PubMed · 14913177
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D I MACHT, T HOFFMASTER. 1952-01-25. An improved method for measuring coagulation time.. https://doi.org/10.1126/science.115.2978.91
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A mixed film bearing nanoscale domains of one chemical functionality surrounded by another chemical functionality is shown to prolong material-induced coagulation of whole human blood plasma. In comparison, surfaces with uniform silane chemistry or physical mixtures of control surfaces bearing two different, uniform silane chemistries are found to be much more efficient activators of plasma coagulation on a per-unit-area basis. Binary mixed films are deposited on glass substrates by the sequential adsorption of 0.0001% 3-aminopropyltriethoxysilane (APS) followed by 0.1% n-butyltrichlorosilane (BTS). Creation of APS islands in a sea of BTS is confirmed by atomic force microscopy in friction mode. Results suggest that some yet-to-be-determined interfacial phenomena, perhaps associated with protein adsorption near the interface, may be altered by this nanoscale spatially distributed chemical heterogeneity, causing a decrease in contact activation.
Formation of thrombin is triggered when membrane-localized tissue factor (TF) is exposed to blood. In closed models of this process, thrombin formation displays an initiation phase (low rates of thrombin production cause platelet activation and fibrinogen clotting), a propagation phase (>95% of thrombin production occurs), and a termination phase (prothrombin activation ceases and free thrombin is inactivated). A current controversy centers on whether the TF stimulus requires supplementation from a circulating pool of blood TF to sustain an adequate procoagulant response. We have evaluated the requirement for TF during the progress of the blood coagulation reaction and have extended these analyses to assess the requirement for TF during resupply ("flow replacement"). Elimination of TF activity at various times during the initiation phase indicated: a period of absolute dependence (<10 s); a transitional period in which the dependence on TF is partial and decreases as the reaction proceeds (10-240 s); and a period in which the progress of the reaction is TF independent (>240 s). Resupply of reactions late during the termination phase with fresh reactants, but no TF, yielded immediate bursts of thrombin formation similar in magnitude to the original propagation phases. Our data show that independence from the initial TF stimulus is achieved by the onset of the propagation phase and that the ensemble of coagulation products and intermediates that yield this TF independence maintain their prothrombin activating potential for considerable time. These observations support the hypothesis that the transient, localized expression of TF is sufficient to sustain a TF-independent procoagulant response as long as flow persists.
Classical hemophilia results from a defect of the intrinsic tenase complex, the main factor X (FX) activator. Binding of factor VIIa to tissue factor triggers coagulation, but little amplification of thrombin production occurs. Handling of hemophilia by injection of the deficient or missing (thus foreign) factor often causes immunological complications. Several strategies have been designed to bypass intrinsic tenase complex, but none induce true auto-amplification of thrombin production. In an attempt to re-establish a cyclic amplification of prothrombin activation in the absence of tenase, we prepared a chimera of FX having fibrinopeptide A for the activation domain (FX(FpA)). We reasoned that cascade initiation would produce traces of thrombin that would activate FX(FpA) (contrary to its normal homologue). Given that the activation domain of FX is released upon activation, thrombin cleavage would produce authentic FXa that would produce more thrombin, which in turn would activate more chimeras. FX(FpA) was indeed activable by thrombin, albeit at a relatively low rate (5 x 10(3) M(-1) s(-1)). Nevertheless, FX(FpA) allowed in vitro amplification of thrombin production, and 100 nM efficiently corrected thrombin generation in tenase-deficient plasmas. A decisive advantage of FX(FpA) could be that the artificial cascade is self-regulating: FX(FpA) had little influence on the clotting time of normal plasma, yet corrected that of tenase deficiency. Another advantage could be the half-life of FX(FpA) in blood; FX has a half-life of about 30 h (less than 3 h for FVIIa). It is also reasonable to expect little or no immunogenicity, because FX and fibrinopeptide A both circulate normally in the blood of hemophiliacs.