Vascular injury may activate the coagulation cascade (only the extrinsic cascade is shown) by allowing plasma factor VII to interact with its extravascular cofactor TF. The TF:VIIa complex activates factor X, and Xa converts prothrombin to thrombin with the help of cofactor factor Va. Thrombin not only triggers thrombosis by cleaving fibrinogen and activating platelets through PARs (PAR4 in mice, PAR1 and PAR4 in humans), but also activates mural cells and leukocytes through PAR1. Partial loss (by haploinsufficiency of TFPI, or HCII in the current study by Aihara et al.; ref. 14) or interruption (by APC resistance induced by the presence of factor V Leiden) of natural inhibitor function is associated with enhanced pathologic remodeling in animal models; AT appears to be an exception. Conversely, recombinant anticoagulant therapy (e.g., use of VIIai, TFPI, TM, or hirudin) reduces remodeling, as does loss or inhibition of the thrombin receptor PAR1. This suggests that thrombin contributes to pathologic remodeling and may imply a direct pathway from TF exposure to vascular injury through PAR1 signaling (red) (14), although other effectors of thrombin or upstream coagulation factors may also contribute to this process. VIIai, active site-inhibited VIIa.