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Abstract 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.

Ana Marco-Rico,1,2 Pascual Marco-Vera2,3 1Hemostasis and Thrombosis Department, Hematology Service, University General Hospital Dr. Balmis, Alicante, Spain; 2Biomedical Research Institute (ISABIAL), Alicante, Spain; 3Clinical Medicine Department, Miguel Hernández University, Alicante, SpainCorrespondence: Ana Marco-Rico, Hemostasis and Thrombosis Department, Hematology Service, University General Hospital Dr. Balmis, Pintor Baeza Avenue, 12, Alicante, 03010, Spain, Tel +34 965913863, Fax +34 965913869, Email marco_anaric@gva.esAbstract: 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.Keywords: hereditary antithrombin deficiency, thrombosis, anticoagulation, heparin resistance, SERPINC1 gene mutation

• 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]

Hereditary antithrombin (AT) deficiency is an autosomal dominant inherited thrombophilia. In three pedigrees of hereditary type I AT deficiency, we identified novel variants c.126delC (p.Lys43Serfs*7), c.165C > G (p.Tyr55*), and c.546delA (p.Lys182Asnfs*102) in the open reading frame encoding AT in each patient. Each of these aberrant variants leads to premature termination of AT protein synthesis. To investigate whether these abnormal variants are involved in the pathogenesis of type I AT deficiency, we analyzed the function of these variants in HEK293 cells. Results of western blot analysis and immunofluorescence microscopy showed that all abnormal variants were expressed intracellularly, but p.Lys43Serfs*7 and p.Tyr55* protein were aggregated in the cells. These three variants were not detected in the spent culture medium, indicating that these novel variants affect protein secretion. In summary, we suggest that these variants in the AT-encoding gene are translated in the cell, but form abnormal proteins that form aggregates and/or inhibit secretion. These results provide insight into novel mechanisms of type I AT deficiency and potential therapies for the condition. [ABSTRACT FROM AUTHOR]

Background: Patients with hereditary antithrombin deficiency (HAD) have an increased risk of venous thromboembolism (VTE). The American Thrombosis and Hemostasis Network (ATHN) 12: HAD Pilot Project established a registry to collect data on patients with HAD., Objectives: To inform current practice and serve as a platform to design a multicenter global registry for patients with HAD., Methods: The HAD registry was designed in 2020 to identify 100 patients with HAD receiving care at ATHN-affiliated centers. Demographics, type of HAD, thrombotic events, risk factors, anticoagulants, and antithrombin (AT) concentrate administration were recorded., Results: Ninety-four patients were included; 65% were females; 51% had type 1 HAD. Mean age at diagnosis was 26 years (SD, 18 years); 61% had VTE: 55% deep vein thrombosis and 27% pulmonary embolisms. Eight patients had arterial thrombosis. Recurrent thrombosis occurred in 58.6% of patients (44.8%) despite anticoagulation. The main risk factor for thrombosis in females was estrogen. Direct oral anticoagulants were prescribed in 30%, heparin in 34%, and warfarin in 32%. There were 139 pregnancies. Low-molecular-weight heparin was administered in 33% and AT concentrate in 19% and 11% prior to and after delivery, respectively. Twelve patients developed thrombosis in pregnancy. Seventy-nine patients underwent 239 surgeries or procedures, mainly gastrointestinal and vascular. Overall, 35% of participants received AT concentrate without adverse events., Conclusion: In ATHN 12, VTE was the predominant manifestation, frequently recurrent. There was a trend toward using direct oral anticoagulants. Low-molecular-weight heparin was administered in one-third of pregnancies and AT concentrate in one-fifth without adverse events. These data should encourage prospective studies to optimize the management of these patients., Competing Interests: Declaration of competing interests M.T.D.: participation on Pharmacosmos Advisory Board and member of American Society of Hematology Panel on Practice Guidelines for Anticoagulation in COVID-19. E.S.: no conflict of interest. J.C.R.: has received honorarium from F. Hoffman-La Roche AG, Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, and Takeda. M.D.T.: received consulting fees from Pfizer, Sanofi, Sobi-Swedish Orphan, Biovitrum, Takeda Amgen, Octapharma Inc, Genentech, BioMarin, UCB Biosciences Dova Pharmaceuticals, and Novo Nordisk and payment/honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational event from Sobi-Swedish Orphan Biovitrum, Genentech, Amgen, Novartis, BioMarin, and Sanofi. J.S.: no conflict of interest. J.C.: no conflict of interest. M.R.: consulting for Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, and uniQure and leadership or fiduciary role in Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders, Thrombosis and Hemostasis Societies of North America., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Although P5 (preventive, personalized, predictive, participatory, psychocognitive) medicine and patient-focused healthcare are gaining ground in various healthcare areas, the diagnosis of antithrombin deficiency (ATD) is still based on crude diagnostic tests, clustering patients into clinically heterogeneous subgroups whereby relevant thrombophilia phenotypes may go unnoticed. Clinical pathways and the majority of evidence are based on these tests; therefore, generic treatment is still the norm., Objectives: To unravel the heterogeneity of ATD, a mass spectrometry (liquid chromatography coupled to multiple-reaction-monitoring mass spectrometry [LC-MRM-MS])-based test for antithrombin was developed allowing molecular characterization of the antithrombin proteoforms in patient plasma. This study provides the first insight into the tests' clinical performance., Methods: Plasma from 91 unrelated ATD patients and 41 patients with a congenital disorder of glycosylation affecting antithrombin glycosylation were characterized functionally, genetically, and analyzed by LC-MRM-MS. An established data analysis strategy was applied for quantitation and molecular characterization of antithrombin proteoforms., Results: The test recognized patients with a quantitative defect, discriminated between type I and type II ATD, and identified variant proteoforms. Overall, the diagnostic sensitivity for ATD was 100% for LC-MRM-MS compared with 81.1% by the functional test. Type II ATD, a subtype prone to misdiagnosis, revealed an even larger difference of 100% identification by LC-MRM-MS vs 56.8% by functional test., Conclusion: The qualitative and quantitative mass spectrometry-based AT-test can serve as a platform for investigating the molecular basis of the clinical heterogeneity of ATD. This "precision diagnostics" approach for ATD can lower diagnostic uncertainty and modernize the ATD diagnostic and clinical pathways., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Hereditary antithrombin (AT) deficiency is an uncommon autosomal dominant thrombogenic disorder, which can cause venous thromboembolism (VTE). Although conservative treatment options for hereditary AT deficiency-associated VTE such as anticoagulation (warfarin, direct oral anticoagulant, or heparin), intravenous thrombolysis, and recombinant AT are well known, interventional treatment options have not been reported so far. Case summary A 19-year-old man with a family history of thrombogenic diseases, referred to our hospital with left leg pain, was diagnosed with AT deficiency-associated VTE. In the absence of symptomatic relief with intravenous thrombolysis and anticoagulation, he received venous intervention and catheter directed thrombolysis (CDT) for 4 days for left iliac venous thrombosis. Following a second venous intervention, venous thrombus disappeared almost entirely on cross-sectional imaging, and his symptoms improved. He was discharged on apixaban and has been recurrence-free for one and a half years. Discussion This case presents CDT and maintenance therapy with apixaban as possible treatment options for VTE in patients with hereditary AT deficiency, especially following failure of conservative therapy. Individual risks and benefits should be considered when CDT is performed for acute VTE in patients with AT deficiency. [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]

Background: Hereditary antithrombin (AT) deficiency is an uncommon autosomal dominant thrombogenic disorder, which can cause venous thromboembolism (VTE). Although conservative treatment options for hereditary AT deficiency-associated VTE such as anticoagulation (warfarin, direct oral anticoagulant, or heparin), intravenous thrombolysis, and recombinant AT are well known, interventional treatment options have not been reported so far., Case Summary: A 19-year-old man with a family history of thrombogenic diseases, referred to our hospital with left leg pain, was diagnosed with AT deficiency-associated VTE. In the absence of symptomatic relief with intravenous thrombolysis and anticoagulation, he received venous intervention and catheter directed thrombolysis (CDT) for 4 days for left iliac venous thrombosis. Following a second venous intervention, venous thrombus disappeared almost entirely on cross-sectional imaging, and his symptoms improved. He was discharged on apixaban and has been recurrence-free for one and a half years., Discussion: This case presents CDT and maintenance therapy with apixaban as possible treatment options for VTE in patients with hereditary AT deficiency, especially following failure of conservative therapy. Individual risks and benefits should be considered when CDT is performed for acute VTE in patients with AT deficiency., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

A 37-year-old woman developed deep venous thrombosis (DVT) of the left lower extremity at 8 weeks of gestation during her second pregnancy. There was no personal or family history of thrombosis. She received intravenous heparin, but heparin resistance was noted. The plasma antithrombin activity decreased to 45% in the acute phase, and it remained low postpartum. Her mother also had low plasma antithrombin activity (46%), and genetic testing revealed a heterozygous SERPINC1 mutation. Even without a family history of thrombosis, we should suspect hereditary antithrombin deficiency in patients with initial DVT and perform thorough investigation.

Objective: Hereditary antithrombin (AT) deficiency increases the risk of venous thromboembolism (VTE) in pregnant woman. We report the first case of administration of recombinant human antithrombin (rhAT) to a pregnant Japanese woman with AT deficiency., Case Report: A 30-year-old woman, gravida 2 para 0, was referred to our hospital because of AT deficiency. Unfractionated heparin was administered from 13 weeks of gestation and rhAT was administered from labor onset. A cesarean section was performed and the patient and her baby were healthy, with no sequelae., Conclusion: We concluded that rhAT was effective for preventing VTE during delivery, with no potential infection risks., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To review insights gained in the past several years about hereditary antithrombin (AT) deficiency and to outline approaches to the management of patients with AT deficiency in the acute and chronic settings., Data Sources: An extensive literature search of Scopus (January 2008-April 2016) was performed for the terms congenital antithrombin deficiency, inherited antithrombin deficiency, or hereditary antithrombin deficiency Additional references were identified by reviewing literature citations., Study Selection: All relevant English-language case reports, reviews, clinical studies, meeting abstracts, and book chapters assessing hereditary AT deficiency were included., Data Synthesis: AT deficiency significantly increases the risk of venous thromboembolism (VTE). The risk of VTE is particularly high during pregnancy, the postpartum period, and following major surgery. Effective clinical management includes determination of the appropriate type and duration of antithrombotic therapy (ie, AT replacement for acute situations) while minimizing the risk of bleeding. For persons newly diagnosed with AT deficiency, age, lifestyle, concurrent medical conditions, family history, and personal treatment preferences can be used to individualize patient management. Patients should be informed of the risks associated with hormonal therapy, pregnancy, surgical procedures, and immobility, which further increase the risk of VTE in patients with AT deficiency., Conclusion: AT deficiency poses the highest risk for VTE among the hereditary thrombophilias, often requiring long-term anticoagulation. Undertaking an evaluation for hereditary thrombophilia is controversial; however, a diagnosis of VTE in association with AT deficiency can have management implications. An important treatment option for patients with this disorder in high-risk situations is AT concentrate., (© The Author(s) 2016.)