FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834

Thromb Res. 2001 Aug 15;103(4):281-97. doi: 10.1016/s0049-3848(01)00330-9.


During thrombosis, vascular wall cells are exposed to clotting factors, including the procoagulant proteases thrombin and factor Xa (FXa), both known to induce cell signaling. FXa shows dose-dependent induction of intracellular Ca(2+) transients in vascular wall cells that is active-site-dependent, Gla-domain-independent, and enhanced by FXa assembly into the prothrombinase complex. FXa signaling is independent of prothrombin activation as shown by the lack of inhibition by argatroban, hirudin and the sulfated C-terminal peptide of hirudin (Hir(54-65)(SO3(-))). This peptide binds to both proexosite I in prothrombin and exosite I in thrombin. In contrast, signaling is completely blocked by the FXa inhibitor ZK-807834 (CI-1031). No inhibition is observed by peptides which block interaction of FXa with effector cell protease 1 receptor (EPR-1), indicating that this receptor does not mediate signaling in the cells assayed. Receptor desensitization studies with thrombin or peptide agonists (PAR-1 or PAR-2) and experiments with PAR-1-blocking antibodies indicate that signaling by FXa is mediated by both PAR-1 and PAR-2. Potential pathophysiological responses to FXa include increased cell proliferation, increased production of the proinflammatory cytokine IL-6 and increased production of prothrombotic tissue factor. These cellular responses, which may complicate vascular disease, are inhibited by ZK-807834.

MeSH terms

  • Amidines / pharmacology
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Factor V / pharmacology
  • Factor Xa / pharmacology*
  • Factor Xa Inhibitors
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Pyridines / pharmacology
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Cell Surface
  • Receptors, Thrombin / physiology*
  • Serine Proteinase Inhibitors / pharmacology
  • Signal Transduction / drug effects*
  • Survivin
  • Thrombin / pharmacology


  • Amidines
  • BIRC5 protein, human
  • Factor Xa Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Pyridines
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Cell Surface
  • Receptors, Thrombin
  • Serine Proteinase Inhibitors
  • Survivin
  • prothrombinase complex
  • Fidexaban
  • Factor V
  • Thrombin
  • Factor Xa