What is all that thrombin for?

Abstract

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.

Comparison of antithrombin‐dependent and direct inhibitors of factor Xa or thrombin on the kinetics and qualitative characteristics of blood clots

“…This amount of thrombin appears to be sufficient for inducing normal fibrin polymerization and clot firmness. This finding is in accordance with the mathematical model developed by Mann et al32 who showed that tiny amounts of thrombin, appeared at the beginning of the initiation phase of coagulation, are required for normal fibrin polymerization. In the presence of fondaparinux at concentrations which induced comparable inhibition of thrombin generation as rivaroxaban, although the minimum thrombin generation was preserved, clot formation kinetics were altered.…”

HD1, a Thrombin-directed Aptamer, Binds Exosite 1 on Prothrombin with High Affinity and Inhibits Its Activation by Prothrombinase

“…Efficient prothrombin activation by prothrombinase is essential for generating a burst of thrombin at sites of vascular injury (50). For efficient activation to occur, prothrombin must incorporate into the prothrombinase complex.…”

During coagulation, thrombin generation shifts from chemical to diffusional control

“…Experiments in the presence of platelets and tissue factor bearing cells suggest that, as soon as such structures are present, physical transport through diffusion might play a role in determining thrombin generation velocities [5,6,7]. In coagulation experiments in plasma in vitro, procoagulant phospholipids are added to platelet-poor plasma (PPP) in the form of vesicles; in plateletrich plasma (PRP), they are provided by activated platelets [8].At the moment that a clot forms, $98% of thrombin is still to be generated [9,10]. The total amount of thrombin formed is an important determinant of the quality of hemostasis or the extent of thrombosis [11] and this thrombin is almost all formed within the fibrin mesh of the clot.…”