two and four weeks after coronary stent placement: analysis of 5,678 patients with a four-week ticlopidine regimen. J Am Coll Cardiol
37: 2066-2073
[Abstract][Full Text]
Hiatt, W. R.
(2001). Medical Treatment of Peripheral Arterial Disease and Claudication. NEJM
344: 1608-1621
[Full Text]
Kallianpur, A. R., Poehling, K. A., Dittus, R. S.
(2001). High Time for Action. NEJM
344: 48-51
[Full Text]
Patrono, C., Coller, B., Dalen, J. E., FitzGerald, G. A., Fuster, V., Gent, M., Hirsh, J., Roth, G.
(2001). Platelet-Active Drugs : The Relationships Among Dose, Effectiveness, and Side Effects. Chest
119
: 39S-63S
[Full Text]
Albers, G. W., Amarenco, P., Easton, J. D., Sacco, R. L., Teal, P.
(2001). Antithrombotic and Thrombolytic Therapy for Ischemic Stroke. Chest
119
: 300S-320S
[Full Text]
Popma, J. J., Ohman, E. M., Weitz, J., Lincoff, A. M., Harrington, R. A., Berger, P.
(2001). Antithrombotic Therapy in Patients Undergoing Percutaneous Coronary Intervention. Chest
119
: 321S-336S
[Full Text]
(2000). The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme. Rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J
21: 2033-2041
[Abstract]
Paradiso-Hardy, F. L., Angelo, C. M., Lanctot, K. L., Cohen, E. A.
(2000). Hematologic dyscrasia associated with ticlopidine therapy: evidence for causality. CMAJ
163: 1441-1448
[Abstract][Full Text]
Salliere, D., Kassler-Taub, K. B., Trontell, A. E., Honig, P. K., Brooker, J. Z., Cheung, R. T.F., Goldstein, M. R., Bennett, C. L., Connors, J. M., Moake, J. L., Wood, A. J.J.
(2000). Clopidogrel and Thrombotic Thrombocytopenic Purpura. NEJM
343: 1191-1194
[Full Text]
Al Suwaidi, J., Berger, P. B., Holmes, D. R. Jr
(2000). Coronary Artery Stents. JAMA
284: 1828-1836
[Abstract][Full Text]
Braunwald, E., Antman, E. M., Beasley, J. W., Califf, R. M., Cheitlin, M. D., Hochman, J. S., Jones, R. H., Kereiakes, D., Kupersmith, J., Levin, T. N., Pepine, C. J., Schaeffer, J. W., Smith, E. E. III, Steward, D. E., Theroux, P., Gibbons, R. J., Alpert, J. S., Eagle, K. A., Faxon, D. P., Fuster, V., Gardner, T. J., Gregoratos, G., Russell, R. O., Smith, S. C. Jr
(2000). ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina). J Am Coll Cardiol
36: 970-1062
[Full Text]
(2000). TTP Associated with Clopidogrel. JWatch General
2000: 1-1
[Full Text]
Previous
