Primary antiphospholipid syndrome: emerging strategies and current limitations in diagnosis and management

Primary antiphospholipid syndrome (PAPS) is an autoimmune thrombo-inflammatory disorder characterized by persistent antiphospholipid antibodies (aPL) and a broad spectrum of thrombotic, obstetric, microvascular, and non-thrombotic manifestations. Despite advances in the understanding of its pathogenesis, major challenges remain concerning diagnosis, risk stratification and clinical management. This review discusses current limitations in PAPS diagnosis, particularly the technical and interpretative difficulties of lupus anticoagulant testing, variability among traditional aPL assays, and the evolving role of non-criteria aPL in diagnosis and risk stratification. It also explores emerging diagnostic approaches, including thrombin generation assay, which may help overcome some limitations of conventional laboratory testing and improve risk assessment. In parallel, important therapeutic challenges are addressed, including the limitations of anticoagulation-based strategies, difficulties in vitamin K antagonist monitoring, and the management of refractory, microvascular, and non-thrombotic disease manifestations. Current and emerging adjunctive therapies, including hydroxychloroquine, statins, biologic agents, and immune-modulating strategies, are reviewed, together with future potential therapeutic targets based on evolving pathogenic mechanisms. Improved disease activity assessment, more accurate thrombotic risk stratification, and mechanistic therapeutic approaches may support a transition toward a more individualized and precise management of PAPS. This narrative review was based on a targeted PubMed search conducted from March to June 2026.