The multifaceted role of fibrinogen in tissue injury and inflammation

Abstract

The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological end points of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that affect the spectrum of tissue injury, remodeling, and repair. Indeed, fibrin(ogen) deposits are a near-universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor-targeted therapies for a range of tissue injuries and disease.

Figure 1.

Coagulation and fibrinolytic systems in the acute phase response. The biological systems activated during the acute phase response rapidly change and can be generally divided into 2 biologically distinct phases: “contain” and “remodel/repair.” Following injury, exposure of activating cell surfaces and/or matrices activates coagulation and acute inflammation, which work together and lead to thrombin activation and conversion of fibrinogen to fibrin. Together, acute inflammation, thrombin activity, and fibrin serve to contain ruptured compartments (eg, bleeding) and prevent or mitigate invasion by pathogens. Once containment is achieved, the acute phase response transitions to remodel/repair (circular arrows). Importantly, although inflammatory cells are crucial in both phases of the acute phase response, their phenotype and biological role is different in their respective phases. Plasmin promotes remodeling/repair because it is used by reparative inflammatory cells to degrade and remove damaged tissues and fibrin to promote angiogenesis and tissue differentiation/reconstruction. Collectively, in cases of a normal reparative response to injury, coagulation and fibrinolytic components work in concert to promote the transition of inflammatory cells to a reparative (tissue remodeling) phenotype as well as other mechanisms, culminating in timely tissue regeneration.

Figure 2.

A dysregulated acute phase response leads to destructive inflammation and impaired tissue remodeling. Genetic or environmental dysregulation of coagulation can provoke degenerative tissue disease and impair tissue repair through a multitude of mechanisms. Reciprocally, extreme and prolonged liberation of inflammatory cytokines leads to not only local, but also systemic activation of cellular inflammatory pathways, prolonging thrombin activation. Alternatively, impaired fibrinolysis (plasmin activity) prolongs the presence of fibrin, delaying the resolution of its inflammatory properties. Regardless of the mechanism, the prolonged acute inflammatory response interferes with transition to reparative inflammatory processes, evoking impaired tissue repair and degenerative tissue disease.

Figure 3.

Coagulation and fibrinolytic system components in inflammation. Summary of mechanisms by which fibrinogen, thrombin, and fibrinolytic proteins contribute to inflammatory mechanisms. Boxed A indicates FXIII A subunit; circled B indicates FXIII B subunit. APC, activated protein C; EC, endothelial cell; ePCR, endothelial cell protein C receptor; FDP, fibrin degradation product; Plg, plasminogen; Plg-R, plasminogen receptor; TF, tissue factor; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.