P118 Increased atherothrombotic risk in SLE patients: the role of oxidative stress in fibrinogen structural and functional modifications

Objective Patients with systemic lupus erythematosus (SLE) show accelerated atherosclerosis and are at higher risk of developing myocardial infarction, stroke and peripheral vasculopathy, carrying an overall 2- to 10-fold higher risk of cardiovascular events as compared to the general population. The pathogenetic mechanisms underlying this increased risk are still unclear, but several studies suggest a central role of oxidation in promoting vascular damage in SLE. Consequently, this study aimed to investigate the potential role of oxidation-mediated structural and functional alterations of fibrinogen in the pathogenesis of atherothrombosis in SLE. Methods A cross-sectional study was conducted enrolling 144 adult SLE patients and 90 matched controls, and the production of reactive oxygen species (ROS) by leucocytes and overall redox status were assessed. Furthermore, the structural and functional characteristics of fibrinogen (including thrombin-catalysed fibrin polymerisation and the susceptibility of fibrin to plasmin-induced lysis) and their correlation with redox parameters were investigated. Results Compared to controls, SLE patients showed increased ROS production by lymphocytes, monocytes, and neutrophils, mainly due to neutrophil NADPH oxidase (42432 ± 18998 vs. 13234 ± 4223 RLU/s, p=0.001), in parallel with increased plasma lipid peroxidation, reduced antioxidant defences and increased fibrinogen oxidation (294 (256–329) vs 163 (121–184) RFU, p < 0.0001). SLE patients also presented marked alterations in fibrinogen and clot structure, mainly characterised by reduced porosity and by a dense fibrin network with reduced average filaments size. A significant difference was found in alterations of the functional characteristics of fibrinogen, especially in thrombin-catalysed fibrin polymerisation and in fibrin susceptibility to plasmin-induced lysis. Additionally, these functional and structural alterations significantly correlated with redox parameters, which in turn correlated with SLE disease activity. Conclusions These data suggest that ROS induce structural and functional changes to fibrinogen in SLE. This could represent a novel pathogenetic mechanism underlying atherothrombosis in SLE. Acknowledgements All people who contributed to this work are listed among co-authors.