Genetic determinants of arterial thrombosis in primary antiphospholipid syndrome: a systematic review

Primary Antiphospholipid Syndrome (PAPS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis and obstetric morbidity. Arterial thrombosis, although less frequent than venous events, is associated with substantial morbidity and mortality. Alongside environmental and acquired factors, several genetic polymorphisms affecting coagulation, endothelial function, fibrinolysis, and platelet activation have been investigated in relation to thrombotic risk. Clarifying their contribution may help refine hypotheses for risk stratification.

To systematically review the available evidence on genetic polymorphisms associated with arterial thrombosis in PAPS and to evaluate their reported associations with arterial thrombotic manifestations.

Electronic searches were conducted in MEDLINE, the Cochrane Library, ClinicalTrials.gov, the GWAS Catalog, the Genetic Association Database, and Google Scholar for studies published up to November 2024.

Case-control, cohort, and genome-wide association studies were included if they assessed genetic variants in confirmed PAPS with arterial thrombosis. Comparators included healthy controls, patients with other autoimmune diseases, or APS without arterial events.

Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane and ROBINS-I tools. Due to substantial heterogeneity in study design, populations, and outcome definitions, meta-analysis was not feasible, and results were summarized narratively.

Eighteen studies published between 1994 and 2023 were identified, of which seventeen contributed to the genetic association synthesis. Variants in platelet membrane glycoproteins (GPIa 807T, GPIbα Kozak TC, and combined GPIa 807T plus GPIIb/IIIa PlA2) were the most frequently reported positive associations with arterial thrombosis. PAI-1 (4G) and MTHFR (C677T) showed inconsistent and weak associations, while the EPCR (PROCR) H1 haplotype was negatively associated with arterial thrombosis in isolated analyses. Classical thrombophilic mutations, including Factor V Leiden and Prothrombin G20210A, did not show consistent associations with arterial events. Overall certainty of evidence was low to very low.

The currently reviewed evidence indicates that inherited susceptibility to arterial thrombosis in PAPS is more frequently linked to platelet-related, endothelial, and fibrinolytic pathways than to classical coagulation gene mutations. These associations are based on small, heterogeneous, and largely non-replicated studies and should be considered hypothesis-generating.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024603974, identifier CRD42024603974.