Role of thrombin signalling in platelets in haemostasis and thrombosis

Platelets are critical in haemostasis and in arterial thrombosis, which cau ses heart attacks and other events triggered by abnormal clotting(1-5). The coagulation protease thrombin is a potent activator of platelets ex vivo(6 ). However, because thrombin also mediates fibrin deposition and because mu ltiple agonists can trigger platelet activation(7), the relative importance of platelet activation by thrombin in haemostasis and thrombosis is unknow n. Thrombin triggers cellular responses at least in part through protease-a ctivated receptors (PARs)(8). Mouse platelets express PAR3 and PAR4 (ref. 9 ). Here we show that platelets from PAR4-deficient mice failed to change sh ape, mobilize calcium, secrete ATP or aggregate in response to thrombin. Th is result demonstrates that PAR signalling is necessary for mouse platelet activation by thrombin and supports the model that mouse PAR3 (mPAR3) does not by itself mediate transmembrane signalling but instead acts as a cofact or for thrombin cleavage and activation of mPAR4 (ref. 10). Importantly, PA R4-deficient mice had markedly prolonged bleeding times and were protected in a model of arteriolar thrombosis. Thus platelet activation by thrombin i s necessary for normal haemostasis and may be an important target in the tr eatment of thrombosis.