TRANSIENT INTERRUPTION OF ARTERIAL THROMBOSIS BY INHIBITION OF FACTORXA RESULTS IN LONG-TERM ANTITHROMBOTIC EFFECTS IN BABOONS

Recombinant tick anticoagulant peptide (r-TAP) is a potent and specifi c inhibitor of activated coagulation factor X which effectively interr upts in vivo arterial thrombosis during treatment. It is, however, unc ertain if it also affects thrombosis after treatment is stopped. This was tested in a baboon model of arterial thrombosis where platelet dep osition onto Dacron vascular graft segments, inserted as extensions in to permanent femoral arteriovenous shunts, was measured. The baboons w ere intravenously treated with 10 mu g/kg/min (low dose, aPIT = 39 +/- 1 s) and 25 mu g/kg/min (high dose, aPTT = 58 +/- 2 s) r-TAP for two hours. During treatment the r-TAP inhibited thrombin formation and dos e-dependently interrupted platelet deposition onto the graft segment. This effect lasted for up to two hours after treatment with the low do se. Following treatment with the high dose, the graft segments were ke pt in place for 53 h. After treatment was slopped, platelets again dep osited, but at a much lower rate than in control studies. Maximum depo sition was approximately 38% lower than in the control studies. Total platelet deposition over 55 h, calculated as the area under the deposi tion curve, was approximately 40% (p <0.05) less than in the control s tudies. A significant shortening in the mean platelet life span and an approximately 15-fold increase in thrombin-antithrombin III complexes during the first 31 h indicated that the thrombus surface remained th rombogenic and that the effect of r-TAP was transient. We have shown t hat 2 h of treatment with a full antithrombotic dose of r-TAP markedly reduced both the rate of platelet deposition after treatment was stop ped and the total number of platelets deposited over 55 h. This was in spite of the finding that the antithrombotic effect of r-TAP was tran sient.