Hereditary Antithrombin Deficiency Research Articles

Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene

To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency. A pedigree diagnosed at the the Second Affiliated Hospital of Wenzhou Medical University, Yuying Children's Hospital in June, 2020 was selected as the study subject. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and thrombin time (TT) of the probands and their pedigree members were determined using a STA-R automatic coagulation analyzer. Antithrombin activity (AT: A) and antithrombin antigen (AT: Ag) in plasma were determined with chromogenic substrate and immunonephelometry assays. All exons and flanking sequences of the anticoagulant protein gene SERPINC1 were amplified by PCR and subjected to Sanger sequencing. Candidate variants were verified with bioinformatic tools (PolyPhen-2, SIFT, Mutation Taster and PYMOL) to explore their effect on the function and structural conformation of the protein. The probands (II-2, II-10), their brother (II-5) and sons (III-1, III-8) had shown normal PT, APTT, FIB, and TT, but significantly decreased AT: A and AT: Ag, with their levels being 34%, 57%, 56%, 48%, 53% and 13.51 mg/dL, 13.44 mg/dL, 18.39 mg/dL, 17.36 mg/dL, 17.71 mg/dL, respectively. The remaining pedigree members had normal values. Sanger sequencing revealed that the probands and all affected pedigree members had harbored a heterozygous c.851T>C (p.Met284Thr) missense variant in exon 5 of the SERPINC1 gene. Bioinformatic analysis and simulation suggested that the variant has resulted in alteration of hydrogen bonds at the c.851 position, which may affect the structure of the protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS1+PM1+PM5+PP1+PP4). The probands and other affected members were all diagnosed with type I hereditary AT deficiency, for which the c.851T>C (p.Met284Thr) variant of the SERPINC1 gene may be accountable.

PB0987 Hereditary Antithrombin Deficiency Pilot Project Registry from the American Thrombosis and Hemostasis Network (ATHN)

PB0987 Hereditary Antithrombin Deficiency Pilot Project Registry from the American Thrombosis and Hemostasis Network (ATHN)

Antithrombin Therapy: Current State and Future Outlook.

Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit.

Identification and functional analysis of three novel genetic variants resulting in premature termination codons in three unrelated patients with hereditary antithrombin deficiency.

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.

Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice.

Hereditary antithrombin deficiency is caused by SERPINC1 gene mutations and predisposes to recurrent venous thromboembolism that can be life-threatening. Therefore, lifelong anticoagulation is required, which has side effects and may not be effective. In this study, peripheral blood mononuclear cells from a patient with severe antithrombin deficiency were reprogrammed into induced pluripotent stem cells (iPSCs). The mutation was corrected using CRISPR-Cas9 and Cre/LoxP genome editing. iPSCs were differentiated into hepatocytes, which were injected into the spleen of antithrombin knockout mice to restore the activity of antithrombin and reduce the thrombophilic state. Human iPSC-differentiated hepatocytes colonized mice and secreted antithrombin stably, normalizing antithrombin in plasma (activity: from 46.8±5.7% to 88.6±7.6%, P<0.0001; antigen: from 146.9±19.5nanograms per milliliter to 390.7±16.1nanograms per milliliter, P<0.0001). In venous thrombosis model, the rate of thrombosis in mice treated with edited hepatocytes, parental hepatocytes, and wild-type mice were 60, 90, and 70%, respectively. The thrombus weight was much lighter in mice treated with edited hepatocytes compared with parental hepatocytes (7.25±2.00milligrams versus 15.32±2.87milligrams, P=0.0025) and showed no notable difference compared with that in wild-type mice (10.41±2.91milligrams). The activity and concentration of antithrombin remained high for 3 weeks after injection. The liver and kidney function markers showed no obvious abnormality during the observation period. This study provides a proof of principle for correction of mutations in patient-derived iPSCs and potential therapeutic applications for hereditary thrombophilia.

Hereditary Antithrombin Deficiency Pilot Project Registry from the American Thrombosis and Hemostasis Network (ATHN)

Background: Hereditary antithrombin deficiency (HAD) is a severe rare thrombophilia with an estimated prevalence of 0.02% to 0.2% in the general population. Patients with HAD have a high risk of developing arterial and venous thromboembolism (VTE). The purpose of ATHN 12: HAD Pilot Project is to collect data on participants diagnosed with HAD across the United States to better understand this rare thrombophilia and to develop guidelines regarding timing of screening for HAD, type of antithrombotic therapy, and indications for using antithrombin concentrate. The ATHN 12 study is sponsored by the American Thrombosis and Hemostasis Network (ATHN). ATHN will leverage its existing data collection infrastructure and its ATHN-affiliated network of 146 hemostasis and thrombosis treatment centers in the United States to identify a cohort of approximately 100 patients with HAD who are receiving care in these centers. Methods: We designed a national HAD registry to collect clinical, laboratory, and treatment data for participants with HAD with the goal of optimizing their management. The ongoing prospective HAD registry project (ATHN 12) was created in 2020 to identify a cohort of 100 adult and pediatric participants with HAD receiving care at thrombosis centers affiliated with ATHN. We collected information on demographics, laboratory data, thrombotic events, risk factors, antithrombotic therapy, and use of antithrombin (AT) concentrate during pregnancy and procedures. Results: 71 participants have been enrolled, 47 (66.2%) are female; mean age is 35 years (1-82); the majority 58 (82%) are White and 31 (43.6%) have type 1 HAD; 62 (87.32%) had a known diagnosis of HAD; 45 (63.38%) had a history of VTE (Table 1). The most common VTE locations included: lower extremity deep vein thrombosis 51 events (57%) and pulmonary embolisms 23 events (26%). 23 participants (51%) had recurrent VTEs. 4 participants (5.5%) had history of arterial thrombosis (AT) and 1 (25%) had a recurrent event. Of 45 participants, 17 (38%) had no other known risk factors for VTE; 21 (46.5%) were estrogen-related; 11 (24.4%) occurred after surgery, prolonged immobilization, hospitalization, travel, or trauma (Table 1). A total of 173 anticoagulants were prescribed on 45 (63.38%) participants (Table 2) There were 87 pregnancies in 37 women. Low molecular weight heparin (LMWH) was administered in 46% of the pregnancies and in 3 women LMWH was switched to UFH between 36 to 38 weeks of gestation. AT concentrate was administered in 22 (25%) of the pregnancies before delivery and in 14 pregnancies 24 hours post-delivery. 31 women (36%) restarted anticoagulation post-delivery. The earliest initiation of anticoagulation was 6 hours after delivery. Overall, there were 34 (39%) pregnancy complications: 23 pregnancy losses mainly in first trimester, 4 thrombosis, 4 pre-eclampsia, and 6 other complications (Table 2). 59 participants (83%) had a total of 171 surgeries or procedures. The most frequent surgeries were gastrointestinal, and the most common procedures were vascular (Table 2). Overall, 28 (39.4%) have received AT concentrate without adverse events. Conclusions: VTE was the most frequent clinical manifestation with DVT accounting for 57% of events and PE 26%. Oral factor Xa inhibitors were the most common anticoagulants prescribed. LMWH was administered in almost half of the pregnancies and AT concentrates in 25% of the pregnancies before delivery, and in 39.4% overall in pregnancies and procedures without reported adverse events. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional Characterization of Antithrombin Mutations by Monitoring of Thrombin Inhibition Kinetics.

Inactivation of thrombin by the endogenous inhibitor antithrombin (AT) is a central mechanism in the regulation of hemostasis. This makes hereditary AT deficiency, which is caused by SERPINC1 gene mutations, a major thrombophilic risk factor. Aim of this study was to assess to what extent AT mutations impair thrombin inhibition kinetics. The study population included 36 thrombophilic patients with 19 different mutations and mean AT levels of 65% in a thrombin-based functional assay, and 26 healthy controls. To assess thrombin inhibition kinetics, thrombin (3.94 mU/mL final concentration) was added to citrated plasma. Subsequently, endogenous thrombin inhibition was stopped by addition of the reversible thrombin inhibitor argatroban and the amount of argatroban-complexed thrombin quantified using an oligonucleotide-based enzyme capture assay. The plasma half-life of human thrombin was significantly longer in patients with AT mutations than in the controls (119.9 versus 55.9 s). Moreover, it was disproportionately prolonged when compared with preparations of wild type AT in plasma, in whom a comparable thrombin half-life of 120.8 s was reached at a distinctly lower AT level of 20%. These findings may help to better understand the increased thrombotic risk of SERPINC1 mutations with near normal AT plasma levels in functional assays.

Ilio-femoral venous thrombosis with hereditary antithrombin deficiency: a case report of rare thrombotic disease and successful treatment with catheter directed thrombolysis

BackgroundHereditary 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 summaryA 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.DiscussionThis 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.

Тромботические события при редких формах генетических тромбофилий

Цель исследования: изучить лабораторный фенотип редких мутаций Лейдена [FVL А(1961)A] и гена протромбина [FII А(20210)A] при их клинической реализации в виде тромбозов. Материалы и методы. Проведено многоцентровое проспективное наблюдательное исследование, включающее 80 носителей редких генетических форм тромбофилий: FVL А(1961)A (n = 31), FII А(20210)A (n = 10) и компаунд FII G(20210)A + FVL G(1691)A (n = 39). У всех пациентов исследована резистентность фактора Va к активированному протеину С (APC-R) по нормализованному отношению (НО) и уровень активности протромбина в плазме крови в состоянии физического здоровья и в случае эпизода тромботического события. Результаты. Определена ассоциативная связь развития тромботических событий со снижением НО при оценке APC-R как у гомозиготных носителей мутации Лейден (Ме = 0,35; 95% ДИ = 0,31–0,37 по НО), так и гетерозиготных компаундов (Ме = 0,43; 95% ДИ = 0,42–0,45 по НО). Заключение. Лабораторный мониторинг пациентов с редкими формами генетических тромбофилий позволяет выделить группу высокого тромбогенного риска, нуждающуюся в пролонгированной тромбопрофилактике. Objectives: to study the laboratory phenotype of rare Leiden mutation [FVL A(1961)A] and the prothrombin gene mutation [FII А(20210)A] implementating clinically as thrombosis. Patients / Methods. A multicenter prospective observational study included 80 carriers of rare genetic kinds of thrombophilia: FVL A(1961)A (n = 31), prothrombin FII А(20210)A (n = 10) and the compound FII G(20210)A + FVL G(1691)A (n = 39). All patients were tested for the factor Va resistance to activated protein C (APC-R), normalized ratio (NR), and the plasma prothrombin activity (%) in healthy conditions and in the case of thrombotic event. Results. An associative relation between the development of thrombotic events and a decrease in NR was determined when assessing APC-R, both in homozygous carriers of the Leiden mutation (Me = 0.35; 95% CI = 0.31–0.37 in NR) and heterozygous compounds (Me = 0.43; 95% СI = 0.42–0.45 in NR). Conclusions. Laboratory follow up for patients with rare kinds of genetic thrombophilias allows to identify a group at high thrombogenic risk requiring prolonged thromboprophylaxis.

Clinical and genetic analysis of a pedigree affected with type I hereditary antithrombin deficiency due to a g.2736dupT variant of the AT gene

To analyze the phenotype and genotype of a patient affected with inherited antithrombin deficiency. All exons and exon-intron boundaries of the AT genes were subjected to PCR amplification and Sanger sequencing. The influence of variants on the disease was predicted using bioinformatic software (MutationTaster). The results of all coagulation tests were normal, though the antithrombin activity and antigen content of the proband and his father have decreased significantly (34%, 48% and 12.97 mg/dL, 15.60 mg/dL, respectively). His mother was normal. Genetic analysis revealed that the proband and his father both carried a heterozygous g.2736dupT variant of the AT gene. Bioinformatic analysis suggested that the variant may be pathogenic. The proband and his father both had type I hereditary antithrombin deficiency caused by a g.2736dupT variant of the AT gene. The variant was unreported previously.

Antithrombin p.Thr147Ala: The First Founder Mutation in People of African Origin Responsible for Inherited Antithrombin Deficiency.

Hereditary antithrombin deficiency is a rare autosomal-dominant disorder predisposing to recurrent venous thromboembolism (VTE). To date, only two founder mutations have been described. We investigated the antithrombin p.Thr147Ala variant, found in 12 patients of African origin. This variant is known as rs2227606 with minor allele frequency of 0.5% in Africans and absent in Europeans. A possible founder effect was investigated. Phenotypical characterization was established through immunological and functional methods, both under basal and stress conditions. Recombinant antithrombin molecules were constructed by site-directed mutagenesis and expressed in HEK-293T cells. Secreted antithrombin was purified and functionally characterized. Structural modeling was performed to predict the impact of the mutation on protein structure. A novel nanopore sequencing approach was used for haplotype investigation. Ten patients experienced VTE, stroke, or obstetric complications. Antithrombin antigen levels and anti-IIa activity were normal or slightly reduced while anti-Xa activity was reduced with only one commercial assay. On crossed immunoelectrophoresis, an increase of antithrombin fractions with reduced heparin affinity was observed under high ionic strength conditions but not under physiological conditions. The recombinant p.Thr147Ala protein displayed a reduced anti-Xa activity. Structural modeling revealed that residue Thr147 forms three hydrogen bonds that are abolished when mutated to alanine. The investigated patients shared a common haplotype involving 13 SERPINC1 intragenic single nucleotide polymorphisms. Antithrombin p.Thr147Ala, responsible for antithrombin type II heparin binding site deficiency, is the first founder mutation reported in people of African ancestry. This study further emphasizes the limitations of commercial methods to diagnose this specific subtype.

Novel SERPINC1 missense mutation (Cys462Tyr) causes disruption of the 279Cys-462Cys disulfide bond and leads to type Ⅰ hereditary antithrombin deficiency

BackgroundAntithrombin (AT) is the primary physiological anticoagulant of normal hemostasis. Hereditary AT deficiency, an autosomal dominant thrombotic disease caused by mutations in the AT gene (SERPINC1), is associated with venous thromboembolism. ObjectiveWe investigated the phenotypes, genotypes, and pathogenesis of hereditary AT deficiency in a 12-year-old boy (proband) who developed a pulmonary embolism and a subsequent deep vein thrombosis. MethodsThe AT activity and AT antigen level of the proband and his family members were measured. Mutation sites in all seven exons of SERPINC1 were identified. Analysis of conserved regions around codon 462 of the SERPINC1 gene and functional predictions were performed using bioinformatics tools. ResultsThe proband, his father, and his paternal grandmother demonstrated reduced AT activity and antigen levels consistent with Type I AT deficiency. A novel heterozygous missense mutation, c.1385G>A (Cys462Tyr) was identified in all three symptomatic family members. This missense mutation causes disruption of the 279Cys-462Cys disulfide bond and leads to type Ⅰ hereditary AT deficiency. ConclusionA SERPINC1 missense mutation (Cys462Tyr) causing damage to the 279Cys-462Cys disulfide bond of the AT protein appears to be the cause of Type I AT deficiency in this family. These findings indicate one pathological mechanism associated with hereditary AT deficiency.

New genetic variant in the SERPINC1 gene: hereditary Antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling

BackgroundInherited deficiency of the antithrombin (hereditary antithrombin deficiency, AT deficiency, OMIM #613118) is a relatively rare (1:2000–3000) autosomal-dominant disorder with high risk of venous thromboembolism. Mutations in the serpin family C member 1 gene (SERPINC1) can lead to Quantitative (type I) and Qualitative (type II) types of antithrombin deficiency. We describe a new genetic variant in the SERPINC1 gene and our approach to variant interpretation.Case presentationWe observed a 29 y.o. female proband with the episode of venous thrombosis at the age of 18 and family history of thrombosis. The antithrombin level in our patient was low, 44–48% (AT deficiency type I). A new genetic variant c.662G > C (p.W221S) in the SERPINC1 gene was detected in proband and affected father but was absent in healthy sister. We used in silico tools to evaluate the possible impact of p.W221S variant on protein structure and function. In mutated SERPINC1 protein a new N-linked glycosylation site is formed, however, it is unclear if the glycosylation at 219–221 site is possible.ConclusionThe proband was provided with appropriate genetic counseling and referred to a hematologist. Based on all the evidence we classify the p.W221S variant as variant of unknown clinical significance. In this paper we discuss some aspects of genetic counseling, variant interpretation and thromboembolic prophilaxis.

Thromboprophylaxis with antithrombin gamma and unfractionated heparin for a pregnant woman complicated by hereditary antithrombin deficiency.

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.

Two Novel Mutations Cause Hereditary Antithrombin Deficiency in a Chinese Family

Objective: To study the molecular basis of hereditary antithrombin (AT) deficiency in a Chinese family. It will help us understand the pathogenesis of this type of disease. Method: AT activity (AT:A) and the AT antigen (AT:Ag) level were tested by chromogenic substrate and immunoturbidimetry, respectively. To identify the novel mutations, SERPINC1 gene sequencing was carried out. The possible impact of the mutations was analyzed by model and bioinformatic analyses. Results: AT:A and the AT:Ag level of the proband were 43% and 113 mg/L (normal range: 98–119% and 250–360 mg/L), respectively. Sequencing analysis revealed compound heterozygous mutations, including a frameshift mutation (c.318_319insT) resulting in Asn75stop and a missense mutation (c.922G>T) resulting in Gly276Cys. The bioinformatic and model analyses indicated that these mutations may disrupt the function and structure of the AT protein. Conclusion: We detected 2 novel heterozygous mutations (c.318_319insT and c.922G>T) in the proband, and these were associated with decreased AT:A.

SERPINC1 variants causing hereditary antithrombin deficiency in a Danish population

IntroductionAntithrombin deficiency is associated with increased risk of venous thromboembolism (VTE). We aimed to identify variants causing antithrombin deficiency in a Danish population. Materials and methodsWe performed Sanger sequencing and, in relevant cases, multiplex ligation-dependent probe amplification analyses, in 46 individuals (23 index cases) with and 9 relatives without antithrombin deficiency. Furthermore, in order to explore whether a combination of antithrombin type II heparin binding site (HBS) deficiency and factor V Leiden single nucleotide variant (SNV) conferred a higher risk of VTE than either risk factor alone, we performed genotyping for factor V Leiden in most of the carriers of type II HBS deficiency (n = 25). ResultsWe detected causal variants in all 46 carriers: three large and two small deletions, all causing type I antithrombin deficiency, and seven SNVs: one causing type I, one causing type II reactive site (RS), four causing type II HBS and one causing pleiotropic effect (PE) type II antithrombin deficiency. None of the relatives without antithrombin deficiency had the family variant. All detected SNVs have been reported previously. Majority (n = 27) of carriers had type II HBS deficiency, most often caused by the p.(Pro73Leu) SNV (n = 19). Heterozygosity for factor V Leiden was observed in three (3/25 = 12%) carriers of type II HBS deficiency. Only four (4/25 = 16%) carriers of type II HBS antithrombin deficiency experienced VTE, and two of these were heterozygous for factor V Leiden. ConclusionsIn a systematic search to identify variants causing hereditary antithrombin deficiency in a Danish population, we achieved a variant detection rate of 100%.

Association of hereditary antithrombin deficiency with intrauterine growth restriction

: Antithrombin is a major suppressor of thrombin, factor Xa and blood coagulation. Inherited antithrombin deficiency is rare and is considered among the common causes of inherited thrombophilia. The relationship between antithrombin and IUGR, is questionable. The aim of this study was to trace the relationship between antithrombin deficiency and the intrauterine weight reduction and neonatal morbidity. The study was conducted on 55 full-term neonates (including 25 baby boys and 30 baby girls), all were admitted to Neonatal Intensive Care Unit in Cairo University Hospitals with IUGR; and another 110 healthy full-term neonates as control group. ATIII activities were assessed in citrated of patient and control samples automatically on coagulometer (Stago, France). There was a highly significant relationship regarding ATIII deficiency in IUGR group in relation to control group (P value <0.001). In conclusion, we have identified antithrombin deficiency in Egyptian infants as an additional cause for low-birth weight and intrauterine growth retardation.

β-Antithrombin, subtype of antithrombin deficiency and the risk of venous thromboembolism in hereditary antithrombin deficiency: A family cohort study

Hereditary antithrombin deficiency is associated with a high incidence of venous thromboembolism (VTE), but VTE risk differs between families. Beta-antithrombin is reported to be the most active isoform of antithrombin in vivo. Whether β-antithrombin activity and subtypes in antithrombin deficiency have impact on VTE risk has not been investigated outside the proband setting.We performed a retrospective family cohort study to investigate whether subtypes of antithrombin deficiency or β-antithrombin levels are associated with the risk of first or recurrent VTE.Eighty-one subjects from 21 families were included, of which 52 were antithrombin deficient. Βeta-antithrombin levels were decreased in most type I and type IIPE subjects, but normal levels were found in all subtypes of antithrombin deficiency.The annual incidence of VTE in antithrombin-deficient family members was 1.24%, 95%CI: 0.72–1.99%, in low β-antithrombin 1.36% (95%CI: 0.76–2.25%) and in normal β-antithrombin 0.79% (95%CI: 0.10–2.77). The annual incidence of recurrence in family members was 3.1% (95%CI: 0.9–7.1%). Duration of anticoagulation had an impact on recurrence risk: In family members annual recurrence with fixed duration was 10% (95%CI: 2.1–29.2%), with indefinite duration 1.5% (95%CI: 0.2–5.4%), p < 0.05. Beta-antithrombin levels were not associated with the risk for first or recurrent VTE in antithrombin deficient subjects. ConclusionsIn this high-risk antithrombin-deficient population, both subjects with low and normal plasma β-antithrombin activity had high risks of first and recurrent VTE. This puts the importance of β-antithrombin into question. Long-term anticoagulation is warranted in antithrombin-deficient VTE patients.

Activated Factor X-Based versus Thrombin-Based Antithrombin Testing in Thrombophilia Workup in the DOAC Era.

Antithrombin (AT) activity tests are used for diagnosing hereditary AT deficiency, a main genetic determinant of thrombophilia. They are either based on inhibition of thrombin (FIIa) or activated factor X (FXa). FXa-based assays have been suggested to be preferable to FIIa-based assays due to their higher sensitivity for certain AT deficiency causing mutations. To assess the performance of these two methods in a real-world scenario, 745 consecutively collected samples from patients referred to our institute during a 3-month period for thrombophilia testing were analysed. In samples from patients not receiving direct-acting oral anticoagulants or heparins (n = 485), both methods showed good agreement (r = 0.874, Bland-Altman limits of agreement 6.57%, -15.76%). While similar results were obtained in patients receiving low-molecular-weight heparin (LMWH, n = 76, r = 0.891, 4.09%, -14.35%), the agreement was lower in patients receiving rivaroxaban (n = 86, r = 0.570, 5.97%, -49.43%) and apixaban (n = 72, r = 0.735, 3.77%, -42.45%). Direct FXa inhibitors but not LMWH increased FXa-based assay results in a dose-dependent manner, while the FIIa-based test was unaffected. Both assay types were equally successful in detecting hereditary AT deficiency in our study population, as samples from 9 out of 10 patients with AT deficiency causing mutations were detected by each method. These data suggest that FXa-based AT testing can be preferred over FIIa-based methods only in the absence of direct FXa inhibitors. In patients receiving direct FXa inhibitors, AT activity testing should be performed using FIIa-based assays.

Management of hereditary antithrombin deficiency in pregnancy

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency.