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Semin Vasc Med 2003; 03(4): 385-390
DOI: 10.1055/s-2004-817687
THERAPEUTICS

Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Glycoprotein IIb/IIIa Antagonists in Acute Coronary Syndromes: Where Are We Now?

Andrew Maree, Desmond J. Fitzgerald
  • Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland
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Publication History

Publication Date:
03 February 2004 (online)

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ABSTRACT

Vascular inflammation, coronary constriction, and thrombus formation are central to all acute coronary syndromes (ACSs). Adhesion and aggregation of activated platelets, initially described during thrombosis, now appear pivotal to all three processes. Several platelet adhesion receptors participate but the integrin glycoprotein (GP) IIb/IIIa occupies a critical role. GPIIb/IIIa antagonists used as an adjunct to percutaneous coronary intervention show clear benefit. However in the setting of ACS results have been disappointing. Indeed, trials of oral GPIIb/IIIa antagonists in patients with ACS were associated with increased mortality. Difficulties with drug dosing and variable pharmacodynamics may contribute to suboptimal receptor occupancy, incomplete inhibition of platelet aggregation, paradoxical partial agonist activity, and proinflammatory effects. Moreover, variable responses of patients to GPIIb/IIIa antagonists may reflect population heterogeneity.

KEYWORDS

Glycoprotein IIb/IIIa antagonist - thrombosis - inflammation - partial agonist

REFERENCES

  • 1 Angelillo-Scherrer A, de Frutos P, Aparicio C. et al . Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.  Nat Med . 2001;  7 215-221
    PubMedSearch in Google Scholar
  • 2 Wagner C L, Mascelli M A, Neblock D S, Weisman H F, Coller B S, Jordan R E. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets.  Blood . 1996;  88 907-914
    PubMedSearch in Google Scholar
  • 3 Nurden A. Human platelet glycoproteins. In: Bloom A, Forbes CD, eds. Haemostasis and Thrombosis 3rd ed. New York: Churchill Livingstone 1994: 115-165
    Search in Google Scholar
  • 4 Plow E F, D'Sousa S E, Ginsberg M H. Ligand binding to GPIIb-IIIa: a status report.  Semin Thromb Hemost . 1992;  18 324-332
    PubMedSearch in Google Scholar
  • 5 May A E, Kalsch T, Massberg S, Herouy Y, Schmidt R, Gawaz M. Engagement of glycoprotein IIb/IIIa (alpha(IIb) beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells.  Circulation . 2002;  106 2111-2117
    CrossrefPubMedSearch in Google Scholar
  • 6 Henn V, Slupsky J R, Grafe M et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.  Nature . 1998;  391 591-594
    Search in Google Scholar
  • 7 Bihour C, Durrieu-Jais C, Besse P, Nurden P, Nurden A T. Flow cytometry reveals activated GP IIb-IIIa complexes on platelets from patients undergoing thrombolytic therapy after acute myocardial infarction.  Blood Coagul Fibrinolysis . 1995;  6 395-410
    PubMedSearch in Google Scholar
  • 8 Quinn M, Lincoff A M, Kereiakes D. et al . Long-term mortality benefit of abciximab in percutaneous intervention.  Circulation . 2001;  104 II-387
    PubMedSearch in Google Scholar
  • 9 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. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis.  Circulation . 1997;  96 1445-1453
    PubMedSearch in Google Scholar
  • 10 The ESPRIT investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial.  Lancet . 2000;  356 2037-2044
    CrossrefPubMedSearch in Google Scholar
  • 11 Topol E J, Moliterno D J, Herrmann H C. et al . Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization.  N Engl J Med . 2001;  344 1888-1894
    CrossrefPubMedSearch in Google Scholar
  • 12 Batchelor W B, Tolleson T R, Huaung Y. et al . Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial.  Circulation . 2002;  106 1470-1476
    CrossrefPubMedSearch in Google Scholar
  • 13 Braunwald E, Antman E M, Beasley J W. et al . ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: 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).  Circulation . 2002;  106 1893-1900
    CrossrefPubMedSearch in Google Scholar
  • 14 The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet . 2001;  357 1905-1914
    CrossrefPubMedSearch in Google Scholar
  • 15 Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators.  N Engl J Med . 1998;  338 1488-1497
    CrossrefPubMedSearch in Google Scholar
  • 16 O'Neill W W, Serruys P, Knudtson M. et al . Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events.  N Engl J Med . 2000;  342 1316-1324
    CrossrefPubMedSearch in Google Scholar
  • 17 Chew D P, Bhatt D L. Oral glycoprotein IIb/IIIa antagonists in coronary artery disease.  Curr Cardiol Rep . 2001;  3 63-71
    PubMedSearch in Google Scholar
  • 18 Fitzgerald D J, Roy L, Catella F, FitzGerald G A. Platelet activation in unstable coronary disease.  N Engl J Med . 1986;  315 983-989
    CrossrefPubMedSearch in Google Scholar
  • 19 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Blystone S D. Kinetic regulation of beta 3 integrin tyrosine phosphorylation.  J Biol Chem . 2002;  277 46886-46890
    CrossrefPubMedSearch in Google Scholar
  • 21 May A E, Kalsch T, Massberg S, Herouy Y, Schmidt R, Gawaz M. Engagement of glycoprotein IIb/IIIa (alpha(IIb) beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells.  Circulation . 2002;  106 2111-2117
    CrossrefPubMedSearch in Google Scholar
  • 22 O'Donnell C, Larson M G, Feng D. et al . Genetic and environmental contributions to platelet aggregation: the Framingham heart study.  Circulation . 2001;  103 3051-3056
    PubMedSearch in Google Scholar
  • 23 Adderley S R, Fitzgerald D J. Glycoprotein IIb/IIIa antagonists induce apoptosis in rat cardiomyocytes by caspase-3 activation.  J Biol Chem . 2000;  275 5760-5766
    CrossrefPubMedSearch in Google Scholar