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Title: The role of the coagulation system in the pathogenesis of liver injury
Author: Dhar, Ameet
ISNI:       0000 0004 2714 8558
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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There is a growing body of evidence that suggests a role for the coagulation cascade in promoting liver injury, in particular fibrosis. With the exception of thrombin, the expression and role of individual coagulation proteins in liver injury is poorly understood. The aim of this body of work was to further our understanding of the role of specific coagulation proteins in liver injury and consider viable targets as anti-fibrotic therapies. We examined these concepts using immunohistochemical, cell line, and animal based studies as well as translational studies in human subjects. Using immunohistochemical techniques, upregulation of coagulation proteins in both acute and chronic liver injury in mice and humans was demonstrated and correlated with severity of injury. Data from cell line studies demonstrated stellate cells, the principal cell involved in hepatic fibrosis, were sensitive to both thrombin and Factor Xa. Furthermore the direct inhibition of both thrombin and Factor Xa using novel anticoagulants in cell line studies and chemical induced murine models of liver fibrosis exhibited anti-fibrotic effects. Two unique translational studies were undertaken to determine the applicability of these findings in humans. A pilot study demonstrated that warfarin anticoagulation resulted in a significant reduction in liver stiffness measurements, a surrogate marker of liver fibrosis, in patients with pre-existing hepatitis C related liver fibrosis, and the interim results of a larger study, performed in the setting of hepatitis C post liver transplantation, has shown a reduction in fibrosis scores. The studies presented in this thesis add to the growing body of evidence suggesting a role for coagulation proteins in the pathogenesis of liver injury and are the first to show the potential anti-fibrotic benefits of both novel anticoagulants in murine models of liver fibrosis and warfarin anticoagulation in patients with hepatitis C related liver fibrosis pre and post transplantation.
Supervisor: Thursz, Mark Sponsor: Astellas Pharma Ltd ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral