Cofactor-assisted substrate interactions of thrombin on the endothelial cell and platelets. (A) Thrombin is bound to endothelial cell thrombomodulin (TM) by exosite I interaction with EGF-like domains 5 and 6. Exosite II can also interact with any chondroitin sulfate side chain present on the proteoglycan. Protein C (PC) binds to thrombomodulin on EGF-like domain 4, in a position favorable for its activation by thrombin. The high efficiency of activation may arise both from approximation of thrombin and protein C on thrombomodulin, and from exosite-induced conformational change in the active site of thrombin. (B) Thrombin bound via exosite II on endothelial cell heparan sulfate proteoglycan side chains is efficiently inhibited by antithrombin (AT). (C) Thrombin bound to platelet GpIbα via exosite II is brought into proximity to PAR-1 and enhances its activation using exosite I to make contact. (D) The thrombin-GpIbα complex can enhance cleavage of GpV, resulting in hyperactive platelets. (E) The thrombin-GpIbα complex can also activate factor XI (FXI) bound to GpIbα at a separate site in the leucine-rich repeat region. The images of GpIbα interactions have been adapted with permission from Dumas et al⁵¹  and Sadler⁵²  (original illustration, Katharine Sutliffe). Copyright 2003 AAAS.