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

## TL;DR

This paper reviews four decades of progress in understanding and managing antiphospholipid syndrome, highlighting key discoveries and future directions for personalized treatment.

## Contribution

The paper provides a comprehensive overview of advancements in APS pathogenesis, diagnostics, and treatment, emphasizing recent innovations and remaining challenges.

## Key findings

- Standardized aCL assays and β2GPI identification improved APS diagnostics.
- The 'two-hit' hypothesis explains thrombosis through aPL-induced priming and external triggers.
- Multimodal biomarkers and precision diagnostics are proposed for future personalized APS management.

## Abstract

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.