title: Anticoagulation by factor Xa inhibitors.
abstract: BACKGROUND
  Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach.
  
  
  OBJECTIVE
  To assess anticoagulant strategies targeting FXa.
  
  
  METHODS
  A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications.
  
  
  RESULTS
  Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex.
  
  
  CONCLUSIONS
  The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo.
authors.affiliation: Department of Biochemistry, University of Vermont, Colchester, VT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Orfeo
authors.forename: S
authors.initials: S
authors.lastname: Butenas
authors.forename: K E
authors.initials: KE
authors.lastname: Brummel-Ziedins
authors.forename: M
authors.initials: M
authors.lastname: Gissel
authors.forename: K G
authors.initials: KG
authors.lastname: Mann
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D003198:Computer Simulation; D005165:Factor V / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006801:Humans; D009025:Morpholines / Q000627:therapeutic use; D011134:Polysaccharides / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D000069552:Rivaroxaban; D012984:Software; D013876:Thiophenes / Q000627:therapeutic use; D013917:Thrombin / Q000096:biosynthesis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D011134:Polysaccharides; D011994:Recombinant Proteins; D013876:Thiophenes; C022475:prothrombinase complex; D005165:Factor V; D000069552:Rivaroxaban; D013917:Thrombin; D015951:Factor Xa; D000077425:Fondaparinux