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Objectives Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis driven by complex interactions between the innate immune system, autoantibodies, the coagulation cascade, and platelets. However, integrated analyses capturing these interactions, particularly during high disease activity, are lacking. We aimed to delineate the dynamic interplay among the prothrombotic systems in SLE and to assess their alteration following treatment initiation.Methods We prospectively enrolled (during 2023-2024) 20 newly diagnosed, treatment-naïve SLE patients with high disease activity and followed them for 6 months after standard-of-care therapy initiation. All participants provided informed consent and the study was approved by the Danish ethics committee. Blood samples were collected at baseline and follow-up. Seven prothrombotic systems: platelets, autoantibodies (incl. anti-phospholipid antibodies, (aPL)), complement, endothelium, coagulation, fibrinolysis, and type I interferon (IFN-I), were assessed using immunoassays, functional assays, and by N-terminomic/proteomic profiling to detect in vivo proteolytic events.Results Mean age was 42.7 years; 70% were female and 90% of White ethnicity. All patients met the EULAR/ACR 2019 SLE criteria; 35% were persistently aPL positive. All patients initiated hydroxychloroquine ± glucocorticoids ± other immunosuppressants according to standard-of-care. Median (range) SLEDAI-2K decreased from 13.5 (5–24) to 2 (0–8) after 6 months, with 85% achieving LLDAS remission.Log2 fold-change analysis revealed broad modulation across systems, most pronounced in IFN-I and complement markers (figure 1). Correlation network analysis (Spearman ρ > 0.5, p < 0.05) demonstrated extensive cross-talk among platelet activation, aPL, and coagulation pathways during high disease activity, which markedly diminished during remission.Principal component analysis of representative markers from each system identified a distinct aPL-positive cluster, primarily driven by platelet activation (soluble P-selectin) (figure 2). Proteolytic profiling is ongoing.Abstract PO:06:164 Figure 1–2Conclusions This integrated multi-pathway approach shows that high disease activity in SLE amplifies cross-talk among prothrombotic pathways, particularly between aPL, platelets, and coagulation, driving a platelet-dominated procoagulant state. The clustering of aPL-positive patients supports a shared platelet-driven mechanism of heightened thrombogenicity. These findings emphasize the need for rapid disease control and support a treat-to-target strategy incorporating targeted antithrombotic interventions focused on platelet activity in aPL-positive SLE, especially early after diagnosis.