Antithrombin deficiency

Hereditary antithrombin deficiency results from germline pathogenic variants in SERPINC1. SERPINC1 encodes antithrombin, the principal serine protease inhibitor (serpin) that inactivates thrombin and other coagulation proteases; heparin binding amplifies its inhibitory activity. Loss-of-function variants reduce circulating antithrombin levels (Type I, quantitative deficiency), while missense variants typically impair antithrombin function with preserved antigen concentrations (Type II, qualitative deficiency). Reduced endogenous anticoagulant capacity underlies the predisposition to venous thromboembolism in affected individuals.

Hereditary antithrombin deficiency is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Once the familial pathogenic variant has been identified, prenatal molecular testing is technically possible.

The diagnosis rests on biochemical testing: a heparin-cofactor (functional) antithrombin activity assay demonstrates reduced antithrombin function in affected individuals. Combined functional and antigen assays differentiate the quantitative and qualitative subtypes. Molecular genetic testing of SERPINC1 confirms the diagnosis and identifies the underlying pathogenic variant.

• Establishing the diagnosis: a molecular genetic finding confirms the clinical suspicion and provides the affected individual and family with diagnostic certainty.
• Specific and individualised clinical management: a confirmed molecular diagnosis is the prerequisite for targeted medical care, enabling decisions on management to be made by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant has been identified, predictive testing can be offered to at-risk relatives, allowing them to make informed decisions about their own healthcare.

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