Subscribe to RSS
DOI: 10.1055/s-0037-1613330
Acute Thrombocytopenia in Patients Treated with the Oral Glycoprotein IIb/IIIa Inhibitors Xemilofiban and Orbofiban: Evidence for an Immune Etiology
Supported by grants HL-13629 and HL-44612 from the National Heart, Lung, and Blood Institute.Publication History
Received
20 May 2002
Accepted after resubmission
13 August 2002
Publication Date:
09 December 2017 (online)
Summary
Thrombocytopenic episodes occurring in 18,845 patients treated with the GPIIb/IIIa inhibitors xemilofiban and orbofiban (“fibans”) were analyzed by a blinded review panel and 73 patients were classified as having “possible fiban-induced thrombocytopenia”. When the treatment codes were broken, a significant association between drug exposure and assignment to this group was found (p <0.001). Twenty-eight (82%) of 34 archived serum samples from these patients contained fiban-dependent antibodies specific for GPIIb/IIIa, but no such antibodies were found in 61 drug treated patients not classified as having “possible fiban-induced thrombocytopenia” (p <0.001). We conclude that fiban-dependent antibodies were the major cause of acute, severe thrombocytopenia in patients judged on the basis of clinical findings to have thrombocytopenia “possibly-induced” by xemilofiban and orbofiban. Measurement of drug-dependent antibodies may be helpful in determining the basis for acute thrombocytopenia in fiban-treated patients and possibly for identification of patients at risk to develop thrombocytopenia.
-
References
- 1 Topol EJ, Byzova TV, Plow EF. Platelet GPIIb/IIIa blockers. Lancet 1999; 353: 227-31.
- 2 Mousa SA. Antiplatelet therapies: Recent advances in the development of platelet glycoprotein IIb/IIIa antagonists. Curr Interv Cardiol Rep 1999; 01: 243-52.
- 3 Verstraete M. Platelet glycoprotein IIb/IIIa receptor antagonization. Biomed Prog 2000; 13: 27-30.
- 4 McClure MW, Berkowitz SD, Sparapani R. et al. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome. The platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using Integrilin therapy (PURSUIT) trial experience. Circulation 1999; 99: 2892-900.
- 5 Llevadot J, Coulter SA, Giugliano RP. A practical approach to the diagnosis and management of thrombocytopenia associated with glycoprotein IIb/IIIa receptor inhibitors. J Thromb Thrombolysis 2000; 09: 175-80.
- 6 Giugliano RP. Drug-induced thrombocytopenia: Is it a serious concern for glycoprotein IIb/IIIa receptor inhibitors?. J Thrombo Thrombolysis 1998; 05: 191-202.
- 7 Madan M, Berkowitz SD. Understanding thrombocytopenia and antigenicity with glycoprotein IIb-IIIa inhibitors. Am Heart J 1999; 138: 317-26.
- 8 Cines DB. Glycoprotein IIb/IIIa antagonists: Potential induction and detection of drug-dependent antiplatelet antibodies. Am Heart J 1998; 135: S152-9.
- 9 Kereiakes DJ, Kleiman N, Ferguson JJ. et al. Sustained platelet glycoprotein IIb/IIIa blockade with oral Xemilofiban in 170 patients after coronary stent deployment. Circulation 1997; 96: 1117-21.
- 10 Nicholson NS, Abood NA, Panzer-Knodle SG. et al. Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist. Medicinal Research Reviews 2001; 21: 211-26.
- 11 Cannon CP, McCabe CH, Wilcox RG. et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000; 102: 149-56.
- 12 O’Neill WW, Serruys P, Knudtson M. et al. Long-term treatment with a platelet glycoprotein receptor antagonist after percutaneous coronary revascularization. N Engl J Med 2000; 342: 1316-24.
- 13 Kereiakes DJ, Kleiman NS, Ferguson JJ. et al. Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet glycoprotein IIb/IIIa receptor blockade with oral xemilofiban. Results of a multicenter, placebocontrolled, randomized trial. Circulation 1998; 98: 1268-78.
- 14 Ferguson JJ, Deedwania DC, Kereiakes DJ. et al. Sustained platelet glycoprotein IIb/IIIa blockade with oral orbofiban: Interin pharmacodynamic results of the SOAR study. J Am Coll Cardiol 1998; 31: 185A (abstract).
- 15 Curtis BR, McFarland JG, Wu GG. et al. Antibodies associated with sulfonamide-induced immune thrombocytopenia react preferentially with calcium-dependent epitopes on the glycoprotein IIb/IIIa complex. Blood 1994; 84: 176-83.
- 16 Peterson JA, Visentin GP, Newman PJ. et al. A recombinant soluble form of the integrin alpha IIb (GPIIb/IIIa) assumes an active, ligand-binding conformation and is recog-nized by GPIIb-IIIa-specific monoclonal, allo-, auto-, and drug-dependent platelet antibodies. Blood 1998; 92: 2053-63.
- 17 Berkowitz SD, Sane DC, Sigmon KN. et al. Occurrence and clinical significance of thrombocytopenia in a population of high-risk percutaneous coronary revascularization. J Amer Coll Cardiol 1998; 32: 311-9.
- 18 Visentin GP, Ford SE, Scott JP. et al. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994; 93: 81-8.
- 19 Visentin GP, Malik M, Cyganiak KA. et al. Patients treated with unfractionated heparin during open-heart surgery are at high risk to form antibodies reactive with heparin: platelet factor 4 complexes. J Lab Clin Med 1996; 128: 376-83.
- 20 Cox D, Smith R, Quinn M. et al. Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes. J Amer Coll Cardiol 2000; 36: 1514-9.
- 21 Jubelirer SJ, Koenig BA, Bates MC. Acute profound thrombocytopenia following C7E3 Fab (abciximab) therapy: Case reports, review of the literature, and implications for therapy. Am J Hematol 1999; 61: 205-8.
- 22 The PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338: 1498-505.
- 23 The PRISM-PLUS Study Investigatorsv. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488-97.
- 24 The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96: 1445-53.
- 25 The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/ IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436-43.
- 26 Aster RH. Drug-induced immune thrombocytopenia: An overview of pathogenesis. Sem Hematol 1999; 36: 2-6.
- 27 Bednar B, Cook JJ, Holohan MA. et al. Fibrinogen receptor antagonistinduced thrombocytopenia in chimpanzee and Rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa. Blood 1999; 94: 587-99.
- 28 Hongo RH, Brent BN. Association of eptifibatide and acute, profound thrombocytopenia. Amer J Cardiol 2001; 88: 428-31.
- 29 Paradiso-Hardy FL, Mandan M, Radhakrishnan S. et al. Severe thrombocytopenia possibly related to re-administration of eptifibatide. Catatt Cardiovasc Intervent 2001; 54: 63-7.
- 30 Frelinger AL, III Lam SC, Plow EF. et al. Occupancy of an adhesive glycoprotein receptor modulates expression of an antigenic site involved in cell adhesion. J Biol Chem 1988; 263: 12397-402.
- 31 Jennings LK, Haga JH, Slack SM. Differential expression of a ligand induced binding site (LIBS) by GPIIb-IIIa ligand recognition peptides and parenteral antagonists. Thromb Haemost 2000; 84: 1095-102.
- 32 Guigliano RP, McCabe SH, Sequiera RF. et al. First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: Results of the TIMI 15A and 15B trials. Am Heart J 2000; 140: 81-93.
- 33 Bilheimer JT, Dicker IB, Wynn R. et al. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated. Blood 2002; 99: 3540-6.