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Prevention of experimental arterial thrombosis by topical administration of active site-inactivated factor VIIa
B Arnljots1, M Ezban, U Hedner
1Department of Plastic and Reconstructive Surgery, University Hospital, Malmö, Sweden.
Purpose:
In vivo, the coagulation pathway is triggered by formation of a high-affinity complex between the tissue factor of the injured vascular wall and the activated form of blood coagulation factor VII (VIIa). We used a rabbit model of arterial thrombosis to examine the antithrombotic effect of topically administered active site-inactivated recombinant human factor VIIa (VIIai), which binds to tissue factor but is unable to initiate coagulation.
Methods:
Segments of both central arteries of rabbits' ears were isolated between vascular clamps, followed by arteriotomies and deep-vessel wall trauma. In each rabbit, the injured vessel segments were superfused with either VIIai (0.5 mg in 200 microliters vehicle) or vehicle alone in a blinded random manner (n = 20). The vessels were then closed with running sutures and reperfused. The effect of intravenously infused VIIai (4 mg/kg) or vehicle was studied in a separate series.
Results:
The administration of VIIai increased patency rates from 40% and 30% in the vehicle group at 30 and 120 minutes after reperfusion, respectively, to 85% and 75% in the VIIai group (p = 0.008 and p = 0.004). No antihemostatic side effects occurred: median arteriotomy bleeding times were 2 minutes in the vehicle group and 1 1/2 minutes in the VIIai group (p = 1). By contrast, intravenous infusion of VIIai produced no antithrombotic effect.
Conclusions:
We have shown that topical administration of VIIai at arterial trauma sites produces an antithrombotic effect without the expense of a hemostatic defect. This mode of treatment seems to be highly attractive in the prevention of thrombotic complications in surgery on blood vessels.
Insights
Topical administration of factor VIIa inhibitor (VIIai) prevents arterial thrombosis in rabbits without causing bleeding. This targeted approach offers a promising strategy for preventing blood clots during vascular surgery.
Area of Science:
- Vascular Biology
- Hemostasis and Thrombosis
- Pharmacology
Background:
- The coagulation pathway initiates thrombosis via tissue factor and activated factor VII (VIIa).
- Factor VIIa inhibitors are being explored for antithrombotic therapies.
Purpose of the Study:
- To evaluate the antithrombotic effect of topically applied active site-inactivated recombinant human factor VIIa (VIIai).
- To assess VIIai's efficacy in a rabbit model of arterial thrombosis.
Main Methods:
- Rabbit ear arteries were subjected to trauma and treated with topical VIIai or vehicle.
- Vessel patency and bleeding times were measured after reperfusion.
- Intravenous VIIai administration was also tested for comparison.
Main Results:
- Topical VIIai significantly increased arterial patency rates compared to vehicle (85% vs. 40% at 30 min).
- VIIai treatment did not increase bleeding times, indicating no hemostatic defect.
- Intravenous VIIai infusion showed no antithrombotic effect.
Conclusions:
- Topical VIIai demonstrates effective antithrombotic action at arterial injury sites.
- This localized treatment prevents thrombosis without compromising hemostasis.
- VIIai is a potential therapeutic agent for preventing surgical thrombotic complications.