Inhibition of Platelet Aggregation with a Glycoprotein IIb-IIIa Antagonist Does Not Prevent Thrombin Generation in Patients Undergoing Thrombolysis for Acute Myocardial Infarction Neal S. Kleiman, 1 Russell P. Tracy, 2 J. David Talley, 3 Kristina Sigmon, 5 Diane Joseph, 5 Eric J. Topol, 4 Robert M. Califf, 5 Michael Kitt, 6 , and E. Magnus Ohman, 5 1 Baylor College of Medicine and the Methodist Hospital, Houston, Texas, Department of Medicine, Section of Cardiology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas; 2 Department of Pathology, The University of Vermont, Colchester, Vermont; 3 Department of Medicine, University of Arkansas, Little Rock, Arkansas; 4 Cleveland Clinic Foundation, Cleveland, Ohio; 5 Duke Clinical Research Institute, Durham, North Carolina; 6 COR Therapeutics, South San Francisco, California, USA 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 epti~batide (Integrilin TM ) administered concomi- tantly 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. Epti~batide inhibited platelet aggregation in response to 20 lM ADP. Levels of ~brinopeptide A (FPA), thrombin–antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with epti~batide than in the control group. In the course of dose escalation, two groups of patients received the same 135 lg/kg bolus of epti~batide, 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 Throm- bolysis in Myocardial Infarction (TIMI) grade 3 angiog- raphic _ow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, de- spite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used. Key Words. epti~batide, thrombolysis, glycoprotein IIb- IIIa, myocardial infarction The formation of an arterial thrombus represents the culmination of a complex series of interactions between aggregating platelets and the soluble coagulation sys- tem. After adhering to the injured arterial wall, plate- lets aggregate, forming a hemostatic plug. Adherent platelets also contribute to thrombosis by presenting a large phospholipid surface on which coagulation factors Va and Xa combine with calcium to form the prothrom- binase complex, which accelerates the conversion of prothrombin to thrombin [1,2], although other cell types may contribute as well. Thrombin, in turn, performs a variety of actions that establish arterial thrombosis. Extensive evidence from experimental and clinical studies indicates that thrombin generation and activity actually are enhanced in patients treated with throm- bolytic therapy for myocardial infarction, and suggests that this thrombin plays a role in the failure to restore antegrade _ow through an occluded coronary artery and contributes to the process of reocclusion [3,4]. The platelet surface glycoprotein (GP) IIb-IIIa (inte- grin a 2B b 3 ) binds the circulating ligands ~brinogen and von Willebrand Factor (vWF), and permits the ~nal common step in the process of platelet aggregation [5]. Antagonism of this receptor–ligand binding process greatly reduces or eliminates platelet aggregation [6]. In patients receiving thrombolytic therapy for acute myocardial infarction, GP IIb-IIIa inhibition increases the frequency with which early reperfusion occurs and may limit the rate of reocclusion in animal models [7,8] as well as in patients [9,10]. The purpose of this study was to determine whether inhibition of platelet aggre- gation with epti~batide (Integrilin TM ), a highly speci~c Address for correspondence: Neal S. Kleiman, MD, 6565 Fannin, M.S. F-1090, Houston, TX, 77030, USA E-mail: nklei- man@bcm.tmc.edu 5 Journal of Thrombosis and Thrombolysis 2000;9:5–12 © Kluwer Academic Publishers. Boston. Printed in the Netherlands.