Abstract 3293: The Active Metabolite of Prasugrel Inhibits Platelet Procoagulant Activities
Prasugrel is a novel prodrug of the same thienopyridine class as clopidogrel and ticlopidine. In vivo metabolism of prasugrel generates the active metabolite R-138727, an antagonist of the platelet P2Y12 ADP receptor, inhibiting ADP-mediated platelet activation and aggregation. Collagen-stimulated platelet procoagulant activity (annexin V binding, tissue factor expression on monocyte-platelet aggregates, and enhanced thrombin generation) is mediated in part by ADP, and added ADP increases these responses. In the present study, we evaluated in vitro R-138727 inhibition of platelet procoagulant activities stimulated by ADP 20 μM, collagen 20 μg/mL, and ADP 20 μM plus collagen 20 μg/mL in normal donor blood (n=6). R-138727 10 μM significantly inhibited synergistic ADP/collagen-stimulated annexin V binding to platelets (Table⇓). R-138727 also inhibited tissue factor expression on ADP-, collagen-, and ADP/collagen-stimulated monocyte-platelet aggregates (Table⇓). R-138727 reduced the percent of monocytes incorporated into monocyte-platelet aggregates, further inhibiting tissue factor expression (tissue factor was not increased on individual monocytes). To determine if inhibition of these platelet procoagulant activities significantly inhibited thrombin generation, we measured the kinetics of thrombin generation in re-calcified whole blood. ADP, collagen, and ADP/collagen accelerated the kinetics of thrombin generation and R-138727 10 μM significantly inhibited this acceleration (Table⇓). Similarly, clot development in a modified thromboelastograph system was inhibited by the active metabolite of prasugrel (IC50 0.7±0.1μM, data not shown). These findings suggest that inhibition of platelet procoagulant activity by the active metabolite of prasugrel results in the functional consequences of delayed thrombin generation and impaired clot development.