Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits

Inhibition of factor Xa (FXa) may interrupt thrombus progression This study compared the antithrombotic activity of a novel FXa inhibitor, ZK-807834 [ MW, 527 D; Ki (human FXa), 0.11 nM], with recombinant tick anticoagulant pe ptide [rTAP: MW, 6,685 D; K-i, (human FXa) = 0.28 nM], and DX-9065a [MW 445 D, K-i (human FXa), 40 nM] in rabbits with arterial thrombosis induced by electrical vascular injury. 2K-807834 also was compared with low molecular weight heparin (LMWH; MW, 5,500 Di during Venous thrombosis induced by plac ing a copper wire and threads in the vena cava. Inhibitors were administere d as an i.v. bolus and 2-h infusion. Total dosages of ZK-807834, greater th an or equal to 0.7 mu mol/kg (n = 18); rTAP, greater than or equal to 1 mu mol/kg(n = 18); or DX-9065a, greater than or equal to 11 mu mol/kg(n = 18) decreased the incidence of arterial thrombotic occlusion compared with cont rol animals (p < 0.05). However, five of six animals given the lowest effec tive dosage of rTAP and four of six animals given DX-9065a bled from a surg ical incision >5 min, but only two of dr animals given ZK-807834 bred >5 mi n. Venous clot weights were reduced compared with controls for dosages of Z K-807834 greater than or equal to 0.007 mu mol/kg (n = 36) or LMWH greater than or equal to 0.2 mu mol/kg (n = 18). Prothrombin time (PT) and activate d partial thromboplastin time (aPTT) were unchanged from baseline at the mi nimally effective dose of 2R-807834, whereas aPTT was increased twofold at the effective dose of LMWH. Thus ZK-807834 may he useful to attenuate throm bosis at lower dosages and with less perturbation of systemic hemostasis co mpared with available agents.