Anti-Annexin A5 Antibodies and Annexin A5 Resistance in Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis

To provide an updated systematic review and meta-analysis of the estimated pooled of anti–Annexin A5 antibodies (AnxA5-Abs) and Annexin A5 resistance (A5R) across antiphospholipid syndrome (APS) phenotypes. PubMed, EMBASE, and the Cochrane Library were searched from inception to June 2018 and updated in August 2025. Eligible studies included adults tested for AnxA5-Abs (IgG/IgM) and/or A5R who fulfilled revised Sapporo/Sydney APS clinical criteria. Pooled prevalences were estimated using Freeman–Tukey random-effects models and stratified by phenotype, serologic status, and autoimmune disease. Univariable and multivariable meta-regression evaluated predictors of IgG AnxA5-Abs and A5R. The protocol was registered in PROSPERO (CRD42018099462). Fifty-eight studies were included, comprising 6,960 patients and 2,417 controls. In obstetric APS cohorts, pooled IgG AnxA5-Abs prevalence was 21.2% (95% CI 7.4–39.2) versus 4.0% (1.7–7.1) in controls; thrombotic APS showed 10.3% (5.7–15.8). IgM AnxA5-Abs were less frequent and showed weaker associations. IgG AnxA5-Abs prevalence was higher in seropositive APS (27.1%) and seronegative APS (20.4%) than in mixed/unstratified APS (11.7%). Among systemic lupus erythematosus (SLE) patients with APS-related clinical manifestations, IgG AnxA5-Abs prevalence was 31.7% versus 16.3% in SLE controls without clinical APS manifestations. A5R prevalence was higher in obstetric (29.9%) and thrombotic APS (28.8%) than in controls (17.5%). Obstetric APS independently predicted higher IgG AnxA5-Abs prevalence. IgG AnxA5-Abs and A5R are enriched in Sapporo-defined obstetric APS, with weaker and less consistent associations in thrombosis-only APS. These findings support the biological plausibility of AnxA5 disruption in obstetric APS and identify AnxA5-related biomarkers as promising candidates for future validation. However, prospective external validation using standardized assays, pre-specified thresholds, and demonstration of incremental prognostic value are essential prerequisites before clinical risk stratification use. • IgG anti–Annexin A5 antibodies and Annexin A5 resistance are enriched in Sapporo-defined obstetric APS compared with controls. • These biomarkers show weaker and less consistent patterns in thrombosis-only APS and in unexplained pregnancy loss not meeting Sapporo criteria. • Annexin A5–related abnormalities appear phenotype-specific, suggesting biological relevance in obstetric APS that warrants prospective validation before clinical risk stratification use.