Comprehensive Review of Antiphospholipid Syndrome: Over Four Decades of Advances and Challenges

Antiphospholipid syndrome (APS), first described in 1983, is a systemic autoimmune disorder characterized by recurrent arterial and venous thrombosis, pregnancy complications, and persistent antiphospholipid antibodies (aPL). Over four decades, significant advancements have been made in understanding APS pathogenesis, diagnostics, and treatment. Key discoveries include the development of standardized anticardiolipin antibody (aCL) assays, the identification of β2-glycoprotein I (β2GPI) as a critical cofactor, and the elucidation of the "two-hit" hypothesis, which explains thrombotic events through a combination of aPL-induced prothrombotic priming and secondary external triggers. Recent research has highlighted the roles of complement activation, neutrophil extracellular traps (NETs), and genetic predispositions shared with systemic lupus erythematosus (SLE). Innovations like the antiphospholipid score (aPL-S) and updated classification criteria, including the 2023 ACR/EULAR guidelines, have improved diagnostic precision and risk stratification. Despite these advances, challenges remain in assay standardization and addressing seronegative APS. Future directions emphasize the integration of multimodal biomarkers, precision diagnostics, and targeted therapies aimed at complement and NET pathways. These efforts aim to achieve individualized care, improving outcomes for APS patients through harmonized diagnostics, mechanistic therapeutics, and data-driven approaches. This review underscores the evolving understanding of APS and its potential for personalized management strategies.