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Prevention of microvascular thrombosis by topical application of recombinant tissue factor pathway inhibitor
L A Lantieri1, M R Ozbek, E G Deune
1Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Mo., USA.
Abstract:
Tissue factor pathway inhibitor is a naturally occurring protein inhibitor of factor X and the tissue factor-factor VII complex of the extrinsic pathway of coagulation. The potential of tissue factor pathway inhibitor as a topical antithrombotic agent was evaluated in a rabbit model of thrombosis that combined intimal injury, anastomosis, and a twisted pedicle. In 207 rabbit ears, a near-complete amputation was performed, preserving the central ear artery and vein. The central ear artery was transected, the intima was removed mechanically over a 1-cm length, 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 pathway inhibitor (10, 40, 125, or 250 microgram/ml), heparin and tissue factor pathway inhibitor together, or vehicle (control). Upon arterial reflow, the ears were observed for 7 days. Patency rates after 7 days were 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 higher concentrations of tissue factor pathway inhibitor led to significantly higher patency rates than heparin, hirudin, or control solutions. Electron microscopic evaluation of specimens irrigated with gold- labeled tissue factor pathway inhibitor revealed the inhibitor bound to the injured intimal surface for at least 3 days postoperatively. Coagulation studies showed no change in the clotting profile upon intravascular infusion with tissue factor pathway inhibitor even at the highest dose used topically. We conclude that tissue factor pathway inhibitor is a more effective topical antithrombotic agent than either heparin or hirudin.
Insights
Tissue factor pathway inhibitor demonstrated superior antithrombotic efficacy compared to heparin and hirudin in a rabbit thrombosis model. This natural inhibitor offers a promising topical treatment for preventing blood clots.
Area of Science:
- Vascular Surgery
- Thrombosis Research
- Biochemistry
Background:
- Coagulation is tightly regulated by intrinsic and extrinsic pathways.
- Tissue factor pathway inhibitor (TFPI) is a key endogenous regulator of the extrinsic coagulation pathway.
- The antithrombotic potential of TFPI as a topical agent requires further investigation.
Purpose of the Study:
- To evaluate the efficacy of topical tissue factor pathway inhibitor (TFPI) in preventing thrombosis.
- To compare TFPI's antithrombotic activity against heparin and hirudin in a rabbit surgical model.
Main Methods:
- A rabbit ear model simulating surgical thrombosis was created, involving near-complete amputation, arterial transection, intimal injury, anastomosis, and pedicle twisting.
- The surgical site was irrigated with varying concentrations of TFPI, heparin, hirudin, or a control vehicle prior to reperfusion.
- Vessel patency was assessed over 7 days, with additional electron microscopy for TFPI binding and coagulation studies.
Main Results:
- TFPI achieved significantly higher 7-day patency rates (75-90%) compared to heparin (43-50%), hirudin (30-55%), and vehicle (6%).
- Higher TFPI concentrations correlated with improved patency.
- Electron microscopy confirmed TFPI binding to the injured intima for at least 3 days postoperatively, with no observed changes in systemic clotting profiles.
Conclusions:
- Topical tissue factor pathway inhibitor is a more effective antithrombotic agent than heparin or hirudin in this rabbit surgical thrombosis model.
- TFPI demonstrates sustained local activity at the site of vascular injury.
- TFPI represents a promising therapeutic candidate for topical antithrombotic applications in vascular surgery.