Alterations in both coagulation and fibrinolytic pathways mediate thrombosis in the skin during murine Graft-Versus-Host (GVH)-induced scleroderma (48.5)

Abstract

Scleroderma is a systemic autoimmune disease characterized by fibrosis, inflammation and vasculopathy of the skin, kidney and lung. The vasculopathy features occlusion of small arteries due vasoconstriction, intimal proliferation and thrombosis. Thrombosis results from an imbalance between coagulation and fibrinolysis. Whether thrombosis in scleroderma is primarily due to alteration in fibrinolysis or coagulation remains unclear. In this study, we investigated thrombosis in a murine GVH model of human scleroderma exhibiting an occlusive vasculopathy. We looked at fibrinolysis and coagulation biomarkers in skin, kidney and lung using qPCR and IHC. GVH skin showed microthrombi in dermis blood vessels. This was associated with an increase in a number of key regulators of fibrinolysis (PAI-1, tPA and uPAR) and coagulation (Tissue Factor, Factor VII and X), suggesting that thrombosis in GVH skin is caused by alterations in both fibrinolysis and coagulation pathways. Unlike skin, kidney and lung did not show fibrinolysis and coagulation alterations, suggesting that vasoconstriction rather than thrombosis mediates the occlusive vasculopathy in these tissues, consistent with increased endothelin-1 levels in kidney VSMCs. In conclusion, our study suggests that the GVH mouse is a useful model to study the balance of fibrinolysis and coagulation leading to thrombosis in scleroderma vasculopathy in the skin.