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

Abstract

Factor Xa (fXa) plays a pivotal role in the activation of the coagulation system during thrombosis, but, unlike GPIIb/IIIa receptor antagonists, the role of fXa inhibition in arterial passivation is not well defined. We compared the long-term antithrombotic efficacy of a direct fXa inhibitor, FXV673, and heparin after short-term infusion in conscious dogs. Dogs were instrumented surgically to induce carotid artery thrombosis by electrolytic injury. On day 1, dogs received a 3-h infusion of placebo (n = 10), FXV673 (100 microg/kg + 10 microg/kg/min, n = 7), or heparin (60 U/kg + 0.7 U/kg/min, n 7). Injury (100 microA) was initiated concomitantly for 1 h. The procedure was repeated on day 2 with injury of 200 microA for 3 h. Carotid artery blood flow (CBF) 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 placebo-treated group was 26% of baseline with 70% incidence of occlusion. None of the vessels occluded in the heparin and FXV673 groups; however, the CBF 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 group 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+/-10 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 superior to standard heparin and underscore the role of direct fXa inhibition in arterial passivation.

• Authors: S S Rebello, C J Kasiewski, W Wang, R G Bentley, S R Morgan, V Chu, D Colussi, K Brown, M H Perrone, R J Leadley
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 38 Issue 2 Pg. 288-97 (Aug 2001) ISSN: 0160-2446 [Print] United States
• PMID: 11483879 (Publication Type: Journal Article)

Chemical References

• Cyclic N-Oxides
• Factor Xa Inhibitors
• Fibrinolytic Agents
• Pyridines
• otamixaban

Topics

• Animals
• Carotid Artery Thrombosis (blood, drug therapy, physiopathology)
• Consciousness (drug effects, physiology)
• Cyclic N-Oxides (chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Dogs
• Factor Xa Inhibitors
• Female
• Fibrinolytic Agents (chemistry, pharmacology, therapeutic use)
• Male
• Pyridines (chemistry, pharmacology, therapeutic use)
• Regional Blood Flow (drug effects, physiology)