We have developed a model of the extrinsic blood coagulation system that includes the stoichiometric anticoagulants. The model accounts for the formation, expression, and propagation of the vitamin K-dependent procoagulant complexes and extends our previous model by including: (a) the tissue factor pathway inhibitor (TFPI)-mediated inactivation of tissue factor (TF)⅐VIIa and its product complexes; (b) the antithrombin-III (AT-III)-mediated inactivation of IIa, mIIa, factor VIIa, factor IXa, and factor Xa; (c) the initial activation of factor V and factor VIII by thrombin generated by factor Xa-membrane; (d) factor VIIIa dissociation/activity loss; (e) the binding competition and kinetic activation steps that exist between TF and factors VII and VIIa; and (f) the activation of factor VII by IIa, factor Xa, and factor IXa. These additions to our earlier model generate a model consisting of 34 differential equations with 42 rate constants that together describe the 27 independent equilibrium expressions, which describe the fates of 34 species. Simulations are initiated by "exposing" picomolar concentrations of TF to an electronic milieu consisting of factors II, IX, X, VII, VIIa, V, and VIIII, and the anticoagulants TFPI and AT-III at concentrations found in normal plasma or associated with coagulation pathology. The reaction followed in terms of thrombin generation, proceeds through phases that can be operationally defined as initiation, propagation, and termination. The generation of thrombin displays a nonlinear dependence upon TF, AT-III, and TFPI and the combination of these latter inhibitors displays kinetic thresholds. At subthreshold TF, thrombin production/ expression is suppressed by the combination of TFPI and AT-III; for concentrations above the TF threshold, the bolus of thrombin produced is quantitatively equivalent. A comparison of the model with empirical laboratory data illustrates that most experimentally observable parameters are captured, and the pathology that results in enhanced or deficient thrombin generation is accurately described.

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.

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...

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Studies focused on patient responsiveness to antiplatelet therapies, particularly aspirin and clopidogrel, have increased in recent years. However, the relations of in vivo platelet function and adverse clinical events to results of ex vivo platelet function tests remain largely unknown. This article describes current methods of measuring platelet function in various clinical and research situations and their advantages and disadvantages, reviews evidence for antiplatelet response variability and resistance, discusses the potential pitfalls of monitoring platelet function, and demonstrates emerging data supporting the positive clinical and treatment implications of platelet function testing.