Abstract-The central event of the hemostatic process is the generation of thrombin through the tissue factor pathway. This is a highly regulated, dynamic process in which thrombin itself plays many roles, positively and negatively its production and destruction. The hemostatic process is essential to normal physiology and is also the Achilles heel of our aging population. The inappropriate generation of thrombin may lead to vascular occlusion with the consequence of myocardial infarction, stroke, pulmonary embolism, or venous thrombosis. In this review, we summarize our present views regarding the tissue factor pathway by which thrombin is generated and the roles played by extrinsic and intrinsic factor Xa generating complexes in hemostasis and the roles of the stoichiometric and dynamic inhibitors that regulate thrombin generation. Key Words: coagulation Ⅲ fibrinogen Ⅲ aggregation Ⅲ coagulation inhibitors T he inventory of molecular components and the presumed physiology of the hemostatic process and its regulation have been established on the basis of plasma abundance, hemorrhagic or thrombotic pathology, in vitro tests, and chemical signatures. Two in vitro plasma tests, the prothrombin time and the activated partial thromboplastin time, were prominent in the development of the inventory. The former test relies on the addition of an extrinsic tissue factor source (thromboplastin), whereas the latter is based on the introduction of a foreign surface to initiate coagulation using only this surface contact and the biological constituents intrinsic to plasma. Both tests rely on a fibrin formation (clotting) end point. These assays permitted identification of connectivity between the component activities identified as required for plasma coagulation and defined the concept of intrinsic and extrinsic coagulation pathways, which converge at the step of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in human pathology associated with bleeding or thrombosis. The primary pathway leading to hemostatic and thrombotic pathologies is associated with the tissue factorinitiated extrinsic coagulation pathway, whereas components unique to the intrinsic or contact pathway (factor XI, factor XII, prekallikrein, HMW kininogen) may have accessory roles in the process. Therefore, in this review, we focus on the dynamics of the reactions associated with the introduction of tissue factor to blood, leading to the formation of thrombin.An evaluation of the reactions involved in the formation of thrombin leads to the conclusion that the physiologically relevant hemostatic mechanism is composed of 3 procoagulant vitamin K-dependent enzyme complexes (which use the proteases factor IXa, factor Xa, and factor VIIa) and one anticoagulant vitamin K-dependent complex. 1 Each complex involves a vitamin K-dependent serine protease and a cofactor protein with the protein-protein complex assembled on a membrane surface provided by activated or damaged cells. The same hemostati...

Summary. The hemostatic process initiated by the exposure of tissue factor to blood is a threshold limited reaction which occurs in two distinct phases. During an initiationphase, small amounts of factor (F)Xa, FIXa and thrombin are generated. The latter activates the procofactors FV and FVIII to the activated cofactors which together with their companion serine proteases form the intrinsic FX activator (FVIIIa-FIXa) and prothrombinase (FVa-FXa) which generate the bulk of FXa and thrombin during a propagation phase. The clotting process (fibrin formation) occurs at the inception of the propagation phase when only 5-10 nM thrombin has been produced. Consequently, the vast majority (greater than 95%) of thrombin is produced after clotting during the propagation phase of thrombin generation. The blood of individuals with either hemophilia A or hemophilia B has no ability to generate the intrinsic FXase, and hence is unable to support the propagation phase of the reaction. Since clot based assays conclude before the propagation phase they are not sensitive to hemophilia A and B. The inception and magnitude of the propagation phase of thrombin generation is influenced by genetic polymorphisms associated with thrombotic and hemorrhagic disease, by the natural abundance of proand anticoagulants in healthy individuals and by pharmacologic interventions which influence thrombotic pathology. Therefore, it is our suspicion that the performance of the entire process of thrombin generation from initiation through propagation and termination phases of the reaction are relevant with respect to both hemorrhagic and thrombotic pathology.

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Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.