ROS-induced modifications of fibrin clots connect immune responses to atherothrombosis in systemic lupus erythematosus

Abstract

Objective: Cardiovascular events are major determinants of morbidity and mortality in systemic lupus erythematosus (SLE), particularly in patients with renal involvement. While oxidative stress has been implicated in driving vascular and renal damage in SLE, the specific mechanisms remain unclear. This study investigated the potential role of oxidative stress-induced alterations in fibrinogen structure and function in the pathogenesis of atherothrombosis in SLE.

Methods: In this cross-sectional study, we enrolled 144 adult patients with SLE and 90 matched controls. We measured blood leukocyte reactive oxygen species (ROS) production, systemic redox status, and the structural and functional features of purified fibrinogen. Correlations between these parameters and disease activity were also investigated. In vitro experiments to clarify the causal relationships among ROS levels, protein oxidation, and fibrin abnormalities provided mechanistic insights of the observed alterations.

Results: SLE patients showed increased leukocyte ROS production, mainly due to neutrophil NADPH oxidase activation. Interestingly, renal biopsies from SLE patients with active proliferative lupus nephritis exhibited the NADPH oxidase enzyme complex p22phox overexpression. This was accompanied by plasma oxidative stress as indicated by elevated plasma lipid peroxidation and reduced antioxidant defenses. Fibrinogen oxidation was associated with structural and functional changes, leading to the formation of denser fibrin networks with lower clot porosity and reduced susceptibility to plasmin-mediated fibrin lysis. Interestingly, these fibrinogen modifications correlated with alterations in redox status and disease activity.

Conclusion: Oxidative stress may drive structural and functional modifications of fibrinogen in SLE, potentially acting as a novel pathogenetic mechanism in atherothrombosis among these patients.