PHARMACOLOGICAL PROFILING OF RECOMBINANT TISSUE FACTOR PATHWAY INHIBITOR

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine proteas e inhibitor found within the vascular system that is known to be relea sed upon heparin administration, Tissue factor pathway inhibitor regul ates the extrinsic pathway by inhibiting both factors VIIa and Xa, The role of TFPI in the prevention of thrombosis is currently being eluci dated, These studies describe the pharmacological profile of recombina nt variants of this inhibitor that have recently been made available f or study, Recombinant TFPI (rTFPI) exhibits potent anticoagulant (PT) and antiprotease actions (anti-Xa), While carboxy truncated forms of t he inhibitor were not observed to prolong the PT, potent anti-Xa effec ts were still noted, In a rabbit model of stasis-thrombosis, full-leng th rTFPI dose-dependently inhibited thrombus formation, producing a co mplete inhibition of thrombosis at a dose of 500 mu g/kg. At doses tha t were antithrombotically effective, minor increases in blood loss wer e observed in a rabbit ear bleeding model, The effect of TFPI on the i nhibition of platelet activation was assessed using a flow cytometric assay, Three hundred nmol/L of rTFPI were observed to block the activa tion 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 formatio n.