AbstractsBiology & Animal Science

The Role of the Fibrinolytic System and Fibrin in Fracture Healing

by Nicholas Anthony Mignemi

Institution: Vanderbilt University
Department: Pathology
Degree: PhD
Year: 2015
Keywords: Fibrin; Vascularity; Fracture; Bone;
Record ID: 2057878
Full text PDF: http://etd.library.vanderbilt.edu/available/etd-03232015-144133/


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.