Bridging laboratory assays, genetics, and clinical phenotypes in antithrombin deficiency: Rethinking the diagnostic...

Area of Science:

• Hematology
• Genetics
• Thrombosis Research

Background:

• Antithrombin deficiency (ATD) is a severe inherited thrombophilia.
• Current diagnosis relies on functional assays with uncertain sensitivity.
• Routine ATD characterization is limited by scarce clinical data.

Purpose of the Study:

• Evaluate diagnostic sensitivity of commercial antithrombin (AT) activity assays.
• Assess clinical differences among ATD types for improved diagnostic approaches.
• Refine the diagnostic strategy for inherited thrombophilia.

Main Methods:

• Analyzed 88 patients with decreased AT activity and 124 with unprovoked venous thromboembolism.
• Measured AT activity using six commercial assays.
• Performed genetic analysis of SERPINC1 via Sanger sequencing, MLPA, and whole-genome sequencing.

Main Results:

• Detected 15 SERPINC1 variants, including two novel ones; AT Padua I was most prevalent (49%).
• Assay sensitivity varied significantly; two assays showed high sensitivity (93%), others poor (46%).
• ATD type characterization improved risk stratification, linking Type I to venous thrombosis and Type IIHBS to arterial thrombosis.

Conclusions:

• Assay sensitivity for ATD diagnosis is highly variable; few assays are suitable first-line tests.
• Integrate genetic testing for undetectable variants and ATD characterization into diagnostic algorithms.
• Recommend screening young patients with arterial thrombosis for ATD.