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Title: The role of the coagulation cascade in liver injury
Author: Petts, Gemma Susan
ISNI:       0000 0004 5994 3484
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Liver disease affects approximately 600,000 people in England and Wales and is the third biggest cause of premature death. Acute and chronic liver injury occur due to a number of aetiologies and affect the function of the liver in the short and long term through pathological inflammation and fibrosis. Given the variety of aetiologies and growing burden of disease in the population, there is a need to find universal therapies that alter the progression of liver injury and fibrosis beyond the initiating insult. This work focuses on investigating the role of the coagulation cascade, specifically Tissue Factor Pathway Inhibitor (TFPI), in liver injury and it’s use as a potential therapeutic target for altering the progression of acute and chronic liver injury. Using two transgenic strains of mice, expressing TFPI in a cell specific manner I have shown that TFPI decreases the extent and progression of liver injury in models of acute liver injury but does not modify the development of liver fibrosis in a model of chronic liver injury. In the models of acute liver injury there was decreased liver injury associated with decreased fibrin deposition, decreased hepatic stellate cell activation, decreased total liver macrophage content and decreased PAR2 expression. The pattern of changes suggests that TFPI acts early in the injury process, limiting total hepatocyte injury and resulting in a decrease in hepatic stellate cell activation and macrophage recruitment, rather than the other way round. Further work should focus on defining the inflammatory cytokine profile of the liver of these transgenic mice in acute liver injury with the aim of describing the biological mechanism for the action of TFPI in acute liver injury and taking forward the trial of TFPI administration to control mice in a manner that could be carried forward to human studies.
Supervisor: Goldin, Robert ; Thursz, Mark Sponsor: Pathological Society of Great Britain and Ireland ; Jean Shanks Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral