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Introduction Systemic sclerosis (SSc) is an autoimmune disease marked by microvascular injury, immune dysregulation, and fibrosis. Vasculopathy is an early and defining feature of SSc. Neutrophil extracellular traps (NETs), a specialized immune response mechanism, have been implicated in the development of various vasculopathies. However, their contribution to SSc pathophysiology remains insufficiently defined. This study examines the involvement of NETs and thromboinflammatory mediators in limited SSc as well as their association with vascular complications.Material and Methods Sixteen patients with limited SSc (ACR/EULAR 2013 criteria; mean age 66.2 ± 10.3 years; 87.5% women) and sixteen age- and sex-matched healthy controls were enrolled. Among the SSc cohort, six patients had vascular complications [ischemic toe ulcers (n=4) and/or pulmonary arterial hypertension (n=2)], while ten had no vascular organ damage. Citrullinated histone 3 (CitH3), a robust marker of NETs, interleukin(IL)-1b, thrombin–antithrombin complex (TAT), and terminal complement complex (TCC) were quantified in blood serum or plasma by ELISA. Data were either compared between patients and controls or analyzed with subgroup comparisons based on vascular involvement and autoantibody profile (ACA versus anti-Scl-70).Results Patients with limited SSc showed significantly elevated CitH3, IL-1b, TAT, and TCC circulating levels compared to healthy controls (p < 0.001). Within the SSc cohort, no significant differences were observed between patients with or without vascular complications. Similarly, no differences were detected between ACA-positive and anti-Scl-70-positive patients.Conclusions The study demonstrates activation of NETs and thromboinflammatory pathways in limited SSc, independent of vascular involvement. Larger, more comprehensive studies using advanced analytical tools are needed to clarify the mechanisms driving vasculopathy in SSc.This work has received funding from the Hellenic Foundation for Research and Innovation (H.F.R.I.) in the framework of the project ‘Vaccination-induced trained immunity in autoimmune diseases: A friend or foe?’ (Acronym: Vital; Project Number: 26282)