PREVENTION OF MICROVASCULAR THROMBOSIS BY TOPICAL APPLICATION OF RECOMBINANT TISSUE FACTOR PATHWAY INHIBITOR

Tissue factor pathway inhibitor is a naturally occurring protein inhib itor of factor X and the tissue factor-factor VII complex of the extri nsic pathway of coagulation. The potential of tissue factor pathway in hibitor as a topical antithrombotic agent was evaluated in a rabbit mo del of thrombosis that combined intimal injury, anastomosis, and a twi sted pedicle. In 207 rabbit ears, a near-complete amputation was perfo rmed, preserving the central ear artery and vein. The central ear arte ry was transected, the intima was removed mechanically over a 1-cm len gth, the artery was anastomosed, and the ear was twisted 360 degrees, wrapping the intact vein around the artery. Before recirculation, the lumen was irrigated on a blinded, randomized basis with either hirudin (100 or 500 units/ml), heparin (50 or 100 units/ml), tissue factor pa thway inhibitor (10, 40, 125, or 250 mu g/ml), heparin and tissue fact or pathway inhibitor together, or vehicle (control). Upon arterial ref low, the ears were observed for 7 days. Patency rates after 7 days wer e as follows: hirudin, 30 and 55 percent; heparin, 43 and 50 percent; tissue factor pathway inhibitor, 75 and 90 percent; heparin and tissue factor pathway inhibitor, 75 percent; and, vehicle, 6 percent The hig her concentrations of tissue factor pathway inhibitor led to significa ntly higher patency rates than heparin, hirudin, or control solutions. Electron microscopic evaluation of specimens irrigated with gold-labe led tissue factor pathway inhibitor revealed the inhibitor bound to th e injured intimal surface for at least 3 days postoperatively. Coagula tion studies showed no change in the clotting profile upon intravascul ar infusion with tissue factor pathway inhibitor even at the highest d ose used topically. We conclude that tissue factor pathway inhibitor i s a more effective topical antithrombotic agent than either heparin or hirudin.