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 early and late-stage patients with both limited and diffuse systemic sclerosis. Based on a timed series of excision wounds, retention on the fibrin deposit of the splice variant domain, fibrinogen αEC, indicated a recent event, while fibrin networks lacking the EC domain were older. Application of this timing tool to SSc revealed considerable heterogeneity in αEC domain distribution providing unique insight into disease activity. Intriguingly, the fibrinogen-αEC 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 defective in fibrin clearance. Unresolved fibrin deposition might then incite chronic tissue remodeling.