Association of the p.Phe155del mutation in SERPINC1 with changed antithrombin function and increased risk of venous thromboembolism: clinical and functional observations.

INTRODUCTION: Antithrombin (AT) deficiency, often caused by mutations in the SERPINC1 gene, is a well-established risk factor for venous thromboembolism (VTE), which can lead to serious complications such as deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST). Syndecan-4 (SDC4), an endothelial cell membrane protein, enhances AT's anticoagulant function by facilitating its interaction with the vascular endothelium, thereby supporting hemostatic balance. METHODS: Our team enrolled a patient diagnosed with CVST, and subsequent genetic testing identified the SERPINC1 p.Phe155del variant. This study sought to elucidate the interaction between AT mutations and SDC4 in VTE pathogenesis using clinical case analyses, molecular docking, co-immunoprecipitation (Co-IP), and immunofluorescence assays. RESULTS: The patient was diagnosed with Type I hereditary AT deficiency, with a five-generation family pedigree constructed. Molecular docking simulations showed the SERPINC1 p.Phe155del variant weakened the protein's interaction with SDC4. Cell-level co-immunoprecipitation and immunofluorescence results were consistent with molecular docking findings, confirming that the SERPINC1 p.Phe155del mutant binds less strongly to SDC4 than the wild-type. CONCLUSION: This reduced binding may underlie hereditary AT deficiency and increased venous thrombosis risk. The findings from this research deepen understanding of the connection between hereditary hypercoagulable states and VTE -with CVST as one possible clinical manifestation-offering new insights to inform clinical diagnosis and treatment.