title: Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin-dependent anticoagulants, fondaparinux, enoxaparin, and heparin.
abstract: BACKGROUND
  Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]).
  
  
  METHODS
  The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay.
  
  
  RESULTS
  In vitro studies demonstrated that the clotting-time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice.
  
  
  CONCLUSIONS
  Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration.
authors.affiliation: Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukuda
authors.forename: Chikako
authors.initials: C
authors.lastname: Kamisato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Furugohri
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shibano
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D000990:Antithrombin III / Q000235:genetics* / Q000378:metabolism; D001780:Blood Coagulation Tests; D017984:Enoxaparin / Q000494:pharmacology* / Q000627:therapeutic use; D065427:Factor Xa Inhibitors; D005260:Female; D000077425:Fondaparinux; D017353:Gene Deletion; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011134:Polysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D011134:Polysaccharides; D011725:Pyridines; D013844:Thiazoles; D000990:Antithrombin III; D000077425:Fondaparinux; C552171:edoxaban