title: Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies.
abstract: BACKGROUND
  There is strong evidence demonstrating that coagulation system activation contributes to wound healing and promotes organ fibrosis. Several epidemiological studies have now shown that prothrombotic status, including carriage of the factor (F)V Leiden mutation, is associated with rapid progression of hepatic fibrosis.
  
  
  OBJECTIVE
  To assess the effect of a procoagulant state on progression of hepatic fibrosis in a controlled environment and to test whether anticoagulation could attenuate fibrogenesis.
  
  
  METHODS
  We investigated the effects of coagulation status on liver fibrosis development in a mouse model of chronic toxic liver injury. Prothrombotic FV Leiden mutant mice, C57BL/6 control animals and anticoagulated mice were studied after chronic exposure to carbon tetrachloride.
  
  
  RESULTS
  Carriage of the FV Leiden mutation caused a significant increase in hepatic fibrosis. Anticoagulation with warfarin significantly reduced fibrosis progression in wild-type mice but was less effective against the profibrotic FV Leiden mutation. Changes in the fibrosis scores were mirrored by changes in liver hydroxyproline content and hepatic stellate cell activation detected by alpha-smooth muscle actin expression.
  
  
  CONCLUSIONS
  These results demonstrate that coagulation status has a strong influence on hepatic fibrogenesis. It is likely that thrombin signaling through the proteinase-activated receptor 1 (PAR(1)) receptor expressed on hepatic stellate cells is responsible for this relationship. These results represent the first reported use of anticoagulation to slow hepatic fibrogenesis and suggest a potential novel anti-fibrotic therapeutic approach for the future.
authors.affiliation: Faculty of Medicine, Imperial College, London, UK. q.anstee@imperial.ac.uk
authors.forename: Q M
authors.initials: QM
authors.lastname: Anstee
authors.forename: R D
authors.initials: RD
authors.lastname: Goldin
authors.forename: M
authors.initials: M
authors.lastname: Wright
authors.forename: A
authors.initials: A
authors.lastname: Martinelli
authors.forename: R
authors.initials: R
authors.lastname: Cox
authors.forename: M R
authors.initials: MR
authors.lastname: Thursz
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D002251:Carbon Tetrachloride / Q000633:toxicity; D005165:Factor V / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017354:Point Mutation; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000199:Actins; D000925:Anticoagulants; C095381:factor V Leiden; D014859:Warfarin; D005165:Factor V; D002251:Carbon Tetrachloride; D006909:Hydroxyproline