PDF herunterladen
Semin Thromb Hemost 2004; 30(5): 569-577
DOI: 10.1055/s-2004-835677
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Thrombocytopenia Resulting from Sensitivity to GPIIb-IIIa Inhibitors

Richard H. Aster1 , 2 , Brian R. Curtis2 , Daniel W. Bougie2
  • 1Professor of Medicine, Medical College of Wisconsin, Senior Investigator, Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin
  • 2Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
21. Oktober 2004 (online)

    Lizenzen und Reprints

Agents that inhibit the binding of fibrinogen to its platelet receptor (glycoprotein [GP] IIb-IIIa, αIIb/β3 integrin) constitute a promising new group of antithrombotic drugs. Acute thrombocytopenia, often occurring within a few hours of starting treatment, is a recognized side effect of this family of compounds. Although most affected patients recover uneventfully, severe bleeding and fatal outcomes have been described. Both nonimmune and immune mechanisms have been implicated in the pathogenesis of this complication, but accumulating evidence suggests that drug-dependent antibodies are responsible for platelet destruction in many (and perhaps most) affected individuals. These antibodies are unique in that they can be present in persons not previously exposed to a GPIIb-IIIa inhibitor, allowing for the possibility that thrombocytopenia can occur within hours of starting treatment. Additional studies are needed to more fully define the characteristics of these antibodies and to identify risk factors that predispose patients to this complication.

KEYWORDS

GPIIb-IIIa inhibitors - thrombocytopenia - abciximab - tirofiban - eptifibatide

REFERENCES

  • 1 Coller B S. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics.  J Clin Invest. 1997;  99 1467-1471
    PubMedGoogle Scholar
  • 2 Verstraete M. Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development.  Circulation. 2000;  101 E76-E80
    PubMedGoogle Scholar
  • 3 Bennett J S, Mousa S. Platelet function inhibitors in the year 2000.  Thromb Haemost. 2001;  85 395-400
    PubMedGoogle Scholar
  • 4 Topol E J, Byzova T V, Plow E F. Platelet GPIIb-IIIa blockers.  Lancet. 1999;  353 227-231
    CrossrefPubMedGoogle Scholar
  • 5 Kereiakes D J. Oral platelet glycoprotein IIb/IIIa inhibitors.  Coron Artery Dis. 1999;  10 581-594
    PubMedGoogle Scholar
  • 6 Tam S H, Sassoli P M, Jordan R E, Nakada M T. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins.  Circulation. 1998;  98 1085-1089
    PubMedGoogle Scholar
  • 7 Nurden P, Poujol C, Durrieu-Jais C et al.. Labeling of the internal pool of GP IIb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to the transport.  Blood. 1999;  93 1622-1633
    PubMedGoogle Scholar
  • 8 Christopoulos C, Mackie I, Lahiri A, Machin S. Flow cytometric observations on the in vivo use of Fab fragments of a chimeric monoclonal antibody to platelet glycoprotein IIb/IIIa.  Blood Coagul Fibrinolysis. 1993;  4 729-737
    PubMedGoogle Scholar
  • 9 Mascelli M A, Lance E T, Damaraju L, Wagner C L, Weisman H F, Jordan R E. Pharmaco-dynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GPIIb/IIIa receptor blockade.  Circulation. 1998;  97 1680-1686
    PubMedGoogle Scholar
  • 10 EPILOG Investigators . Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization.  N Engl J Med. 1997;  336 1689-1696
    CrossrefPubMedGoogle Scholar
  • 11 CAPTURE investigators . Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: The CAPTURE study.  Lancet. 1997;  349 1429-1435
    CrossrefPubMedGoogle Scholar
  • 12 Berkowitz S D, Sane D C, Sigmon K N et al.. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) Study Group.  J Am Coll Cardiol. 1998;  32 311-319
    CrossrefPubMedGoogle Scholar
  • 13 Jubelirer S J, Koenig B A, Bates M C. Acute profound thrombocytopenia following C7E3 Fab (abciximab) therapy: case reports, review of the literature and implications for therapy.  Am J Hematol. 1999;  61 205-208
    CrossrefPubMedGoogle Scholar
  • 14 Tcheng J E, Kereiakes D J, Lincoff A M et al.. Abciximab readministration: results of the ReoPro Readministration Registry.  Circulation. 2001;  104 870-875
    PubMedGoogle Scholar
  • 15 Kereiakes D J, Berkowitz S D, Lincoff A M et al.. Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade.  Am Heart J. 2000;  140 74-78
    CrossrefPubMedGoogle Scholar
  • 16 Dillon W C, Eckert G J, Dillon J C, Ritchie M E. Incidence of thrombocytopenia following coronary stent placement using abciximab plus clopidogrel or ticlopidine.  Catheter Cardiovasc Interv. 2000;  50 426-430
    PubMedGoogle Scholar
  • 17 Guzzo J A, Nichols T C. Possible anaphylactic reaction to abciximab.  Catheter Cardiovasc Interv. 1999;  48 71-73
    PubMedGoogle Scholar
  • 18 Iakovou Y, Manginas A, Melissari E, Cokkinos D V. Acute profound thrombocytopenia associated with anaphylactic reaction after abciximab therapy during percutaneous coronary angioplasty.  Cardiology. 2001;  95 215-216
    CrossrefPubMedGoogle Scholar
  • 19 Curtis B R, Swyers J, Divgi A, McFarland J G, Aster R H. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets.  Blood. 2002;  99 2054-2059
    CrossrefPubMedGoogle Scholar
  • 20 Vahdat B, Canavy I, Fourcade L et al.. Fatal cerebral hemorrhage and severe thrombocytopenia during abciximab treatment.  Catheter Cardiovasc Interv. 2000;  49 177-180
    PubMedGoogle Scholar
  • 21 Moshiri S, Di Mario C, Liistro F, Melissano G, Chiesa R, Colombo A. Severe intracranial hemorrhage after emergency carotid stenting and abciximab administration for postoperative thrombosis.  Catheter Cardiovasc Interv. 2001;  53 225-228
    PubMedGoogle Scholar
  • 22 Jenkins L A, Lau S, Crawford M, Keung Y K. Delayed profound thrombocytopenia after c7E3 Fab (abciximab) therapy.  Circulation. 1998;  97 1214-1215
    PubMedGoogle Scholar
  • 23 Reddy M S, Carmody T J, Kereiakes D J. Severe delayed thrombocytopenia associated with abciximab (ReoPro) therapy.  Catheter Cardiovasc Interv. 2001;  52 486-488
    PubMedGoogle Scholar
  • 24 Kaluski E, Leitman M, Khiger I, Cotter G. Delayed thrombocytopenia following abciximab therapy.  J Cardiovasc Interv. 2001;  4 151-155
    PubMedGoogle Scholar
  • 25 Sharma S, Bhambi B, Nyitray W et al.. Delayed profound thrombocytopenia presenting seven days after use of abciximab (ReoPro).  J Cardiovasc Pharmacol Ther. 2002;  7 21-24
    PubMedGoogle Scholar
  • 26 Desai M, Lucore C L. Uneventful use of tirofiban as an adjunct to coronary stenting in a patient with a history of abciximab-associated thrombocytopenia 10 months earlier.  J Invasive Cardiol. 2000;  12 109-112
    PubMedGoogle Scholar
  • 27 Coto H. Platelet receptor glycoprotein IIb/IIIa inhibition with eptifibatide in a patient with thrombocytopenia after treatment with abciximab.  J Invasive Cardiol. 2000;  12 528-531
    PubMedGoogle Scholar
  • 28 Aster R H. Drug-induced immune thrombocytopenia: an overview of pathogenesis.  Semin Hematol. 1999;  36 2-6
    PubMedGoogle Scholar
  • 29 Peter K, Schwarz M, Ylanne J et al.. Related articles, links free full text induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors.  Blood. 1998;  92 3240-3249
    PubMedGoogle Scholar
  • 30 Peter K, Straub A, Kohler B et al.. Platelet activation as a potential mechanism of GPIIb/IIIa inhibitor-induced thrombocytopenia.  Am J Cardiol. 1999;  84 519-524
    CrossrefPubMedGoogle Scholar
  • 31 Ndoko S, Poujol C, Combrie R, Nurden A, Nurden P. Paradoxical platelet activation was not observed on dissociation of abciximab from GPIIb-IIIa complexes.  Thromb Haemost. 2002;  87 317-322
    PubMedGoogle Scholar
  • 32 Gawaz M, Neumann F J, Schomig A. Evaluation of platelet membrane glycoproteins in coronary artery disease: consequences for diagnosis and therapy.  Circulation. 1999;  99 E1-E11
    PubMedGoogle Scholar
  • 33 Rossi F, Rossi E, Pareti F I, Colli S, Tremoli E, Gallo L. In vitro measurement of platelet glycoprotein IIb/IIIa receptor blockade by abciximab: interindividual variation and increased platelet secretion.  Haematologica. 2001;  86 192-198
    PubMedGoogle Scholar
  • 34 Cazes E, Nurden P, Nurden A T. Abciximab binding to glycoprotein IIb-IIa and protein tyrosine phosphorylation in human platelets.  Blood. 1999;  93 4019-4020
    PubMedGoogle Scholar
  • 35 Osterland C K, Harboe M, Kunkel H G. Anti-gamma globulin factors in human sera revealed by enzymatic splitting of anti-Rh antibodies.  Vox Sang. 1963;  8 133-152
    PubMedGoogle Scholar
  • 36 Persselin J E, Stevens R H. Anti-Fab antibodies in humans: predominance of minor immunoglobulin G subclasses in rheumatoid arthritis.  J Clin Invest. 1985;  76 723-730
    PubMedGoogle Scholar
  • 37 Knight D M, Wagner C, Jordan R et al.. The immunogenicity of the 7E3 murine monoclonal Fab antibody fragment variable region is dramatically reduced in humans by substitution of human for murine constant regions.  Mol Immunol. 1995;  32 1271-1281
    CrossrefPubMedGoogle Scholar
  • 38 Curtis B R, Divgi A, Garritty M, Aster R H. Delayed thrombocytopenia after treatment with abciximab: a distinct clinical entity associated with the immune response to the drug.  J Thromb Haemost. 2004;  2 985-992
    CrossrefPubMedGoogle Scholar
  • 39 Warkentin T E. Laboratory testing for heparin-induced thrombocytopenia.  J Thromb Thrombolysis. 2000;  10(suppl 1) 35-45
    PubMedGoogle Scholar
  • 40 Bennett C L, Connors J M, Carwile J M et al.. Thrombotic thrombocytopenic purpura associated with clopidogrel.  N Engl J Med. 2000;  342 1773-1777
    CrossrefPubMedGoogle Scholar
  • 41 Elmi F, Peacock T, Schiavone J. Isolated profound thrombocytopenia associated with clopidogrel.  J Invasive Cardiol. 2000;  12 532-535
    PubMedGoogle Scholar
  • 42 Christopolous C G, Machin S J. A new type of pseudo-thrombocytopenia: EDTA-mediated agglutination of platelets bearing Fab fragments of a chimeric antibody.  Br J Hacmatol. 1994;  87 650-652
    PubMedGoogle Scholar
  • 43 Sane D C, Damaraju L V, Topol E J et al.. Occurrence and clinical significance of pseudo-thrombocytopenia during abciximab therapy.  J Am Coll Cardiol. 2000;  36 75-83
    CrossrefPubMedGoogle Scholar
  • 44 Phillips D R, Scarborough R M. Clinical pharmacology of eptifibatide.  Am J Cardiol. 1997;  80 11B-20B
    CrossrefPubMedGoogle Scholar
  • 45 Kondo K, Umemura K. Clinical pharmacokinetics of tirofiban, a nonpeptide glycoprotein IIb/IIIa receptor antagonist: comparison with the monoclonal antibody abciximab.  Clin Pharmacokinet. 2002;  41 187-195
    PubMedGoogle Scholar
  • 46 Sieffert D, Stern A M, Ebling W et al.. Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia.  Blood. 2003;  101 58-63
    CrossrefPubMedGoogle Scholar
  • 47 PURSUIT Trial Investigators . Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med. 1998;  339 436-443
    CrossrefPubMedGoogle Scholar
  • 48 PRISM-PLUS Trial Investigators . 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 1488-1497
    CrossrefPubMedGoogle Scholar
  • 49 McClure M W, Berkowitz S D, Sparapani R et al.. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome.  Circulation. 1999;  99 2892-2900
    PubMedGoogle Scholar
  • 50 RESTORE Trial 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 1445-1453
    PubMedGoogle Scholar
  • 51 Paradiso-Hardy F L, Madan M, Radhakrishnan S, Hurden S, Cohen E A. Severe thrombocytopenia possibly related to readministration of eptifibatide.  Catheter Cardiovasc Interv. 2001;  54 63-67
    PubMedGoogle Scholar
  • 52 Bougie D W, Wilker P R, Wuitschick E D et al.. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa.  Blood. 2002;  100 2071-2076
    PubMedGoogle Scholar
  • 53 Salengro E, Mulvihill N T, Farah B. Acute profound thrombocytopenia after use of eptifibatide for coronary stenting.  Catheter Cardiovasc Interv. 2003;  58 73-75
    PubMedGoogle Scholar
  • 54 Tanaka K A, Vega J D, Kelly A B, Hanson S R, Levy J H. Eptifibatide-induced thrombocytopenia and coronary bypass operation.  J Thromb Haemost. 2003;  1 392-394
    CrossrefPubMedGoogle Scholar
  • 55 Nagge J, Jackevicius C, Dzavik V, Ross J R, Seidelin P. Acute profound thrombocytopenia associated with eptifibatide therapy.  Pharmacotherapy. 2003;  23 374-379
    CrossrefPubMedGoogle Scholar
  • 56 Morel O, Jesel L, Chauvin M, Freyssinet J M, Toti F. Eptifibatide-induced thrombocytopenia and circulating procoagulant platelet-derived microparticles in a patient with acute coronary syndrome.  J Thromb Haemost. 2003;  1 2685-2687
    CrossrefPubMedGoogle Scholar
  • 57 Rezkalla S H, Hayes J J, Curtis B R, Aster R H. Eptifibatide-induced acute profound thrombocytopenia presenting as refractory hypotension.  Catheter Cardiovas Interv. 2003;  58 76-79
    PubMedGoogle Scholar
  • 58 Yoder M, Edwards R F. Reversible thrombocytopenia associated with eptifibatide.  Ann Pharmacother. 2002;  36 628-30c
    CrossrefPubMedGoogle Scholar
  • 59 Suleiman M, Gruberg L, Hammerman H et al.. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, eptifibatide and abciximab: outcomes, complications and thrombocytopenia during percutaneous coronary intervention.  J Invasive Cardiol. 2003;  15 319-323
    PubMedGoogle Scholar
  • 60 Khaykin Y, Paradiso-Hardy F L, Madan M. Acute thrombocytopenia associated with eptifibatide therapy.  Can J Cardiol. 2003;  19 797-801
    PubMedGoogle Scholar
  • 61 Brassard J A, Curtis B R, Cooper R A et al.. Acute thrombocytopenia in patients treated with the oral glycoprotein IIb/IIIa inhibitors xemilofiban and orbofiban: evidence for an immune etiology.  Thromb Haemost. 2002;  88 892-897
    PubMedGoogle Scholar
  • 62 Billheimer J T, Dicker I B, Wynn R et al.. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated.  Blood. 2002;  99 3540-3546
    CrossrefPubMedGoogle Scholar
  • 63 Matzdorff A C, Kuhnel G, Kemkes-Matthes B, Pralle H, Voss R, Fareed J. Effect of glycoprotein IIb/IIIa inhibitors on CD62p expression, platelet aggregates, and microparticles in vitro.  J Lab Clin Med. 2000;  135 247-255
    CrossrefPubMedGoogle Scholar
  • 64 Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald D J. Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes.  J Am Coll Cardiol. 2000;  36 1514-1519
    CrossrefPubMedGoogle Scholar
  • 65 Holmes M B, Sobel B E, Cannon C P, Schneider D J. Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an OPUS-TIMI 16 substudy. Orbofiban in patients with unstable coronary syndromes. Thrombolysis in myocardial infarction.  Am J Cardiol. 2000;  85 491-493
    CrossrefPubMedGoogle Scholar
  • 66 Frelinger A L, Furman M I, Krueger L A, Barnard M R, Michelson A D. Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fibrinogen binding or platelet aggregation.  Circulation. 2001;  104 1374-1379
    PubMedGoogle Scholar
  • 67 Seiffert D, Thomas B E, Bradley J D et al.. Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.  Platelets. 2003;  14 179-187
    CrossrefPubMedGoogle Scholar
  • 68 Bednar B, Cook J J, Holahan M A et al.. Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa.  Blood. 1999;  94 587-599
    PubMedGoogle Scholar
  • 69 Dunkley S, Lindeman R, Evans S, Casten R, Jepson N. Evidence of platelet activation due to tirofiban-dependent platelet antibodies: double trouble.  J Thromb Haemost. 2003;  1 2248-2250
    CrossrefPubMedGoogle Scholar
  • 70 Kouns W C, Kirchhofer D, Hadváry P et al.. Reversible conformational changes induced in glycoprotein IIb-IIIa by a potent and selective peptidomimetic inhibitor.  Blood. 1992;  80 2539-2547
    PubMedGoogle Scholar
  • 71 Kunicki T J, Annis D S, Deng Y-J, Loftus J C, Shattil S J. A molecular basis for affinity modulation of Fab ligand binding to integrin alphaIIbbeta33 .  J Biol Chem. 1996;  271 20315-20321
    CrossrefPubMedGoogle Scholar

Richard H AsterM.D. 

Blood Research Institute, Blood Center of Southeastern Wisconsin

P.O. Box 2178, Milwaukee, WI 53201-2178

eMail: rhaster@bcsew.edu