Abstract
Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor found within the vascular system that is known to be released upon heparin administration. Tissue factor pathway inhibitor regulates the extrinsic pathway by inhibiting both factors VIIIa and Xa. The role of TFPI in the prevention of thrombosis is currently being elucidated. These studies describe the pharmacological profile of recombinant variants of this inhibitor that have recently been made available for study. Recombinant TFPI (rTFPI) exhibits potent anticoagulant (PT) and antiprotease actions (anti-Xa). While carboxy truncated forms of the inhibitor were not observed to prolong the PT, potent anti-Xa effects were still noted. In a rabbit model of stasis-thrombosis, full-length rTFPI dose-dependently inhibited thrombus formation, producing a complete inhibition of thrombosis at a dose of 500 μg/kg. At doses that were antithrombotically effective, minor increases in blood loss were observed in a rabbit ear bleeding model. The effect of TFPI on the inhibition of platelet activation was assessed using a flow cytometric assay. Three hundred nmol/L of rTFPI were observed to block the activation of platelets by 4.5 pmol/L recombinant tissue factor. In addition to participating in the maintenance of hemostasis, rTFPI may prove to be an effective therapeutic modality for preventing thrombus formation.
Keywords:
Tissue factor - tissue factor pathway inhibitor (TFPI) - thrombosis - platelets
