THE ROLE OF THE TISSUE FACTOR PATHWAY IN INITIATION OF COAGULATION

Three model systems have been used to study the dynamics of the blood clotting process initiated by tissue factor (TF): synthetic plasma mix tures prepared with purified coagulation proteins and inhibitors; math ematical models based on the reaction constants, stoichiometries and t hermodynamics of individual catalyst and inhibitor reactions; and cont act suppressed whole blood induced to clot in vitro by the addition of exogenous TF. In the three models, the generation of thrombin can be described in terms of an initiation phase in which pmol/l concentratio ns of the coagulation serine proteases are generated and the cofactor proteins factor V (FV) and FVIII are activated. Subsequently, explosiv e thrombin generation occurs during a propagation phase. The complemen tary inhibitory pathways extinguish the generation of thrombin. Tissue factor pathway inhibitor (TFPI), present in low concentrations, prima rily influences the duration of the initiation phase and has little in fluence on the propagation phase. Antithrombin III (ATIII), present in higher concentrations, has little influence during the initiation pha se, but decreases the rate of thrombin generation during the propagati on phase. The protein C pathway cannot act in the absence of thrombin and therefore only influences the duration of the propagation phase by inactivating activated FV. Thus combinations of TFPI plus ATIII and T FPI plus protein C pathway components contribute to the synergistic in hibitory processes. As a consequence of the roles of pro, and anti-coa gulants, the generation of thrombin by the TF pathway becomes a thresh old limited process. Blood Coag Fibrinol 9 (suppl 1):S3-S7 (C) 1998 Li ppincott-Raven Publishers