SummaryAim 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.

Melagatran is the active form of the oral direct thrombin inhibitor ximelagatran. Melagatran does not require antithrombin as a cofactor. Its administration is therefore of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We investigated the effects of increasing amounts of melagatran (0.05-1 micromol/l) on the activated partial thromboplastin time (APTT) and ecarin clotting time (ECT) in cord versus adult plasma. Both the APTT and ECT were dose-dependently prolonged in the presence of increasing amounts of melagatran. Furthermore, the ECT revealed a higher susceptibility of cord plasma to addition of melagatran than adult plasma. Whereas similar amounts of melagatran were required in cord and adult plasma samples to double the APTT (IC(50), 0.47 vs 0.46 micromol/l), significantly less melagatran was required in cord versus adult plasma to double the ECT (IC(50), 0.26 vs 0.56 micromol/l). Based on APTT measurements, similar plasma levels of melagatran might be required in neonates and in adults to treat thromboembolic complications. The APTT, however, is relatively insensitive to plasma melagatran concentrations. When the sensitive indicator ECT is used, results suggest that lower amounts of melagatran might be required in neonates than in adults. This has to be scrutinized in future clinical studies.

The aim of our study was to investigate the combined in vitro effects of melagatran and eptifibatide on platelet aggregation and thrombin generation under low and high coagulant challenge in tissue-factor-activated, platelet-rich plasma. Increasing amounts of melagatran dose-dependently decreased prothrombin fragment 1.2 and activated factor X values, and dose-dependently prolonged the lag phase until the onset of platelet aggregation. Eptifibatide exerted a dose-dependent anti-aggregating effect under both high and low coagulant challenge. The combination of melagatran and eptifibatide resulted in significant additive prolongation of the lag phase until the onset of platelet aggregation, which was more pronounced under low coagulant challenge. Under low, but not under high, coagulant challenge, the combination of melagatran and eptifibatide had a significant additive inhibitory effect on platelet aggregation. No additive effects on decreasing prothrombin fragment 1.2 and activated factor X values were observed with combined administration of the drugs. The present study demonstrates the additive effect of melagatran and eptifibatide on platelet aggregation inhibition and on prolongation of the lag phase until the onset of platelet aggregation.