Skip to main content
SpringerLink
Log in

Inhibition of Platelet-Dependent Prothrombinase Activity and Thrombin Generation by Glycoprotein IIb/IIIa Receptor-Directed Antagonists: Potential Contributing Mechanism of Benefit in Acute Coronary Syndromes

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Falk E. Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;75:699-708.

    Google Scholar 

  2. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418-427.

    Google Scholar 

  3. Fernández-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture. J Am Coll Cardiol 1994;23:1562-1569.

    Google Scholar 

  4. Becker RC, Tracy RP, Bovill EG, Mann KG, Ault K For the TIMI-III Thrombosis and Anticoagulation Study Group. The clinical use of flow cytometry for assessing platelet activation in acute coronary syndrome: Coron Artery Dis 1994;5:339-345.

    Google Scholar 

  5. Becker RC, Bovill EG, Corrao JM, et al. Dynamic nature of thrombin generation, fibrin formation, and Inhibition by GPIIb/IIIa Receptor Directed Antagonists 75 platelet activation in unstable angina and non-Q-wave myocardial infarction. J Thrombo Thrombolysis 1995; 2:57-64.

    Google Scholar 

  6. Becker RC, Bovill EG, Corrao JM, et al. Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q-wave myocardial infarction. J Thromb Thrombolysis 1994;1:95-100.

    Google Scholar 

  7. Coller BS, Peerschke EJ, Scudden LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thromboasthenic-like state in normal patients and binds to glycoprotein IIb and'or IIIa. J Clin Invest 1983;72:325-328.

    Google Scholar 

  8. Moliterno DJ, Califf RM, Aguirre FV, et al. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (The EPIC Trial). Am J Cardiol 1995;75:559-562.

    Google Scholar 

  9. Manning DR, Brass LF. The role of GTP-binding proteins in platelet activation. Thromb Haemost 1991;66:393-399.

    Google Scholar 

  10. Mann KG, Nesheim ME, Church WR, Haley P, Krishnaswamy S. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990;76: 1-16.

    Google Scholar 

  11. Peter K, Schwarz M, Ylänne J, et al. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (α IIb β 3) inhibitors. Blood 1998;92:3240-3249.

    Google Scholar 

  12. Liu L, Freedman J, Hornstein J, Fenton II JW, Ofosu FA. Thrombin binding to platelets and their activation in plasma. Br J Haematol 1994;88:592-600.

    Google Scholar 

  13. Ammar T, Scudder LE, Coller BS. In vitro effects of the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 Fab on the activated clotting time. Circulation 1997;95:614-617.

    Google Scholar 

  14. Dangas G, Badimon JJ, Coller BS, et al. Administration of abciximab during percutaneous coronary intervention reduces both ex vivo platelet thrombus formation and fibrin deposition. Implications for a potential anticoagulant effect of abciximab. Arterioscler Thromb Vasc Biol 1998;18:1342-1349.

    Google Scholar 

  15. Topol EJ, Califf RM, Weisman HF, et al. on behalf of the EPIC Investigators. Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-886.

    Google Scholar 

  16. PRISM Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-1505.

    Google Scholar 

  17. PRISM-Plus Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor and tirofiban in unstable angina and non-Q wave myocardial infarction. N Engl J Med 1998;338:1488-1497.

    Google Scholar 

  18. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor suppression using Integrilin Therapy (PURSUIT) Trial participants. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339:436-443.

    Google Scholar 

  19. Reverter JC, Béguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/ human chimeric 7E3 antibody. J Clin Invest 1996; 98:863-874.

    Google Scholar 

  20. Bihour C, Durrieu-Jaïs C, Macchi L, et al. Expression of markers of platelet activation and the interpatient variation in response to abciximab. Arterioscler Thromb Vasc Biol 1999;19:212-219.

    Google Scholar 

  21. Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: Results from the TIMI-12 trial. J Am Coll Cardiol 1999;33:633-639.

    Google Scholar 

  22. The EPILOG investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689-1696.

    Google Scholar 

  23. Spencer FA, Ball SP, Zhang Q, et al. Enoxaparin, a low molecular weight heparin, inhibits platelet-dependent prothrombinase assembly and activity by factor Xa neuralization. J Thromb Thrombolysis 2000;9:223-228.

    Google Scholar 

  24. Dangas G, Marmur JD, King TE, et al. Effects of platelet glycoprotein IIb/IIIa inhibition with abciximab on thrombin generation and activity during percutaneous coronary intervention. Am Heart J 1999;138:49-54.

    Google Scholar 

  25. Cohen M, Demers C, Gurfinkel EP for the ESSENCE investigators. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337: 447-452.

    Google Scholar 

  26. Antman EM, McCabe CH, Gurfinkel ED, et al. for the TIMI 11B Investigators. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the TIMI 11B Trial. Circulation 1999;100:1593-1601.

    Google Scholar 

  27. Antman EM, Cohen M, Radley D, et al. for the TIMI 11B and ESSENCE Investigators. Assessment of the treatment effect of enoxaparin for unstable angina/ non-Q-wave myocardial infarction. TIMI 11BESSENCE Meta-Analysis. Circulation 1999;100: 1602-1608.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory for Vascular Biology Research, Cardiovascular Thrombosis Research Center, University of Massachusetts Medical School, Worcester, MA

    Youfu Li, Frederick A. Spencer, Steven Ball & Richard C. Becker

Authors
  1. Youfu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frederick A. Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven Ball
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard C. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Y., Spencer, F.A., Ball, S. et al. Inhibition of Platelet-Dependent Prothrombinase Activity and Thrombin Generation by Glycoprotein IIb/IIIa Receptor-Directed Antagonists: Potential Contributing Mechanism of Benefit in Acute Coronary Syndromes. J Thromb Thrombolysis 10, 69–76 (2000). https://doi.org/10.1023/A:1018754906289

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018754906289

Search

Navigation