Coagulation and Autoimmunity in Scleroderma Interstitial Lung Disease

Abstract

Objectives Interstitial lung disease in systemic sclerosis (SSc-ILD) is often an irreversible and progressive fibrosing process that now is the leading cause of scleroderma-related deaths. In this review we present our current understanding of the role played by coagulation and particularly by thrombin in autoimmune-mediated tissue injury and fibrosis, mainly as it relates to SSc-ILD. Methods We used PubMed to search for articles published up to October 2010 for keywords referring to autoimmunity, coagulation, pulmonary fibrosis, and scleroderma. Results SSc-ILD is an autoimmune disease associated with lymphocyte activation and release of various cytokines and growth factors. The production of autoantibodies is a central feature in SSc. Activation of the coagulation cascade with release of thrombin is 1 of the earliest events following tissue injury. Thrombin contributes to autoimmune responses by activating of pathogenic Th2 lymphocyte profile in SSc. Thrombin also modulates tissue repair responses, stimulates transformation of epithelial cells, endothelial cells, and fibroblasts into myofibroblast phenotype, and induces secretion of several pro-immune and profibrotic factors, which serve as antigens for pathogenic autoantibodies production in SSc-ILD. Conclusions The identification of links between autoimmunity and coagulation would provide new insights into the pathogenesis of pulmonary fibrosis associated with autoimmune diseases and further acknowledge the importance of thrombin in the development of SSc-ILD.

Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: A General Population‐Based Study

“…18–20 The endothelial damage observed in SSc leads to the release of thrombin and subsequent initiation of the coagulation cascade. 19 Although this pathway has been best described in the context of SSc-associated pulmonary fibrosis, 43,44 similar mechanisms could potentially lead to a systemic hypercoagulable state and an increased risk of VTE in SSc patients, as observed in our study. Idiopathic pulmonary fibrosis (IPF), another disease characterized by progressive fibrosis, has been shown to be correlated with an increased risk of DVT as well, 45 and it is possible that similar mechanisms are responsible for the link between fibrosis and thrombosis in both SSc and IPF.…”

An Update on the Evaluation and Management of Pulmonary Hypertension in Scleroderma

“…Anemia or a bleeding diathesis such as the gastric antral vascular ectasia (GAVE) syndrome or gastrointestinal telangiectasia are more common in SSc and may preclude such therapy. Evidence from mechanistic studies suggests that thrombin may play an important role in the pathogenesis of SSc [33]; thus, while there are concerns and limited data, there is a rationale for anticoagulation in this population. Retrospective, uncontrolled evidence for immunosuppressive agents in a subgroup of mixed connective tissue disease and systemic lupus erythematosus patients is available, but not for SScassociated PAH [34].…”

Interstitial Lung Disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases

“…In SSc-ILD, microvascular injury and damage to endothelial cells appear to be the initiating factors. Endothelial damage leads to the production of thrombin, endothelin-1, vascular endothelial growth factor, and adhesion molecules, which, in turn, may promote inflammation (59,60). Recent animal data also suggest that injury to epithelial cells may also play an important role in the pathogenesis of SSc-ILD (61).…”