Affordable Access

Access to the full text

Thrombin and factor Xa link the coagulation system with liver fibrosis

Authors
  • Dhar, Ameet1
  • Sadiq, Fouzia1
  • Anstee, Quentin M.2
  • Levene, Adam P.3
  • Goldin, Robert D.3
  • Thursz, Mark R.1
  • 1 Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London, W2 1NY, UK , London (United Kingdom)
  • 2 Institute of Cellular Medicine, Newcastle University, The Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK , Newcastle-upon-Tyne (United Kingdom)
  • 3 Department of Histopathology, Imperial College London, St Mary’s Hospital Campus, London, W2 1NY, UK , London (United Kingdom)
Type
Published Article
Journal
BMC Gastroenterology
Publisher
Springer (Biomed Central Ltd.)
Publication Date
May 08, 2018
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12876-018-0789-8
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundThrombin 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.MethodsHSC-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.ResultsStellate 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).ConclusionsFXa 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.

Report this publication

Statistics

Seen <100 times