Molecular and Biological Characterization of Transient Antithrombin Deficiency: A New Concept in Congenital Thrombophilia

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2118-2118
• Main Authors: de la Morena-Barrio, Maria Eugenia Eugenia, Bravo-Perez, Carlos, De La Morena-Barrio, Belen, Miñano, Antonia, Padilla, Jose, Cifuentes-Riquelme, Rosa, Garrido, Pedro, Vicente, Vicente, Corral, Javier
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-153892

Antithrombin deficiency, mainly but not exclusively due to SERPINC1 gene variants, is a major thrombophilia that is significantly associated to early-onset venous thromboembolism. The diagnostic algorithm of antithrombin deficiency relies on the classical biochemical-molecular sequence, adopted for all thrombophilic states. Therefore, genetic analysis of SERPINC1 is restricted to cases with confirmed antithrombin deficiency, that is, cases with at least two positive findings by using functional assays or with other relatives carrying this disorder. This strategy has enabled the identification of gene variants in up to 80% of cases with antithrombin deficiency and rendered plenty of both biochemical and genetic knowledge about antithrombin. Furthermore, defects of N-glycosylation underlie a proportion of cases with antithrombin deficiency that is not explained by SERPINC1 variants. Nevertheless, diagnosis of antithrombin deficiency still encloses some uncertain puzzling questions. Although the prevalence of antithrombin deficiency is tremendously low, the use of high-throughput nucleotide sequencing for genetic analysis of SERPINC1 in consecutive patients with thromboembolic events suggests that antithrombin deficiency might be and underestimated disorder that surreptitiously increases thrombotic risk. Additionally, false negative results by using functional methods for antithrombin deficiency screening have been reported, all involving type II deficiencies. The present study aimed to identify gene defects and mechanisms involved in a specific type of antithrombin deficiency that might be elusive to an easy diagnosis to the classic diagnostic strategy. We addressed this aim with an original approach, the selection of cases with at least a positive finding by functional methods that however was not confirmed by a second analysis in other laboratory or in other sample from the same patient: what we have called transient antithrombin deficiency. This work included a total of 444 consecutive unrelated subjects, referred to our centre from more than 20 European hospitals during 23 years (1998-2021), with potential antithrombin deficiency, based on at least one positive functional assay performed at the hospital of origin. At least a new sample from all patients was delivered to our centre, so a new functional assay (a uniform anti-FXa assay for all recruited samples) was carried out for validation. By performing a full clinical, biological and characterization,