PMID- 26188924
OWN - NLM
STAT- MEDLINE
DCOM- 20160524
LR  - 20220316
IS  - 1879-2472 (Electronic)
IS  - 0049-3848 (Linking)
VI  - 136
IP  - 3
DP  - 2015 Sep
TI  - 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.
PG  - 658-62
LID - S0049-3848(15)30050-5 [pii]
LID - 10.1016/j.thromres.2015.06.034 [doi]
AB  - INTRODUCTION: 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. 
      METHODS AND 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. CONCLUSION: 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.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Furugohri, Taketoshi
AU  - Furugohri T
AD  - 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.
FAU - Morishima, Yoshiyuki
AU  - Morishima Y
AD  - Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 
      Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20150704
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Anticoagulants)
RN  - 0 (Antithrombins)
RN  - 0 (Azetidines)
RN  - 0 (Benzylamines)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Thiazoles)
RN  - 2A9QP32MD4 (melagatran)
RN  - 9005-49-6 (Heparin)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.21.5 (Thrombin)
RN  - NDU3J18APO (edoxaban)
SB  - IM
MH  - Anticoagulants/administration & dosage
MH  - Antithrombins/administration & dosage
MH  - Azetidines/*administration & dosage
MH  - Benzylamines/*administration & dosage
MH  - Blood Coagulation/*drug effects/*physiology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Factor Xa Inhibitors/administration & dosage
MH  - Heparin/*administration & dosage
MH  - Humans
MH  - Pyridines/*administration & dosage
MH  - Thiazoles/*administration & dosage
MH  - Thrombin/*biosynthesis
MH  - Thromboplastin/metabolism
OTO - NOTNLM
OT  - Activated protein C
OT  - Direct factor Xa inhibitor
OT  - Direct thrombin inhibitor
OT  - Edoxaban
OT  - Intrinsic pathway
OT  - Melagatran
EDAT- 2015/07/21 06:00
MHDA- 2016/05/25 06:00
CRDT- 2015/07/20 06:00
PHST- 2015/03/11 00:00 [received]
PHST- 2015/05/28 00:00 [revised]
PHST- 2015/06/30 00:00 [accepted]
PHST- 2015/07/20 06:00 [entrez]
PHST- 2015/07/21 06:00 [pubmed]
PHST- 2016/05/25 06:00 [medline]
AID - S0049-3848(15)30050-5 [pii]
AID - 10.1016/j.thromres.2015.06.034 [doi]
PST - ppublish
SO  - Thromb Res. 2015 Sep;136(3):658-62. doi: 10.1016/j.thromres.2015.06.034. Epub 
      2015 Jul 4.