1012-104 Monoclonal Antibody to Tissue Factor Inhibits Intravascular Thrombosis without Impairing Extravascular Hemostasis

BackgroundRecent studies suggest that the release of tissue factor (TF) and its interaction with factor VII at the site of vascular injury may be the activator of the coagulation cascade, which along with platelet aggregation leads to occlusive intravascular thrombus formation. We tested this hypothesis in a rabbit carotid artery model of thrombosis.MethodsCarotid artery was instrumented with Doppler flow probe and a needle electrode. Partially occlusive thrombus was formed by applying 150μA of current which damages the endothelium of the carotid artery and promotes thrombus formation. After development of 50% occlusion of the artery by thrombus, the current was stopped and a murine monoclonal antibody against rabbit TF (AP-l) (0.1mg/kg intraarterially) or vehicle (control) was administered. The changes in carotid blood flow were continuously monitored by the Doppler flow probe. Bleeding was assessed by weighing the amount of blood absorbed in a preweighed sponge, placed in a cut wound that was 5cm long and 0.5cm deep.ResultsThe control rabbits (n=12) occluded their arteries in 46.2±13.6 min after stopping the current by a fibrin-platelet thrombus. In contrast, AP-l prevented carotid artery occlusion for >200min (n=6) (p>0.0001). Lower doses of AP-l were ineffective. The deep incisional bleeding times were not different between the control animals and the treated group. Similarly the platelet counts or ex vivo platelet aggregation response to collagen, ADP or arachidoic acid were not different between the control and the treated animals.ConclusionData suggest that TF released at the site of vascular injury plays a role in intravascular coagulation and its activity can be selectively inhibited, without inducing an alteration in hemostatic parameters or platelet functions