Role of short-term inhibition of factor Xa by FXV673 in arterial passivation: A study in a chronic model of thrombosis in conscious dogs

Factor Xa (fXa) plays a pivotal role in the activation of the coagulation s ystem during thrombosis, but, unlike GPIIb/IIIa receptor antagonists, the r ole of fXa inhibition in arterial passivation is not well defined. We compa red the long-term antithrombotic efficacy of a direct fXa inhibitor, FXV673 , and heparin after short-term infusion in conscious dogs. Dogs were instru mented surgically to induce carotid artery thrombosis by electrolytic injur y. On day 1, dogs received a 3-h infusion of placebo (n = 10), FXV673 100 m ug/kg + 10 mug/kg/min, n = 7), or heparin (60 U/kg + 0.7 U/kg/min, n = 7). Injury (100 CLA) was initiated concomitantly for 1 h. The procedure was rep eated on day 2 with injury of 200 muA for 3 h. Carotid artery blood flow (C BF) and coagulation parameters were monitored continuously for 3 h on days 1 and 2 and for 30 min on days 3, 4, and 5. On day 1 at 3 h, CBF in the pla cebo-treated group was 26% of baseline with 70% incidence of occlusion. Non e of the vessels occluded in the heparin and FXV673 groups; however, the CB F was significantly higher in the FXV673 group (92 +/-8 ml/min versus 39 +/ - 12 ml/min). Before injury on day 2, CBF recovered in all groups to 71-89% of baseline. After the second injury, all vessels in the placebo-treated g roup progressed to complete occlusion by 3 h. CBF was significantly higher in FXV673 group compared with heparin throughout the 3-h period. On days 3, 4, and 5 the placebo-treated vessels remained occluded, but the CBF in the heparin group was 33 +/- 20 ml/min, 55 +/- 11 ml/min and 68 +/- 12 ml/min, respectively, compared with 84 +/- 10 ml/min, 98 +/-7 ml/min, and 99 +/- 1 0 ml/min in the FXV673 group. The arterial thrombus mass was significantly lower in FXV673 group (13 +/-4 mg compared with placebo (103 +/- 10 mg) and heparin (44 +/- 11 mg). In summary, these data demonstrate that short-term infusion of FXV673 was associated with long-term efficacy that was superio r to standard heparin and underscore the role of direct fXa inhibition in a rterial passivation.