A pro-inflammatory cytokine signature characterises thrombotic antiphospholipid syndrome despite stable anticoagulation.

Inflammation contributes to primary antiphospholipid syndrome (PAPS) pathogenesis, but cytokine profiles and associated thrombotic phenotypes remain incompletely defined. A panel of 20 cytokines, chemokines and endothelial activation markers was analysed in 37 PAPS patients on stable anticoagulation and 12 healthy controls (HC). We compared concentrations between groups and performed unsupervised hierarchical clustering and principal component analysis (PCA) to identify inflammatory subgroups. Compared with HC, patients with PAPS exhibited significantly elevated levels of 14/20 analytes: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interleukin (IL)-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-13, IL-17a, tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), P-selectin and macrophage inflammatory protein-1β (MIP1β) (all p < 0.05). Unsupervised clustering identified three inflammatory antiphospholipid syndrome (APS) subgroups distinct from HC. A core cytokine signature comprising GM-CSF, IL-6, IL-10, IL-12p70, IL-13 and TNF-α was elevated across all APS clusters. One cluster, enriched for arterial thrombosis, demonstrated a more pronounced inflammatory phenotype, with increased IFN-α. Comparison of phenotypes showed significantly higher concentrations of GM-CSF, IFN-α, IL-1α, IL-4, IL-6, IL-10, IL-17a and TNF-α in arterial versus venous thrombosis. Our findings demonstrate widespread cytokine dysregulation and distinct inflammatory subgroups in PAPS, with arterial thrombosis showing stronger inflammation than venous thrombosis, supporting divergent thrombo-inflammatory mechanisms and potential precision immunomodulatory therapeutic targets.