Multi-omics and network propagation reveal latent innate immune programmes stratifying high-risk thrombotic primary antiphospholipid syndrome

Thrombotic primary antiphospholipid syndrome (thrPAPS) outcomes are associated with thrombosis type (arterial versus venous), recurrence, and antiphospholipid antibody (aPL) profile (single versus triple-aPL). We investigated molecular signatures underlying disease status and high-risk phenotypes. We performed whole-blood transcriptomics and mass spectrometry-based plasma proteomics in patients with thrPAPS and age/sex-matched healthy controls. Analyses included differential expression, pathway enrichment, weighted gene co-expression network analysis (WGCNA) and machine learning. Multi-Omics Factor Analysis (MOFA2) and network propagation were applied to identify latent molecular programmes associated with high-risk phenotypes. Transcriptomic and WGCNA analyses revealed an interferon-associated module associated with high-risk phenotypes. Plasma proteomics distinguished thrPAPS from healthy controls through a coordinated thromboinflammatory signature encompassing complement, acute-phase, platelet, and coagulation-associated pathways. Complement factor D, a rate-limiting enzyme of the alternative complement pathway, discriminated recurrent from single-event thrPAPS (AUC = 0.79) and correlated with thrombotic event count (Spearman's correlation = 0.62, p < 0.001). Mixed arterial/venous phenotype showed the greatest degree of subgroup-specific dysregulation, including complement and coagulation/fibrinolysis-related proteins. MOFA2 identified a proteome-dominant latent factor that increased with aPL burden (Spearman's correlation = 0.33, p = 0.017) and was enriched for complement cascade proteins. Network propagation embedded this signature within immune-cell signalling (STAT-1, PI3K-AKT, MAPK8, SRC), N-linked glycosylation, and mitochondrial oxidative phosphorylation. Longitudinal profiling identified reactive oxygen species-associated proteins during active disease. ThrPAPS is characterised by a complement-, interferon- and platelet-driven thromboinflammatory programme that scales with aPL and thrombosis burden, converging on innate immune activation as a central feature of high-risk disease.