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Background: Antithrombin (AT) is an important anticoagulant in hemostasis. We describe here the characterization of a novel AT mutation associated with clinically relevant thrombosis. A pair of sisters with confirmed type I AT protein deficiency was genetically analyzed on suspicion of an inherited SERPINC1 mutation. A frameshift mutation, c.1247dupC, was identified and the effect of this mutation was examined on the cellular and molecular level. Methods: Plasmids for the expression of wild-type (WT) and mutated SERPINC1 coding sequence (CDS) fused to green fluorescent protein (GFP) or hemagglutinin (HA) tag were transfected into HEK293T cells. Subcellular localization and secretion of the respective fusion proteins were analyzed by confocal laser scanning microscopy and Western blot. Results: The c.1247dupC mutation results in a frameshift in the CDS of the SERPINC1 gene and a subsequently altered amino acid sequence (p.Ser417LysfsTer48). This alteration affects the C-terminus of the AT antigen and results in impaired secretion as confirmed by GFP- and HA-tagged mutant AT analyzed in HEK293T cells. Conclusion: The p.Ser417LysfsTer48 mutation leads to impaired secretion, thus resulting in a quantitative AT deficiency. This is in line with the type I AT deficiency observed in the patients. [ABSTRACT FROM AUTHOR]

• We identified a novel SERPINC1 gene mutation (c.1A>G p.Met1Val). • The p.Met1Val mutation is associated with significantly lower antithrombin levels and an increased risk of early venous thromboembolism. • Heparin therapy may be ineffective for venous thromboembolism caused by p.Met1Val mutation of SERPINC1 gene. • Novel oral anticoagulants may have favorable anticoagulant effects. [ABSTRACT FROM AUTHOR]

Congenital antithrombin (AT) deficiency represents the form of thrombophilia with the highest thrombotic risk. It is characterized by a heterogeneous clinical presentation, depending mostly on the family history of thrombosis and type of genetic mutation. Inherited AT deficiency promotes idiopathic thrombosis at an early age (even in the pediatric population) and at atypical sites. Therefore, a positive family background necessitates ruling out this high-risk thrombophilia at a young age. Studying first-degree relatives, even if they are asymptomatic, is essential to establish thromboprophylaxis and a proper therapeutic approach in case of thrombosis. Patients with congenital AT deficiency require indefinite anticoagulation owing to the high thrombotic recurrence rate. Here, we present four unrelated cases reported in our institution who were diagnosed with hereditary AT deficiency, with a contrasting clinical evolution. [ABSTRACT FROM AUTHOR]

Antithrombin replacement using recombinant human antithrombin (antithrombin gamma) is a well‐tolerated treatment and effective as thromboprophylaxis for a pregnant woman with hereditary antithrombin deficiency. [ABSTRACT FROM AUTHOR]

Goal--The goal of this program is to educate pharmacists about the use of recombinant antithrombin in patients with hereditary antithrombin deficiency. Objectives--At the completion of this program, the reader will be able to: 1. Describe the pharmacology and pharmacokinetics of recombinant antithrombin. 2. Discuss the risks associated with the use of recombinant antithrombin. 3. Discuss the potential benefit of recombinant antithrombin for an individual patient. 4. Apply the information on the use of recombinant antithrombin to a case study. [ABSTRACT FROM AUTHOR]