Tissue Factor and Cardiovascular Disease:

Under physiological conditions, the coagulation system is designed to maintain the circulating blood in a fluid state, but act towards restoration of vascular integrity by rapid clot formation after vessel injury. Historically, the coagulation cascade was divided into 2 major systems: the extrinsic and the intrinsic pathway (Figure 1).1 The tissue factor (TF)factor VII/VIIa (FVII/FVIIa) complex was introduced as the extrinsic system as an exogenous factor (ie, TF) was required to activate circulating clotting factors. TF thereby initiates coagulation by interacting with activated factor FVII (FVIIa) to form the TF-FVIIa complex. In addition, TF is able to bind inactive factor VII (TF-FVII). FVIIa or the TF-FVIIa complex are able to convert the TF-FVII into its active form TF-FVIIa. The intrinsic system contains the circulating components of the coagulation system including factor XII (FXII), XI (FXI), IX (FIX), and VIII (FVIII).2 Even though the 2 coagulation systems may be activated independently, they share a final common pathway represented by the prothrombinase complex FVa-FXa (Figure 1).3 This complex catalyzes the conversion of prothrombin to thrombin, which cleaves fibrinogen into fibrin, activates platelets, and finally induces clot formation. Interestingly, stimulated platelets in a growing thrombus may additionally induce activation of coagulation factors; thus, there is evidence that the coagulation systems may play a role in both thrombus initiation and propagation.4 In clinical practice, the activity of the extrinsic pathway is measured by the prothrombin time, while the activated partial prothrombin time quantifies the function of the intrinsic system. To maintain steady-state conditions, several inhibitory pathways may be activated to counteract the activity of the coagulation system. The serine protease inhibitor TF pathway inhibitor (TFPI) undergoes a quaternary complex with FXa, thus inhibiting the TF-FVIIa-complex.5 Activated protein C associates with protein S and inactivates FV and FVIII,6 while the anticoagulant protein antithrombin (ATIII) targets and inhibits thrombin as well as different clotting factors.7