Reduced prothrombinase inhibition by tissue factor pathway inhibitor contributes to the factor V Leiden hypercoagulable state
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Activated factor V (FVa) and factor X (FXa) form prothrombinase, which converts prothrombin to thrombin. The a isoform of tissue factor (TF) pathway inhibitor (TFPI) dampens early procoagulant events, partly by interacting with FV. FV Leiden (FVL) is the most common genetic thrombophilia in Caucasians. Thrombosis risk is particularly elevated in women with FVL taking oral contraceptives, which produce acquired TFPIa deficiency. In mice, FVL combined with 50% reduction in TFPI causes severe thrombosis and perinatal lethality. However, a possible interaction between FVL and TFPIa has not been defined in humans. Here, we examined this interaction using samples from patients with FVL in thrombin generation and fibrin formation assays. In dilute TF- or FXa-initiated reactions, these studies exposed a TFPI-dependent activation threshold for coagulation initiation that was greatly reduced by FVL. The reduced threshold was progressively overcome with higher concentrations of TF or FXa. Plasma assays using anti-TFPI antibodies or a TFPI peptide that binds and inhibits FVa demonstrated that the decreased activation threshold resulted from reduced TFPIa inhibition of prothrombinase. In assays using purified proteins, TFPIa was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL than with FV. Thus, FVL reduces the threshold for initiating coagulation, and this threshold is further reduced in situations of low TFPIa concentration. Individuals with FVL are likely prone to thrombosis in response to weak procoagulant stimuli that would not initiate blood clot formation in individuals with FV.
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Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-a but not for cell surface-associated tissue factor pathway inhibitorWood, J.; Ellery, Paul; Maroney, S.; Mast, A. (2014)OBJECTIVE - Tissue factor pathway inhibitor (TFPI) is produced in 2 isoforms: TFPIa, a soluble protein in plasma, platelets, and endothelial cells, and TFPIß, a glycosylphosphatidylinositol-anchored protein on endothelium. ...
Translation of human tissue factor pathway inhibitor-ß mRNA is controlled by alternative splicing within the 5' untranslated regionEllery, Paul; Maroney, S.; Martinez, N.; Wickens, M.; Mast, A. (2014)OBJECTIVE - Tissue factor pathway inhibitor (TFPI) blocks the initiation of coagulation by inhibiting TF-activated factor VII, activated factor X, and early prothrombinase. Humans produce two 3' splice variants, TFPIa and ...
Wood, J.; Ellery, Paul; Maroney, S.; Mast, A. (2014)Recent studies of the anticoagulant activities of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPIa and TFPIß, have provided new insight into the biochemical and physiological meagulant activities. An ...