Sepsis is a systemic inflammatory response to infection. It is often accompanied by the pathologic production of thrombin, the key enzyme in blood plasma responsible for coagulation, and by contact activation, which is a pro-inflammatory pathway in plasma. The project described in this dissertation focused on factor XI (FXI), the zymogen of FXIa, a protease that contributes to thrombin generation during coagulation. FXIa is formed by proteolytic cleavage of FXI by thrombin or by factor XIIa, a protease that is generated during contact activation. Building upon earlier work that indicated an influence of FXI on the pathology of murine sepsis, we investigated the importance of FXI to mortality and to the cytokine and coagulation responses after cecal ligation and puncture (CLP). Compared to wild type (WT) littermates, FXI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in WT mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of FXI. There was no evidence of a severe coagulopathy after CLP, with a notable lack of enhanced thrombin generation in any of the mice. Plasma levels of the contact proteins factor XII (FXII) and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation, while levels of these proteins were not reduced in FXI-/- animals. Additional in vivo studies confirmed that FXI deficiency reduces contact activation, with in vitro analysis revealing that FXIa activates FXII in a reaction that is enhanced by polyanions such as polyphosphate and nucleic acids (which may be released during infection). Our data indicate that FXI deficiency confers a survival advantage after CLP by altering the cytokine response to infection and blunting activation of the contact system. The findings support a novel hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11202016-191246 |
| Date | 21 November 2016 |
| Creators | Bane, Charles Edward |
| Contributors | Richard Hoover, Ph.D., Stephen Kania, M.S., Ph.D., Jonathan Schoenecker, M.D., Ph.D., Edward Sherwood, M.D., Ph.D., Charles Stratton, M.D., Keith Wilson, M.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11202016-191246/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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