Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive multiorgan fibrosis. While the cause of SSc remains unknown, a perturbed vasculature is considered a critical early step in the pathogenesis. Using fibrinogen as a marker of vascular leakage, we found extensive extravascular fibrinogen deposition in the dermis of both limited and diffuse systemic sclerosis disease, and it was present in both early and late-stage patients. Based on a timed series of excision wounds, retention on the fibrin deposit of the splice variant domain, fibrinogen α_EC, indicated a recent event, while fibrin networks lacking the α_EC domain were older. Application of this timing tool to SSc revealed considerable heterogeneity in α_EC domain distribution providing unique insight into disease activity. Intriguingly, the fibrinogen-α_EC domain also accumulated in macrophages. These observations indicate that systemic sclerosis is characterized by ongoing vascular leakage resulting in extensive interstitial fibrin deposition that is either continually replenished and/or there is impaired fibrin clearance. Unresolved fibrin deposition might then incite chronic tissue remodeling.