A comprehensive study of antithrombin deficiency in a large cohort of Chinese thrombophilia pedigrees: uncovering 4 SERPINC1 pathogenic variants merely impaired progressive activities.

BACKGROUND

Congenital antithrombin (AT) deficiency, primarily caused by variants in SERPINC1, is associated with a high risk of venous thromboembolism. Existing diagnostic procedures, mainly based on functional assays, may miss certain pathogenic variants.

OBJECTIVES

To comprehensively evaluate AT deficiency prevalence in the Chinese thrombophilia population and identify SERPINC1 variants overlooked by traditional diagnostic procedures.

METHODS

We conducted functional assays and genetic analysis simultaneously in 842 Chinese thrombophilia pedigrees. Supplementary functional assays (progressive assay and thrombin generation test) and in vitro enzymatic assays were used to detect AT defects, assess thrombotic risk, and investigate the pathogenic mechanisms of selected variants.

RESULTS

We identified 72 cases with decreased AT activity (<80%), of which 66 cases carried 61 different SERPINC1 variants, while 6 lacked identifiable variants. Additionally, 11 variants were found in 15 cases with normal AT antigen and activity, including 3 known pathogenic variants (p.N224H, p.E227K, and p.M313T) in 5 cases, 4 variants (p.K289E, p.R293W, p.R294C, and p.V295M) associated with impaired AT progressive activity in 7 cases, and 4 likely benign variants (p.V9I, p.S236L, p.G276A, and p.V387I). Thus, the prevalence of AT deficiency was 8.6% (72/842) by functional assays, and could reach 10.0% (84/842) when incorporating genetic analysis. Pathogenic SERPINC1 variants were found in 9.3% (78/842) of venous thromboembolism patients.

CONCLUSION

We identified a new AT type II reactive-site subtype, characterized by impaired progressive activity but normal heparin cofactor activity, which is overlooked in heparin-containing functional assays. These findings support that AT deficiency is underestimated and highlight the need to optimize current diagnostic algorithm for AT deficiency.