Mechanisms for thrombin generation by collagen in vivo. In flowing blood where there are shear forces, platelets adhere to exposed collagen. Slowed platelets additionally bind to collagen via glycoprotein VI (GPVI). The GPVI-collagen interaction results in platelet activation. Independently, exposed collagen supports zymogen factor XII (XII) autoactivation to enzymatic factor XIIa (XIIa). XIIa initiates thrombin generation through a series of proteolytic reactions. Thrombin then stimulates platelets by activating its receptors, protease activated receptor 1 (PAR1) and 4 (PAR4). PAR activation and GPVI signaling jointly contribute to a platelet thrombus, which amplifies into a fibrin clot and arterial vessel occlusion.