Thromb Haemost 2002; 88(06): 1012-1019
DOI: 10.1055/s-0037-1613348
Involvement of Thrombin Receptors in the Subject-dependent Variability in Ca2+ Signal Generation
Schattauer GmbH

Combined Effects of Eptifibatide and Anticoagulants: Differences between LMWH and UH or rH in Thrombin Generation Inhibition but not in Platelet Aggregation Inhibition

Martin Koestenberger
1   Department of Pediatrics, Haemostasis and Thrombosis, University of Graz, Austria
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
,
Siegfried Gallistl
1   Department of Pediatrics, Haemostasis and Thrombosis, University of Graz, Austria
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
,
Gerhard Cvirn
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
,
Birgit Roschitz
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
,
Martina Petritsch
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
,
Bettina Leschnik
1   Department of Pediatrics, Haemostasis and Thrombosis, University of Graz, Austria
,
Wolfgang Muntean
1   Department of Pediatrics, Haemostasis and Thrombosis, University of Graz, Austria
2   Ludwig Boltzmann Research Institute for Pediatric Haemostasis and Thrombosis, University of Graz, Austria
› Author Affiliations
Further Information

Publication History

Received 02 June 2002

Accepted after resubmission 05 August 2002

Publication Date:
09 December 2017 (online)

Summary

Aim of our study was to investigate effects of eptifibatide and anticoagulants on platelet aggregation and thrombin generation under low and high coagulant challenge in tissue factor-activated platelet rich plasma using a model allowing simultaneous determination of the time course of platelet aggregation and thrombin generation. Eptifibatide exerted a dose-dependent anti-aggregating effect under both high and significantly stronger under low coagulant challenge. Combination of eptifibatide and anticoagulants resulted in significant additive prolongation of the lag phase until the onset of platelet aggregation, more pronounced under low coagulant challenge. Under high, but not under low coagulant challenge combination of eptifibatide and anticoagulants had a significant synergistic inhibitory effect on platelet aggregation. Under low coagulant challenge combination of eptifibatide with LMWH, but not with UH, or rH, resulted in significantly reduced thrombin potential, F 1+2 generation, and FXa formation compared to measurements in the absence of eptifibatide.

We demonstrate a synergistic effect of eptifibatide and anticoagulants on platelet aggregation inhibition and an additional inhibitory effect of LMWH and eptifibatide on thrombin generation. Our results support the notion that combination of eptifibatide and anticoagulants might be beneficial in atherosclerotic disease to palliate the thrombogenic potency of ruptured atherosclerotic plaques.

 
  • References

  • 1 Scarborough RM. Development of eptifibatide. Am Heart J 1999; 138: 1093-104.
  • 2 Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol 1997; 80: 11B-20B.
  • 3 Hemker HC, Beguin S. Thrombin generation in plasma: Its assessment via the endogenous thrombin potential. Thromb Haemost 1995; 74: 134-38.
  • 4 Hemker HC, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993; 70: 617-24.
  • 5 Wielders S, Mukherjee M, Michiels J, Rijkers DT, Cambus JP, Knebel RW, Kakkar V, Hemker HC, Beguin S. The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 1997; 77: 629-36.
  • 6 Neri GGSerneri, Rovelli F, Gensini GF, Pirelli S, Carnovali M, Fortini A. Effectiveness of low-dose heparin in prevention of myocardial reinfarction. Lancet 1987; 01: 937-42.
  • 7 A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Report of the Sixty Plus Reinfarction Study Research Group. Lancet 1980; 02: 989-94.
  • 8 Gallistl S, Muntean W. Thrombin-hirudin complex formation, thrombin-antithrombin III complex formation, and thrombin generation after intrinsic activation of plasma. Thromb Haemost 1994; 72: 387-92.
  • 9 Gallistl S, Muntean W, Leis HJ. Effects of heparin and hirudin on thrombin generation and platelet aggregation after intrinsic activation of platelet rich plasma. Thromb Haemost 1995; 74: 1163-8.
  • 10 Pieters J, Lindhout T. The limited importance of factor Xa inhibition to the anticoagulant property of heparin in thromboplastin-activated plasma. Blood 1988; 72: 2048-52.
  • 11 Koestenberger M, Gallistl S, Cvirn G, Roschitz B, Muntean W. Effects of the glycoprotein IIb/IIIa receptor antagonist c7E3 Fab and anticoagulants on platelet aggregation and thrombin potential under high coagulant challenge in vitro. Blood Coagul Fibrinolysis 2000; 11: 425-32.
  • 12 The IMPACT-II investigators. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Lancet 1997; 349: 1422-8.
  • 13 Ohman EM, Kleiman NS, Gacioch G, Worley SJ, Navetta FI, Talley JD, Anderson HV, Ellis SG, Cohen MD, Sriggs D, Miller M, Kereiakes D, Yakubov S, Kitt MM, Sigmon KN, Califf RM, Krucoff MW, Topol EJ. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with integrilin in acute myocardial infarction. Circulation 1997; 95: 846-54.
  • 14 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.
  • 15 Reverter JC, Beguin 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: 863-74.
  • 16 Herault JP, Peyrou V, Savi P, Bernat A, Herbert JM. Effect of SR 121566A, a potent GP IIb-IIIa antagonist on platelet-mediated thrombin generation in vitro and in vivo. Thromb Haemost 1998; 79: 383-8.
  • 17 Beguin S, Lindhout T, Hemker HC. The effect of trace amounts of tissue factor on thrombin generation in platelet rich plasma, its inhibition by heparin. Thromb Haemost 1989; 61: 25-9.
  • 18 Butenas S, Cawthern KM, van’t Veer C, DiLorenzo ME, Lock JB, Mann KG. Antiplatelet agents in tissue factor-induced blood coagulation. Blood 2001; 97: 2314-22.
  • 19 Li Y, Spencer FA, Ball S, Becker RC. 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 2000; 10: 69-76.
  • 20 Kleiman NS, Tracy RP, Talley JD, Sigmon K, Joseph D, Topol EJ, Califf RM, Kitt M, Ohman EM. 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 2000; 09: 5-12.
  • 21 Suzuki YS, Hillyer P, Miyamoto S, Niewiaroski S, Sun L, Rao AK, Hollenbach S, Edmunds LH. Integrilin prevents prolonged bleeding times after cardiopulmonary bypass. Ann Thorac Surg 1998; 66: 373-81.
  • 22 Furman MI, Krueger LA, Frelinger AL, Barnard MR, Mascelli MA, Nakada MT, Michelson AD. GPIIb-IIIa antagonist-induced in platelet surface factor V/Va binding and phosphatidylserine expression in whole blood. Thromb Haemost 2000; 84: 492-8.
  • 23 Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-9.
  • 24 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50 310-18.
  • 25 Hemker HC, Willems GM, Beguin S. A computer assisted method to obtain the prothrombin activation velocity in whole plasma independent of thrombin decay processes. Thromb Haemost 1986; 56: 9-17.
  • 26 Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-65.
  • 27 Van’t Veer C, Mann KG. Regulation of tissue factor initiated thrombin generation by the stoichiometric inhibitors tissue factor pathway inhibitor, antithrombin-III and heparin cofactor-II. J Biol Chem 1997; 272: 4367-77.
  • 28 Rapaport SI. The extrinsic pathway inhibitor: a regulator of tissue factordependent blood coagulation. Thromb Haemost 1991; 66: 6-15.
  • 29 Dormann D, Clemetson KJ, Kehrel BE. The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity. Blood 2000; 96: 2469-78.
  • 30 Monroe DM, Hoffman M, Roberts HR. Transmission of a procoagulant signal from tissue factor-bearing cells to platelets. Blood Coagul Fibrinolysis 1996; 07: 459-64.
  • 31 Kaul S, Shah PK. Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin?. J Am Coll Cardiol 2000; 35: 1699-712.
  • 32 Cohen M, Theroux P, Weber S, Lavamee P, Huynh T, Borzak S, Diodati JG, Squire IB, Deckelbaum LI, Thornton AR, Harris KE, Sax FL, Lo MW, White HD. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiol 1999; 71: 273-81.
  • 33 Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1-17.
  • 34 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralisation by platelet factor 4. Biochem J 1984; 218: 725-32.
  • 35 Beguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemost 1989; 60: 457-62.
  • 36 Weitz JI. Activation of blood coagulation by plaque rupture: mechanisms and prevention. Am J Cardiol 1995; 75: 18B-22B.
  • 37 Turpie AG. Clinical potential of antithrombotic drugs in coronary syndromes. Am J Cardiol 1998; 82: 11L-14L.