Bridging laboratory assays, genetics, and clinical phenotypes in antithrombin deficiency : rethinking the diagnostic paradigm

Rojnik, Tamara (avtor), Šket, Robert (avtor), Slapnik, Barbara (avtor), Vrhovšek, Blaž (avtor), Mavri, Alenka (avtor), Debeljak, Maruša (avtor), Božič Mijovski, Mojca (avtor)

Background Diagnosis of antithrombin deficiency (ATD), the most severe inherited thrombophilia, commonly relies on functional assays despite their uncertain sensitivity. Moreover, routine characterization of ATD remains uncommon due to limited supporting clinical data. Objectives This study aimed to evaluate the diagnostic sensitivity of commercial antithrombin (AT) activity assays and assess clinical differences among ATD types to refine the current diagnostic approach. Methods Eighty-eight patients with decreased AT activity and 124 consecutive patients with unprovoked venous thromboembolism were included. AT activity was measured using six assays. Genetic analysis of SERPINC1 was performed by Sanger sequencing and multiplex ligation-dependent probe amplification; additionally, long-read whole-genome sequencing was conducted. Results Fifteen SERPINC1 variants were detected, including two novel ones. AT Padua I (p.Arg79His) was the most prevalent (49%). Sensitivity varied across AT activity assays, particularly for types IIRS and IIHBS, with variant-specific discrepancies. AT Dublin (p.Val30Glu), causing transient deficiency, was undetected by all assays. Two assays demonstrated very high sensitivity (93%; p < 0.001), while two others showed poor sensitivity (46%). Regardless of measured AT activity, characterization of ATD type enabled better risk stratification. Type I was associated with early-onset and recurrent venous thromboembolism, and type IIHBS was distinctly linked to arterial thrombosis. Conclusions Assay sensitivity varies considerably, and only a few proved suitable as first-line tests. Genetic testing for common variants undetectable by even the most sensitive assays, along with ATD characterization, should be integrated into diagnostic algorithms. Our results also suggest that young patients with arterial thrombosis should be screened for ATD.

• Jezik: Angleški jezik
• Ključne besede: antithrombin iii deficiency, blood coagulation tests, mutation, thrombophilia
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 10 str.
• Številčenje: Vol. 261, art. 109689
• PID: 20.500.12556/RUL-183691
• UDK: 61
• ISSN pri članku: 1879-2472
• DOI: 10.1016/j.thromres.2026.109689
• COBISS.SI-ID: 281250819
• Datum objave v RUL: 17.06.2026

Gradivo je del revije

• Naslov: Thrombosis Research
• Skrajšan naslov: Thromb. Res.
• Založnik: Elsevier
• ISSN: 1879-2472
• COBISS.SI-ID: 23047685

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Projekti

• Financer: University Medical Centre Ljubljana, Department of Vascular Diseases

• Financer: University Medical Centre Ljubljana, University Children's Hospital