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

Dana R. Abendschein, Pamela K. Baum, Daniel J. Martin, Ron Vergona, Joseph Post, Galina Rumennik, Mark E. Sullivan, Paul R. Eisenberg, David R. Light

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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; K(i) (human FXa), 0.11 nM], with recombinant tick anticoagulant peptide [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. ZK-807834 also was compared with low molecular weight heparin (LMWH; MW, 5,500 D) during venous thrombosis induced by placing a copper wire and threads in the vena cava. Inhibitors were administered as an i.v. bolus and 2-h infusion. Total dosages of ZK-807834, ≥0.7 μmol/kg (n = 18); rTAP, ≥1 μmol/kg (n = 18); or DX- 9065a, ≥11 μmol/kg (n = 18) decreased the incidence of arterial thrombotic occlusion compared with control animals (p < 0.05). However, five of six animals given the lowest effective dosage of rTAP and four of six animals given DX-9065a bled from a surgical incision >5 min, but only two of six animals given ZK-807834 bled >5 min. Venous clot weights were reduced compared with controls for dosages of ZK-807834 ≥0.007 μmol/kg (n = 36) or LMWH ≥0.2 μmol/kg (n = 18). Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were unchanged from baseline at the minimally effective dose of ZK-807834, whereas aPTT was increased twofold at the effective dose of LMWH. Thus ZK-807834 may be useful to attenuate thrombosis at lower dosages and with less perturbation of system c hemostasis compared with available agents.

Original languageEnglish
Pages (from-to)796-805
Number of pages10
JournalJournal of cardiovascular pharmacology
Volume35
Issue number5
DOIs
StatePublished - May 22 2000

Keywords

  • Anticoagulants
  • Factor Xa
  • Thrombosis

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    Abendschein, D. R., Baum, P. K., Martin, D. J., Vergona, R., Post, J., Rumennik, G., Sullivan, M. E., Eisenberg, P. R., & Light, D. R. (2000). Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits. Journal of cardiovascular pharmacology, 35(5), 796-805. https://doi.org/10.1097/00005344-200005000-00018