Fig.3. Schematic model of RAP1-dependent platelet regulation.

Left panel. In platelets circulating healthy vessels RASA3 is active to restrain uncontrolled RAP1 activation and maintain a quiescent, non-adhesive state (no integrin activation). Central panel. At sites of vascular injury, platelets stimulation results in an increase in the cytosolic Ca²⁺ levels and the release of ADP from dense granules. Ca²⁺ activates CalDAG-GEFI, which mediates rapid GTP-loading of RAP1. ADP stimulates the P2Y12 receptor, which leads to decreased RASA3 function and sustained RAP1 signaling. Fast and sustained RAP1/integrin activation results in the formation of stable three-dimensional thrombi over a broad range of hemodynamic shear conditions. Right panel. Inhibitors to P2Y12, such as Clopidogrel, prevent the inactivation of RASA3, prohibit sustained RAP1 signaling and destabilize the growing thrombus.