Platelets initiate arrest of bleeding at sites of vascular injury but also trigger inopportune arterial thrombosis, which causes heart attack and stroke. After formation of a single platelet monolayer at the site of injury, additional platelets are recruited into the growing hemostatic plug. Without further stabilization, the platelet plug disaggregates. Its stabilization is ensured by perpetuation of platelet activation. Drugs designed to prevent thrombus stabilization rather than inhibition of its formation, are currently not available. Platelet signaling of the perpetuation phase of platelet activation might represent a potential target for antiplatelet drugs that would prevent thrombosis without eliciting bleeding.