ANTITHROMBOTIC EFFECTS OF RECOMBINANT HUMAN, ACTIVE SITE-BLOCKED FACTOR VIIA IN A RABBIT MODEL OF RECURRENT ARTERIAL THROMBOSIS

The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequenc e of vascular injury. Increasing evidence indicates that this TF-depen dent activation of the coagulation plays an important role in the path ophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site-blocked activ ated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyc lic now variations (CFVs), due to recurrent thrombus formation, were o btained in stenotic rabbit carotid arteries with endothelial injury. C arotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 mu g.kg(-1).min( -1) intracarotid infusion for 10 minutes, n = 9). If CFVs were abolish ed, animals were followed for 30 additional minutes, after which recom binant human activated FVII (FVIIa) was infused into the carotid arter y (100 mu g.kg(-1).min(-1) for 10 minutes) to determine whether FVIIai could be displaced from TF by FVIIa, thus restoring CFVs. To establis h the duration of action of FVIIai, an additional group of animals rec eived FVIIai at the same dose as above, and after CFVs were inhibited, they were followed until CFVs were restored or for up to 6 hours. To determine whether CFVs could be restored by epinephrine after their ab olition with FVIIai, increasing doses of epinephrine were administered to a third group of 6 animals. FVIIai abolished CFVs in 8 of 9 rabbit s (P < .01). This effect was reversible, as FVIIa administration resto red CFVs in all animals. Prothrombin times and activated partial throm boplastin times did not change significantly throughout the study. One single 10-minute infusion exerted complete antithrombotic effects for at least 6 hours, despite the fact that at this time point, plasma FV IIai levels were well below threshold concentrations, Epinephrine rest ored CFVs in 3 of 6 animals in which CFVs were inhibited by FVIIai. FV IIai exerts potent antithrombotic effects in this model; these effects were prolonged even after FVIIai was almost completely cleared from t he circulation, probably as a result of the tight binding of FVIIai to TF. Thus, FVIIai might represent an antithrombotic substance of poten tial interest.