Genetic and clinical characterization of two families with severe venous thromboembolism due to nonsense mutations in the SERPINC1 gene

Abstract

Antithrombin (AT) III is a key physiological anticoagulant, and its hereditary deficiency represents one of the most severe forms of inherited thrombophilia. However, as a rare disorder, AT III deficiency is frequently underdiagnosed due to the limitations of current clinical algorithms. In this study, we describe two cases of hereditary AT III deficiency accompanied by multiple venous thromboembolic events: a 39-year-old male with extensive lower limb deep venous thrombosis (DVT) involving the iliac, femoral, and popliteal veins, and a 21-year-old female with intermediate-high risk pulmonary embolism (PE). Laboratory evaluation revealed reduced AT III activity levels of 51.9% and 52.7%, respectively. Quantitative ELISA analysis further confirmed a corresponding reduction in AT antigen levels. Both patients showed suboptimal responses to initial low-molecular-weight heparin treatment but responded favorably to oral rivaroxaban. Genetic testing identified two nonsense mutations in the SERPINC1 gene: NM_000488.4:c.906dupT (p.Glu303Ter), a previously unreported variant, and NM_000488.4:c.481 C > T (p.Arg161Ter), reported here for the first time in an Asian individual. Family analyses confirmed that the variants were inherited from the proband's parents, who had a history of venous thromboembolism (VTE). These findings underscore the importance of assessing AT activity in patients with unexplained thrombotic events, particularly at a young age, and support the use of genetic testing to guide personalized anticoagulation strategies in AT III deficiency.

Affiliated Institutions

• Ruijin Hospital CN
• Shanghai Institute of Hematology CN
• Shanghai Jiao Tong University CN
• Shanghai Sixth People's Hospital CN

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