Disease-activity-linked complement-coagulation interactions and persistent platelet activation in treatment-naïve systemic lupus erythematosus

Abstract

Background Thrombosis is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Although multiple prothrombotic pathways have been identified, most have been studied individually or after treatment initiation. We aimed to characterize interactions between prothrombotic pathways in treatment-naïve SLE using an integrated longitudinal approach. Methods In a prospective inception cohort, 20 treatment-naïve SLE patients were studied at diagnosis and after 6 months of treatment. Ten predefined prothrombotic molecular systems were assessed using laboratory assays, plasma proteomics and N-terminomics. Interactions were evaluated using correlation networks, principal component analysis (PCA), and protein–protein interactions. Results Mean age was 42.7 years, 70% were female. Median SLEDAI-2K decreased from 13.5 (baseline) to 2 (6-month follow-up). High disease activity was characterized by an interconnected prothrombotic system network, which declined in eight of ten systems at low disease activity. Platelet activation remained elevated despite reduced disease activity. PCA demonstrated a platelet-dominated interaction profile in antiphospholipid antibody–positive patients. Proteomics and N-terminomics revealed activation of complement and coagulation pathways during active disease, with enrichment of pathway-specific proteolytic cleavages that attenuated following clinical improvement. Conclusions In this treatment-naïve SLE cohort, prothrombotic biology was characterized by dynamic, disease-activity-associated interactions across multiple molecular systems rather than isolated pathway activation. While inflammatory and complement–coagulation activation attenuated with clinical improvement, platelet activation persisted at low disease activity, indicating a component of prothrombotic biology that did not parallel changes in clinical disease activity. These findings provide a mechanistic framework for understanding thrombo-inflammatory pathway changes following treatment in early SLE.