Thrombin can act through PAR activation and/or by targeting specific protein substrates present in the vasculature such as osteopontin and HMW FGF-2. PAR activation occurs when thrombin cleaves the seven transmembrane GPCR generating a tethered ligand (TL, small gray bar) that triggers a cascade of intracellular signaling events. Thrombin can also cleave a number of alternative substrates. Osteopontin cleavage exposes its functional domains: integrin-binding sites with RGD and SVVYGLR domains (grey bar) plus the C-terminal CD44-binding domain (marbled grey bar) critical for cellular recognition/interaction. HMW FGF-2 cleavage by thrombin leads to generation of vasoactive ELF-2 (see text and Figs. 1 and 2). Cleavage of either protein results in modifications of their biological activity which may have profound repercussions on cardiovascular homeostasis. Elucidation of these mechanisms may lead to specifically inhibit and/or control thrombin activity on specific protein substrates without affecting its coagulation properties.