Skip to main content
SpringerLink
Log in

Inhibition of Platelet Aggregation with a Glycoprotein IIb-IIIa Antagonist Does Not Prevent Thrombin Generation in Patients Undergoing Thrombolysis for Acute Myocardial Infarction

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

Abstract

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilin™) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 µM ADP. Levels of fibrinopeptide A (FPA), thrombin–antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 µg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.

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. Swords NA, Mann KG. The assembly of the prothrombinase complex on adherent platelets. Arterioscler Thrombo 1993;13:1602–1612.

    Google Scholar 

  2. Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Ann Rev Biochem 1988;57:915–956.

    Google Scholar 

  3. Eisenberg PR, Sobel BE, Jaffe AS. Activation of prothrombin accompanying thrombolysis with recombinant tissuetype plasminogen activator. J Am Coll Cardiol 1992;19: 1065–1069.

    Google Scholar 

  4. Winters KJ, Santoro SA, Miletich JP, et al. Relative importance of thrombin compared with plasmin-mediated platelet activation in response to plasminogen activation with streptokinase. Circulation 1991;84:1552–1560.

    Google Scholar 

  5. Marguerie GA, Plow EF, Edgington TS. Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem 1979;254:5357–5363.

    Google Scholar 

  6. Coller BS, Folts JD, Scudder LE, et al. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. Blood 1986;68:783–786.

    Google Scholar 

  7. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation 1988;77:670–677.

    Google Scholar 

  8. Kohmura C, Gold HK, Yasuda T, et al. A chimeric murine/ human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons. Arterioscler Thromb 1993;13:1837–1842.

    Google Scholar 

  9. Kleiman NS, Ohman EM, Califf RM, et al. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy. Results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 Pilot Study. J Am Coll Cardiol 1993;22:381–389.

    Google Scholar 

  10. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. Circulation 1997;95: 846–854.

    Google Scholar 

  11. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:723–725.

    Google Scholar 

  12. Chesebro J, Knatterud G, Roberts R, et al. Thrombolysis in myocardial infarction (TIMI) Trial. Phase l: A comparison between intravenous plasminogen activator and intravenous streptokinase. Circulation 1987;76:142–154.

    Google Scholar 

  13. Cushman M, Psaty B, Bovill E, et al. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1998;16:1163–1169.

    Google Scholar 

  14. Bovill E, Terrin M, Stump D, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1998;115: 256–265.

    Google Scholar 

  15. Bovill E, Granger C, Woodlief L, et al. Measures of thrombin activity in the GUSTO trial: Relationship to thrombolytic agent and mode of heparin administration. J Am Coll Cardiol 1998;21:137A.

    Google Scholar 

  16. Krishnaswamy S, Jones KC, Mann KG. Prothrombinase complex assembly. Kinetic mechanism of enzyme assembly on phospholipid vesicles. J Biol Chem 1988;263:3823–3834.

    Google Scholar 

  17. Aronson DL, Chang P, Kessler CM. Platelet-dependent thrombin generation after in vitro fibrinolytic treatment. Circulation 1992;85:1706–1712.

    Google Scholar 

  18. Billy D, Briede J, Heemskerk JM, et al. Prothrombin conversion underflow conditions by prothrombinase assembled on adherent platelets. Blood Coagu Fibrinoly 1997;8: 168–174.

    Google Scholar 

  19. Harker LA. The role of platelets in the early and late vascular responses initiated by mechanical vascular injury. Fibrinoly Proteoly 1997;11:1–103.

    Google Scholar 

  20. Moyer MP, Tracy RP, Tracy PB, et al. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol 1998;18:458–465.

    Google Scholar 

  21. Weiss HJ, Lages B. Platelet prothrombinase activity and intracellular calcium responses in patients with storage pool deficiency, glycoprotein IIb-IIIa deficiency, or impaired platelet coagulant activity — A comparison with Scott syndrome. Blood 1997;89:1599–1611.

    Google Scholar 

  22. Reverter JC, Beguin S, Kessels H, et al. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 anti-body. J Clin Invest 1996;98:863–874.

    Google Scholar 

  23. Hsia J, Hamilton WP, Kleiman N, et al. A comparison between heparin and lowdose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1991;324:1217–1218.

    Google Scholar 

  24. Bleich SD, Nichols TC, Schumacher RR, et al. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infaction. Am J Cardiol 1990;66:1412–1417.

    Google Scholar 

  25. de Bono DP, Simoons ML, Tijssen J, et al. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: Results of a randomised double blind European Cooperative Study Group trial. B Heart J 1992;67:122–128.

    Google Scholar 

  26. Antman EM. Hirudin in acute myocardial infarction — thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation 1996;94:911–921.

    Google Scholar 

  27. White HD, Barbash GI, Califf RM, et al. Age and outcome with contemporary thrombolytic therapy — results from the GUSTO-l trial. Circulation 1996;94:1826–1833.

    Google Scholar 

  28. Collen D, Lu HR, Stassen JM, et al. Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis. Thromb Haemost 1994;71:95–102.

    Google Scholar 

  29. Bugiardini R, Pozzati A, Borghi A, et al. Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome. Am J Cardiol 1991;67:460–464.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Baylor College of Medicine and the Methodist Hospital, Houston, Texas

    Neal S. Kleiman

  2. Department of Medicine, Section of Cardiology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas

    Russell P. Tracy

  3. Department of Medicine, University of Arkansas, Little Rock, Arkansas

    J. David Talley

  4. Duke Clinical Research Institute, Durham, North Carolina

    Kristina Sigmon, Diane Joseph, Robert M. Califf & E. Magnus Ohman

  5. Cleveland Clinic Foundation, Cleveland, Ohio

    Eric J. Topol

  6. COR Therapeutics, South San Francisco, California, USA

    Michael Kitt

Authors
  1. Neal S. Kleiman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Russell P. Tracy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. David Talley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristina Sigmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diane Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric J. Topol
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert M. Califf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Kitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E. Magnus Ohman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Neal S. Kleiman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kleiman, N.S., Tracy, R.P., Talley, J.D. et al. Inhibition of Platelet Aggregation with a Glycoprotein IIb-IIIa Antagonist Does Not Prevent Thrombin Generation in Patients Undergoing Thrombolysis for Acute Myocardial Infarction. J Thromb Thrombolysis 9, 5–12 (2000). https://doi.org/10.1023/A:1018650123272

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018650123272

Search

Navigation