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Thrombin and factor Xa link the coagulation system with Liver fibrosis

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Title: Thrombin and factor Xa link the coagulation system with Liver fibrosis
Authors: Dhar, A
Sadiq, F
Anstee, QM
Levene, AP
Goldin, R
Thursz, M
Item Type: Journal Article
Abstract: Background: Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis. Methods: HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated. Results Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/− 4.12) compared to culturing with FXa or thrombin alone (26.90%+/− 8.90, p = 0.02; 13.1%+/− 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001). Conclusions: FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.
Issue Date: 8-May-2018
Date of Acceptance: 26-Apr-2018
URI: http://hdl.handle.net/10044/1/59299
DOI: https://dx.doi.org/10.1186/s12876-018-0789-8
ISSN: 1471-230X
Publisher: BioMed Central
Journal / Book Title: BMC Gastroenterology
Volume: 18
Copyright Statement: © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G0701716
Keywords: Anticoagulation
Factor Xa
Fibrosis
Hepatic stellate cell
Thrombin
1103 Clinical Sciences
Gastroenterology & Hepatology
Publication Status: Published
Article Number: 60
Appears in Collections:Division of Surgery
Faculty of Medicine



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