PubMed · 13997928
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D VOROSMARTHY. 1962. Solar coagulation.. https://pubmed.ncbi.nlm.nih.gov/13997928/
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The presence of activation peptides (AP) of the vitamin K-dependent proteins in the phlebotomy blood of human subjects suggests that active serine proteases may circulate in blood as well. The goal of the current study was to evaluate the influence of trace amounts of key coagulation proteases on tissue factor-independent thrombin generation using three models of coagulation. With procoagulants and select coagulation inhibitors at mean physiological concentrations, concentrations of factor IXa, factor Xa, and thrombin were set either equal to those of their AP or to values that would result based upon the rates of AP/enzyme generation and steady state enzyme inhibition. In the latter case, numerical simulation predicts that sufficient thrombin to produce a solid clot would be generated in approximately 2 min. Empirical data from the synthetic plasma suggest clotting times of 3-5 min, which are similar to that observed in contact pathway-inhibited whole blood (4.3 min) initiated with the same concentrations of factors IXa and Xa and thrombin. Numerical simulations performed with the concentrations of two of the enzymes held constant and one varied suggest that the presence of any pair of enzymes is sufficient to yield rapid clot formation. Modeling of states (numerical simulation and whole blood) where only one circulating protease is present at steady state concentration shows significant thrombin generation only for factor IXa. The addition of factor Xa and thrombin has little effect (if any) on thrombin generation induced by factor IXa alone. These data indicate that 1) concentrations of active coagulation enzymes circulating in vivo are significantly lower than can be predicted from the concentrations of their AP, and 2) expected trace amounts of factor IXa can trigger thrombin generation in the absence of tissue factor.
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Upon plaque rupture or vascular injury, tissue factor (TF) protein in the vessel wall becomes exposed to flowing blood, initiating a cascade of reactions resulting in the deposition of fibrin and platelets on the injured site. Paradoxically, the growing thrombus may act as a barrier, restricting the convective and diffusive exchange of substrates and coagulation products between the blood and reactive vessel wall, thus limiting the role TF plays in thrombus growth. In this study, various in vitro, platelet-fibrin clots were prepared on TF:VIIa-coated surfaces and the rate at which factor (F) X in the well-mixed clot supernatant permeates the clot and is converted to X(a) was monitored over several hours. The apparent diffusion coefficients of FX((a)) in fibrin and platelet-fibrin clots at 37 degrees C was 2.3 x 10(-7) and 5.3 x 10(-10) cm(2)/second, respectively, indicating that the mean time required for FX((a)), and likely FIX((a)), to diffuse 1 mm in a fibrin clot is 4 hours, and in the presence of platelets, 3.6 months. As complete human thrombotic occlusion has been observed within 10 minutes, an alternative source of procoagulant activity that can localize to the outer surface of growing thrombi, such as platelet factor XI or blood-borne TF, appears essential for rapid thrombus growth.