Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonistdoes not prevent thrombin generation in patients undergoing thrombolysis for acute myocardial infarction

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a ph ospholipid surface on which prothrombin is cleaved to form thrombin. We exa mined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glyc oprotein IIb-IIIa inhibitor eptifibatide (Integrilin(TM)) administered conc omitantly 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 mu M 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 gr oup. In the course of dose escalation, two groups of patients received the same 135 mu g/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 Thro mbolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 mi nutes. These data suggest that thrombin generation and activity persist fol lowing thrombolysis, despite inhibition of platelet aggregation, and that t reatment with inhibitors of thrombin activity may be required even when gly coprotein IIb-IIIa inhibitors are used.