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Title page for ETD etd-03232015-144133

Type of Document Dissertation
Author Mignemi, Nicholas Anthony
Author's Email Address Nicholas.a.mignemi@vanderbilt.edu
URN etd-03232015-144133
Title The Role of the Fibrinolytic System and Fibrin in Fracture Healing
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
David Gailani Committee Chair
Herbert Schwartz Committee Member
Joey Barnett Committee Member
Jonathan Schoenecker Committee Member
Justin Cates Committee Member
  • Fibrin
  • Vascularity
  • Fracture
  • Bone
Date of Defense 2015-03-04
Availability unrestricted
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.
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