This study investigates the roles of protease-activated receptors (PARs) 1, 3, and 4 in the activation of human platelets by thrombin. The authors found that PAR1 and PAR4 are functionally expressed in human platelets and are responsible for most, if not all, thrombin signaling in these cells. Specifically, PAR1 mediates platelet responses at low concentrations of thrombin and is necessary for rapid and robust platelet activation, even at high thrombin concentrations. In contrast, PAR4 mediates platelet activation only at high thrombin concentrations and appears unnecessary for activation when PAR1 function is intact. The study also demonstrated that specific inhibition of PAR1 and PAR4 ablates thrombin signaling in human platelets, suggesting that these receptors are potential targets for developing antithrombotic agents. The findings highlight the importance of understanding the dual thrombin receptor system in platelets and its implications for therapeutic interventions.This study investigates the roles of protease-activated receptors (PARs) 1, 3, and 4 in the activation of human platelets by thrombin. The authors found that PAR1 and PAR4 are functionally expressed in human platelets and are responsible for most, if not all, thrombin signaling in these cells. Specifically, PAR1 mediates platelet responses at low concentrations of thrombin and is necessary for rapid and robust platelet activation, even at high thrombin concentrations. In contrast, PAR4 mediates platelet activation only at high thrombin concentrations and appears unnecessary for activation when PAR1 function is intact. The study also demonstrated that specific inhibition of PAR1 and PAR4 ablates thrombin signaling in human platelets, suggesting that these receptors are potential targets for developing antithrombotic agents. The findings highlight the importance of understanding the dual thrombin receptor system in platelets and its implications for therapeutic interventions.