title: The role of hypercoagulability in liver fibrogenesis.
abstract: The development of hepatic fibrosis on a background of chronic liver injury represents a complex disease trait modulated through the interaction of host genetic factors and environmental influences. Early observations that hepatic inflammation and cirrhosis are associated with the presence of microthrombi within the hepatic vasculature and fibrin/fibrinogen deposition were followed by epidemiological studies showing that carriage of the Factor V Leiden (FvL) mutation, protein C deficiency and increased expression of factor VIII are associated with accelerated progression to cirrhosis in a chronic hepatitis C infection. Additional data suggest that these factors may influence fibrogenesis in many forms of chronic liver disease and extra-hepatic fibrotic processes. Drawing evidence both from liver research and studies of fibrogenesis in other organ systems, two hypotheses may explain how activity of the coagulation cascade influences the rate of hepatic fibrogenesis: tissue ischaemia and parenchymal extinction and direct thrombin mediated stellate cell activation via PAR-1 cleavage. Drawing on preclinical and clinical studies we discuss the evidence for a role for coagulation cascade activity in hepatic fibrogenesis and explore the proposed pathogenic mechanisms that lead to stellate cell activation. The corollary of an association between hypercoagulation and increased fibrosis is that interference with the coagulation cascade may reduce hepatic fibrosis. We conclude this article by examining the implications for future therapeutic intervention.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, The Medical School, 3rd Floor, William Leech Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. quentin.anstee@newcastle.ac.uk
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Ameet
authors.initials: A
authors.lastname: Dhar
authors.forename: Mark R
authors.initials: MR
authors.lastname: Thursz
mesh_terms: D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology*; D044462:Receptors, Proteinase-Activated / Q000502:physiology; D013917:Thrombin / Q000502:physiology; D019851:Thrombophilia / Q000150:complications*
chemical_list: D044462:Receptors, Proteinase-Activated; D013917:Thrombin