A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs

Inhibition of factor Xa (FXa) attenuates thrombus progression. This study w as designed to determine whether a novel, synthetic inhibitor of FXa (ZK-80 7834, molecular mass 527 Da, K-i = 0.11 nM) administered during and briefly after pharmacologic coronary fibrinolysis increases 24-h patency. Either Z K-807834 (less than or equal to1.6 mg/kg, n = 10; 6.5 mg/kg, n = 8; or 13 m g/kg, n = 7); a peptide inhibitor of FXa, recombinant tick anticoagulant pe ptide (rTAP, 13.6 mg/kg, n = 7); heparin (150 U/kg bolus and 50 U/kg/h infu sion) and aspirin (5 mg/kg) (n 5 7); or saline as a control (n 5 13) were a dministered i.v. over 135 min in conscious dogs after thrombotic occlusion induced by electrical injury to a coronary artery. Fibrinolysis was induced with recombinant human tissue-type plasminogen activator (1.0 mg/kg i.v. o ver 1 h), and patency was monitored continuously for 24 h with an implanted Doppler probe. Reocclusion occurred in all control and heparin/aspirin-tre ated dogs within 1 h after fibrinolysis. High dose ZK-807834 prevented reoc clusion in five of six dogs and delayed reocclusion in the other dog (186 m in after recanalization, p = 0.0005 versus heparin/aspirin). Reocclusion wa s delayed (406 +/- 329 min), but still occurred in three of six rTAP-treate d dogs (p = 0.003 versus heparin/aspirin). Patency after 24 h was 100% in Z K-807834-treated and rTAP-treated dogs compared with 67% in control and 83% in heparin/aspirin-treated dogs. PT was increased 3.7-fold, activated part ial thromboplastin time 4.9-fold, and bleeding time 2.5-fold by high dose Z K-807834 compared with 1.2-fold, 11.5-fold, and 2.3-fold, respectively, for heparin/aspirin. Inhibition of FXa with ZK-807834 decreases reocclusion an d improves patency of recanalized arteries without increasing bleeding comp ared with heparin/aspirin.