Bone formation during fracture repair inevitably initiates within, or around, extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone healing by promoting inflammatory and mesenchymal progenitor egress into the zone of injury. However, a failure of efficient fibrin clearance from wound fields can also be detrimental to normal tissue repair. The precise contribution of fibrin to fracture repair, be it supportive or detrimental, is unknown. Thus, in this dissertation I tested the hypothesis that fibrin is indispensable for the initiation of fracture repair but failure to remove fibrin impedes late stages of repair. I monitored fracture healing in mice with either a complete genetically fibrinogen deficiency or plasminogen deficiency and are thus unable to clear fibrin at the fracture site. Unexpectedly, fibrin was not required for long bone fracture repair. However, a failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluding bone union and resulted in robust heterotopic ossification. Notably, pharmacological fibrinogen depletion in plasminogen-deficient animals restored normal fracture healing, rescued impaired fracture vascularization, and significantly limited heterotypic ossification. Fibrin is therefore not essential for fracture repair but inefficient fibrinolysis impairs fracture healing by interfering with endochondral angiogenesis and ossification.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03232015-144133 |
| Date | 09 April 2015 |
| Creators | Mignemi, Nicholas Anthony |
| Contributors | Jonathan Schoenecker, David Gailani, Justin Cates, Joey Barnett, Herbert Schwartz |
| 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-03232015-144133/ |
| 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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