title: Paradoxical enhancement of the intrinsic pathway-induced thrombin generation in human plasma by melagatran, a direct thrombin inhibitor, but not edoxaban, a direct factor Xa inhibitor, or heparin.
abstract: BACKGROUND
  The blood coagulation cascade consists of two pathways, the tissue factor (TF)-dependent extrinsic pathway and the contact factor-dependent intrinsic pathway. We have previously shown that a direct thrombin inhibitor, melagatran, paradoxically increased TF-induced thrombin generation (TG) in thrombomodulin (TM)-containing human plasma in vitro. However, the effect of melagatran on the intrinsic pathway-induced TG remains to be investigated. We investigated whether melagatran enhances the intrinsic pathway-induced TG.
  
  
  RESULTS
  TG was induced by kaolin in human plasma and assayed by the calibrated automated thrombography method. Melagatran at 150 and 300 nM significantly increased the peak level (2.40-fold) and endogenous thrombin potential of TG in normal plasma in the presence of 5 nM TM. In the absence of TM or in protein C (PC)-deficient plasma, the paradoxical enhancement of TG by melagatran disappeared. A direct FXa inhibitor, edoxaban, and an antithrombin-dependent anticoagulant, unfractionated heparin (UFH), did not increase, but simply decreased TG under each condition in a concentration dependent manner.
  
  
  CONCLUSIONS
  Melagatran enhanced the intrinsic pathway-induced TG as well as the extrinsic pathway-induced TG in human plasma under the condition where PC system is active. In contrast, edoxaban and UFH showed concentration-dependent decrease of TG, but no enhancement. These results indicated that edoxaban and UFH may have a low risk of the paradoxical enhancement of TG by both the extrinsic and intrinsic pathway activation.
authors.affiliation: Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: furugori.taketoshi.v5@daiichisankyo.co.jp.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Furugohri
authors.affiliation: Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage; D000991:Antithrombins / Q000008:administration & dosage; D001384:Azetidines / Q000008:administration & dosage*; D001596:Benzylamines / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D065427:Factor Xa Inhibitors / Q000008:administration & dosage; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D011725:Pyridines / Q000008:administration & dosage*; D013844:Thiazoles / Q000008:administration & dosage*; D013917:Thrombin / Q000096:biosynthesis*; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C109573:melagatran; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin; C552171:edoxaban
keywords: Activated protein C; Direct factor Xa inhibitor; Direct thrombin inhibitor; Edoxaban; Intrinsic pathway; Melagatran