Phenotypic and Genotypic Analysis of a Hereditary Antithrombin Deficiency Pedigree Due to a Novel SERPINC1 Mutation (p.Met281Thr)

Abstract

Antithrombin (AT) is one of the physiological anticoagulants that are mainly synthesized in the liver. As a protease inhibitor belonging to the serpin superfamily, AT is able to inactivate thrombin and inhibit activated coagulation factors IX, X, XI, and XII (FIXa, FXa, FXIa, and FXIIa).[1] Moreover, it has been found that AT can inhibit activated FVII (FVIIa) by accelerating dissociation of FVIIa–tissue factor complex and preventing it from recombining.[2] The AT gene (SERPINC1), located on chromosome 1 at q23.1–23.9 and spreads 13.5 kb, is composed of seven extrons and six introns.[3] Hereditary AT deficiency is a rare thrombotic disorder caused by defects in SERPINC1 gene.[4] It is inherited in an autosomal-dominant manner with an incidence of roughly 0.02 to 0.25% in the general population and 2 to 5% in patients with a history of venous thromboembolism (VTE).[1] [5] The most common thrombotic manifestations of patients with AT deficiency are VTEs, and their risks of VTE are approximately 20 times higher than those of nondeficient individuals.[6] And the consequences of thrombophilia caused by AT deficiency are more severe than those of protein C and S protein deficiency,[2] so it should be given sufficient attention.

Publication History

Article published online:
25 May 2020

• References

• 1 Luxembourg B, Delev D, Geisen C. et al. Molecular basis of antithrombin deficiency. Thromb Haemost 2011; 105 (04) 635-646
• 2 Ding Q, Wang M, Xu G. et al. Molecular basis and thrombotic manifestations of antithrombin deficiency in 15 unrelated Chinese patients. Thromb Res 2013; 132 (03) 367-373
• 3 Olds RJ, Lane DA, Chowdhury V, De Stefano V, Leone G, Thein SL. Complete nucleotide sequence of the antithrombin gene: evidence for homologous recombination causing thrombophilia. Biochemistry 1993; 32 (16) 4216-4224
• 4 Kamijima S, Sekiya A, Takata M. et al. Gene analysis of inherited antithrombin deficiency and functional analysis of abnormal antithrombin protein (N87D). Int J Hematol 2018; 107 (04) 490-494
• 5 Tamura S, Hashimoto E, Suzuki N. et al. Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency. Thromb Res 2019; 178: 159-170
• 6 Bauer KA, Nguyen-Cao TM, Spears JB. Issues in the diagnosis and management of hereditary antithrombin deficiency. Ann Pharmacother 2016; 50 (09) 758-767
• 7 Zhang H, Liu S, Luo S. et al. Two novel mutations cause hereditary antithrombin deficiency in a Chinese family. Acta Haematol 2019; 3: 1-6
• 8 Picard V, Nowak-Göttl U, Biron-Andreani C. et al. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mutat 2006; 27 (06) 600