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Title page for ETD etd-11202016-191246

Type of Document Dissertation
Author Bane, Charles Edward Jr.
URN etd-11202016-191246
Title The Role of Factor XI During Murine Polymicrobial Sepsis
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Richard Hoover, Ph.D. Committee Chair
Charles Stratton, M.D. Committee Member
Edward Sherwood, M.D., Ph.D. Committee Member
Jonathan Schoenecker, M.D., Ph.D. Committee Member
Keith Wilson, M.D. Committee Member
Stephen Kania, M.S., Ph.D. Committee Member
  • sepsis
  • cecal ligation and puncture
  • disseminated intravascular coagulation
  • contact activation
  • factor XI
  • inflammation
Date of Defense 2016-07-11
Availability unrestricted
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.

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