Clinical and Genetic Spectrum of Hereditary Antithrombin Deficiency: Correlation of Type, Functional Activity, and Arterial Thrombotic Risk

Introduction Hereditary antithrombin (AT) deficiency is a rare but highly penetrant thrombophilia. While Type I deficiency (quantitative loss) causes pronounced AT reduction, Type II variants lead to functional alterations — particularly in the heparin-binding site (HBS) or reactive center loop. This study analyzed clinical and biochemical differences between patients with and without arterial events, emphasizing genotype–phenotype correlation. Method A total of 70 patients with genetically confirmed SERPINC1 variants were retrospectively analyzed. Clinical variables included age, sex, VTE recurrence, arterial events, and anticoagulation status. Laboratory data comprised AT activity (FII/FX-based) and antigen levels. Genetic data (mutation site and ACMG classification) were used to classify subtypes (Type I vs. Type II; HBS vs. non-HBS variants). Results Type I patients (n=12) showed lower AT antigen (mean≈50%) and activity (55±18%), with higher VTE recurrence (75%) and long-term anticoagulation (75%) than Type II (33%). Arterial events occurred in 10% of all patients — predominantly in males (71%) and those with pathogenic ACMG 5 variants. Some Heparin-binding site mutations (for example p.Arg79His, p.Leu131Phe) were linked exclusively to venous thrombosis. Correlation analysis showed positive associations between arterial events and male sex (r=0.26), recurrent thrombosis (r=0.21), and permanent anticoagulation (r=0.31). AT antigen and functional activity were slightly lower in arterial cases. Conclusion Arterial thrombosis in hereditary AT deficiency occurs frequently in patients with severe quantitative or reactive-site defects. Some Type II-HBS mutations (p.Arg79His) cause a purely venous phenotype with preserved basal AT activity. Integrating functional, clinical, and genetic data enables precise risk stratification and supports individualized anticoagulation management [ 1 ] [ 2 ] [ 3 ]. Fig. 1 Antithrombin Parameters in Patients With vs. Without Arterial Events Grouped boxplots showing AT activity (FII- and FX-based) and AT antigen levels for patients with (1) and without (0) arterial events. Fig. 2 Correlation Matrix of Clinical and Laboratory Variables. Heatmap illustrating Pearson correlations between arterial events and major variables. Positive correlations with: – Permanent anticoagulation (r=0.31) – Male sex (r=0.26) – Recurrent thrombosis (r=0.21) Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany