Mechanisms regulating tissue factor : factor VIIa-dependent coagulation in liver disease
Over 50 million people in the world have a chronic liver disease. Interestingly, as a result of liver disease, patients often acquire complex alterations in their coagulation cascade. The coagulation cascade plays a critical role in preventing hemorrhage after vascular injury through the formation of a blood clot. There is also evidence suggest that the activation of the coagulation cascade worsens the progression of liver disease. However, the mechanisms underlying the activation of coagulation during liver disease are poorly understood. If the mechanisms whereby coagulation is activated during liver disease were known, one could develop targeted strategies to inhibit pathologic coagulation in patients with liver disease.The coagulation cascade is controlled by a complex composed of tissue factor (TF) and its plasma ligand, factor FVIIa (FVIIa). Within the liver, the TF:FVIIa complex exists in a non-procoagulant, 'encrypted' state on hepatocytes. Prior studies focusing on encrypted TF:FVIIa have identified several potential mechanisms underlying the activation of TF:FVIIa. However, the in vivo relevance of these mechanisms has remained unclear, because examples of TF:FVIIa activation triggered by (patho)physiologically-relevant mediators are lacking.A major focus of the work described in this dissertation was to identify activators of coagulation during liver injury. Interestingly, bile acids, cholesterol metabolites produced in the liver, accumulate within the liver parenchyma and plasma during liver disease. Exploring the possibility for bile acids to activate coagulation, I found that pathologically relevant concentrations of the bile acid, glycochenodeoxycholic acid, increased hepatocyte TF:FVIIa activity. Expanding on this finding, I tested the hypothesis that bile acids directly increase TF:FVIIa activity by using TF:FVIIa relipidated in unilamellar vesicles and soluble TF:FVIIa. The bile acids, glycochenodeoxycholic and taurochenodeoxycholic acid, directly increased the activity of relipidated and soluble TF:FVIIa. Interestingly, it was found that not all bile acids act through the same mechanism. Taurocholic acid did not directly activate TF:FVIIa but increased hepatocyte TF:FVIIa activity through the non-apoptotic externalization of phosphatidylserine in vitro. These results indicate that bile acids increase TF:FVIIa procoagulant activity through both direct and indirect mechanisms.Although prior studies have focused on hepatocyte TF, it is unknown if hepatocyte TF is universally required to activate coagulation after challenge with hepatotoxicants. Another focus of this work was to determine the role of hepatocyte TF in acute and chronic challenge with carbon tetrachloride (CCl4). Contrary to my hypothesis that hepatocyte TF drives coagulation after CCl4 challenge, there was no change in the activation of coagulation in mice deficient of hepatocyte TF versus control mice after acute and chronic challenge with CCl4. This suggests another cellular source of TF is driving coagulation after CCl4 challenge. Notably, deficiency in hepatocyte TF did not affect the development of fibrosis. In summary, contrasting other models of liver injury, this suggests hepatocyte TF does not drive coagulation after CCl4 challenge.In summary, these results indicate that bile acids increase TF:FVIIa procoagulant activity, which suggests the possibility for bile acids to activate coagulation during liver disease. Additionally, it was found that hepatocyte TF does not contribute to the activation of coagulation in all models of liver injury, which suggests the potential for another cellular source of TF that is driving coagulation. Overall, this work expands our knowledge of how coagulation is regulated within the liver and identifies potential activators of coagulation that increase during liver disease.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Baker, Kevin Samuel
- Thesis Advisors
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Luyendyk, James P.
- Date
- 2020
- Subjects
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Toxicology
- Degree Level
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Doctoral
- Language
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English
- Pages
- 155 pages
- ISBN
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9798557001267
- Permalink
- https://doi.org/doi:10.25335/mjg2-ms88