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  • Title: Interaction of activated factor VII and active site-inhibited activated factor VII with tissue factor.
    Author: Sørensen BB, Rao LV.
    Journal: Blood Coagul Fibrinolysis; 1998 Mar; 9 Suppl 1():S67-71. PubMed ID: 9819031.
    Abstract:
    The coagulation cascade is initiated by binding of plasma activated or non-activated factor VII [FVII(a)] to cell surface tissue factor (TF). TF-induced coagulation plays a primary role not only in haemostasis but also in the pathogenesis of various thrombotic disorders. Recent studies with animal model systems showed that the administration of active site-inhibited FVIIa (FVIIai) blocked TF-FVIIa-induced fibrin and thrombus formation. These data suggest that FVIIai competes with plasma FVII(a) for a limited number of TF sites expressed on cells either constitutively or induced after the perturbation. To obtain insights into the mechanism(s) by which FVIIai is effective in inhibiting TF-FVIIa induced coagulation in vivo, we compared the interaction of FVIIai and FVIIa with TF using a variety of competition assays and direct binding assays. The TF-FVIIa amidolytic activity competition assay showed that FVIIai bound with a threefold higher affinity than that of FVIIa to TF relipidated in phosphatidylcholine (PC) vesicles, whereas no significant differences were found between FVIIa and FVIIai binding to TF if it had been relipidated in mixed phospholipid vesicles containing PC and phosphatidylserine (PS). When FVIIa and FVIIai binding to TF was analysed in a FXa generation assay, we found that FVIIai bound to TF in PCPS vesicles with two- to fivefold higher affinity than that of FVIIa, whereas the affinity of FVIIai for TF in PC vesicles was seven- to 10-fold higher than that of FVIIa. Direct binding analysis to TF, immobilized on a sensor chip or on a cell surface, showed a faster association and a slower dissociation of FVIIai to TF compared with that of FVIIa. Equilibrium binding to cell surface TF showed that the affinity of FVIIai was fivefold higher than that of FVIIa to non-functional TF, whereas both FVIIa and FVIIai bound functional TF with the same high affinity. The enhanced affinity of FVIIai to TF, particularly to non-functional TF, would make FVIIai a valuable reagent to block TF-induced coagulation before it is triggered by cell injury or a pathological stimuli.
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