Figure.

The unique characteristics of PAR1 and PAR4 may provide an opportunity to fine tune thrombin signaling to optimize platelet response. A) PAR1 and PAR4 are distinct thrombin receptors that have different rates of activation and signaling kinetics. These receptors have complementary roles in hemostasis and cooperate to mediate thrombin signaling in platelets. B) Hemostasis (top left) starts from initial platelet adhesion and activation to form an unstable thrombus. Following additional thrombin generation and fibrin deposition, a stable thrombus forms to stop the bleeding. Thrombosis (top right) is the uncontrolled growth of the thrombus that obstructs blood flow. Inhibition of PAR1 (bottom left) with vorapaxar targets the initial stages of platelet activation at low thrombin concentrations. Inhibition of PAR4 (bottom right) with BMS-986120 targets the later stages of thrombus growth, which preserves the initial platelet aggregation mediated by PAR1.