The hemostatic response to vascular damage results in the focal generation of Α-thrombin to produce a fibrin/platelet clot at the site of vascular injury. This regulated hemostatic response derives from the assembly and activity of enzyme complexes which are localized to surfaces presented by the vascular damage. The product of each enzymatic complex provides the serine protease component required for the assembly and activity of each successive enzyme complex, ultimately leading to the formation of Α-thrombin. When one limits attention to those complexes clearly associated with hemostatic or thrombotic risk, the significance of the vitamin-K-dependent enzyme complexes becomes apparent. Each of these complexes involves a serine protease and a cofactor protein which assemble on a membrane surface in the presence of Ca2+. The expression of an active complex involves, in addition to the activation of zymogen to an enzyme, the presentation or activation of a cofactor protein and the provision of the appropriate membrane to support the reaction. Two plasma cofactors, factor V and factor VIII require proteolytic activation, while the cofactors tissue factor and thrombomodulin are membrane-associated proteins, whose presentation is regulated at the cellular level. The coagulation system that produces Α-thrombin is an explosion which is regulated by multiple feedback reactions which amplify the hemostatic response.