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1.
Medicine (Baltimore) ; 103(10): e37429, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457560

RESUMO

BACKGROUND: Thrombophilia is a coagulation disorder closely associated with venous thromboembolism. Hereditary antithrombin III (AT III) deficiency is a type of genetic thrombophilia. In China, genetic thrombophilia patients mainly suffer from deficiencies in AT III, protein S, and protein C. Multiple mutations in the serpin family C member 1 (SERPINC1) can affect AT III activity, resulting in thrombosis. CASE PRESENTATION: This case presented a 17-year-old adolescent female who developed lower extremity venous thrombosis and subsequently pulmonary embolism (PE) following a right leg injury. A missense mutation in gene SERPINC1 of c.331 T > C, p.S111P was detected on the patient, resulting in a decreased AT III activity and an elevated risk of thrombosis. The patient received anticoagulation treatment for approximately 5 months. During follow-up, the blood clot gradually dissolved, and there have been no recurrent thrombotic events reported thus far. DISCUSSION: Hereditary AT deficiency can be classified into two types based on the plasma levels of the enzymatic activity and antigen. Type I is a quantitative defect, while Type II is a qualitive defect. Until 2021, 486 SERPINC1 gene mutations have been registered, more than 18% of which are point mutations. The SERPINC1 mutation c.331 T > C in was firstly reported in 2017, which was classified into type I AT III deficiency. CONCLUSION: Hereditary thrombophilia is a coagulation disorder with a high omission diagnostic rate. Minor mutations in the SERPINC1 gene can also lead to hereditary AT III deficiency, which in turn can cause PE. We emphasized the importance of etiological screening for hereditary thrombophilia in venous thromboembolism patients without obvious high-risk factors. Long-term anticoagulation treatment and avoidance of potential thrombosis risk factors are critical for such patients.


Assuntos
Deficiência de Antitrombina III , Embolia Pulmonar , Trombofilia , Trombose , Tromboembolia Venosa , Adolescente , Humanos , Feminino , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/genética , Tromboembolia Venosa/genética , Trombose/genética , Embolia Pulmonar/genética , Anticoagulantes/uso terapêutico
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(3): 312-316, 2024 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-38448020

RESUMO

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency. METHODS: 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. RESULTS: 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). CONCLUSION: 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.


Assuntos
Deficiência de Antitrombina III , Masculino , Criança , Humanos , Deficiência de Antitrombina III/genética , Linhagem , Éxons , Fibrinogênio , Anticoagulantes , Antitrombinas , China , Antitrombina III/genética
3.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474138

RESUMO

Antithrombin (AT) is the major plasma inhibitor of thrombin (FIIa) and activated factor X (FXa), and antithrombin deficiency (ATD) is one of the most severe thrombophilic disorders. In this study, we identified nine novel AT mutations and investigated their genotype-phenotype correlations. Clinical and laboratory data from patients were collected, and the nine mutant AT proteins (p.Arg14Lys, p.Cys32Tyr, p.Arg78Gly, p.Met121Arg, p.Leu245Pro, p.Leu270Argfs*14, p.Asn450Ile, p.Gly456delins_Ala_Thr and p.Pro461Thr) were expressed in HEK293 cells; then, Western blotting, N-Glycosidase F digestion, and ELISA were used to detect wild-type and mutant AT. RT-qPCR was performed to determine the expression of AT mRNA from the transfected cells. Functional studies (AT activity in the presence and in the absence of heparin and heparin-binding studies with the surface plasmon resonance method) were carried out. Mutations were also investigated by in silico methods. Type I ATD caused by altered protein synthesis (p.Cys32Tyr, p.Leu270Argfs*14, p.Asn450Ile) or secretion disorder (p.Met121Arg, p.Leu245Pro, p.Gly456delins_Ala_Thr) was proved in six mutants, while type II heparin-binding-site ATD (p.Arg78Gly) and pleiotropic-effect ATD (p.Pro461Thr) were suggested in two mutants. Finally, the pathogenic role of p.Arg14Lys was equivocal. We provided evidence to understand the pathogenic nature of novel SERPINC1 mutations through in vitro expression studies.


Assuntos
Deficiência de Antitrombina III , Antitrombinas , Humanos , Antitrombinas/química , Células HEK293 , Anticoagulantes , Heparina/metabolismo , Mutação , Deficiência de Antitrombina III/genética
4.
Blood Coagul Fibrinolysis ; 35(2): 43-48, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38179715

RESUMO

Antithrombin is an essential protein that acts as a natural anticoagulant in the human body. It is synthesized by the liver and belongs to the serine protease inhibitors, which are commonly referred to as the SERPINS superfamily. The antithrombin molecule comprises 432 amino acids and has a molecular weight of approximately 58 200 D. It consists of three domains, including an amino-terminal domain, a carbohydrate-rich domain, and a carboxyl-terminal domain. The amino-terminal domain binds with heparin, whereas the carboxyl-terminal domain binds with serine protease. Antithrombin is a crucial natural anticoagulant that contributes approximately 60-80% of plasma anticoagulant activities in the human body. Moreover, antithrombin has anti-inflammatory effects that can be divided into coagulation-dependent and coagulation-independent effects. Furthermore, it exhibits antitumor activity and possesses a broad range of antiviral properties. Inherited type I antithrombin deficiency is a quantitative disorder that is characterized by low antithrombin activity due to low plasma levels. On the other hand, inherited type II antithrombin deficiency is a qualitative disorder that is characterized by defects in the antithrombin molecule. Acquired antithrombin deficiencies are more common than hereditary deficiencies and are associated with various clinical conditions due to reduced synthesis, increased loss, or enhanced consumption. The purpose of this review was to provide an update on the structure, functions, clinical implications, and methods of detection of antithrombin.


Assuntos
Deficiência de Antitrombina III , Antitrombinas , Humanos , Antitrombinas/uso terapêutico , Antitrombinas/química , Antitrombina III , Anticoagulantes , Heparina , Coagulação Sanguínea , Deficiência de Antitrombina III/tratamento farmacológico
6.
Pediatr Blood Cancer ; 71(3): e30824, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38155150

RESUMO

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.


Assuntos
Deficiência de Antitrombina III , Deficiência de Proteína C , Deficiência de Proteína S , Trombofilia , Trombose , Recém-Nascido , Feminino , Gravidez , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Japão/epidemiologia , Deficiência de Proteína S/complicações , Deficiência de Proteína S/diagnóstico , Deficiência de Proteína S/genética , Trombofilia/complicações , Trombose/etiologia , Trombose/genética , Deficiência de Proteína C/genética , Deficiência de Proteína C/complicações , Proteína C/genética , Anticoagulantes , Antitrombina III , Antitrombinas
7.
Gene ; 897: 148085, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38104950

RESUMO

INTRODUCTION: Hereditary antithrombin (AT) deficiency is a rare autosomal dominant disorder with significant clinical heterogeneity. In the study, we identified a patient with AT deficiency caused by compound heterozygous mutations in the SERPINC1 gene. METHODS: A total of 9 individuals from three generations were investigated. The mutations were identified by direct sequencing of SERPINC1. Multiple in silico tools were programmed to predict the conservation of mutations and the effect on the AT structure. The coagulation state was evaluated by the thrombin generation assay. Recombinant AT was overexpressed in HEK293T cells; the mRNA level was determined using RT-qPCR. Western blotting, ELISA, and immunocytofluorescence were applied to characterize the recombinant AT protein. RESULTS: The proband was a 26-year-old male who experienced recurrent venous thrombosis. He presented the type I deficiency with 33 % AT activity and a synchronized decrease in AT antigen. Genetic screening revealed that he carried a heterozygous c.318_319insT (p.Asn107*) in exon 2 and a heterozygous c.922G > T (p.Gly308Cys) in exon 5, both of which were completely conserved in homologous species and resulted in enhanced thrombin generation capability. Hydrophobicity analysis suggested that the p.Gly308Cys mutation may interfere with the hydrophobic state of residues 307-313. In vitro expression studies indicated that the levels of the recombinant protein AT-G308C decreased to 46.98 % ± 2.94 % and 41.35 % ± 1.48 % in transfected cell lysates and media, respectively. After treatment with a proteasome inhibitor (MG132), the quantity of AT-G308C protein in the cytoplasm was replenished to a level comparable to that of the wild type. The mRNA level of AT-N107* was significantly reduced and the recombinant protein AT-N107* was not detected in either the lysate or the culture media. CONCLUSION: These two mutations were responsible for the AT defects and clinical phenotypes of the proband. The p.Gly308Cys mutation could lead to proteasome-dependent degradation of the AT protein in the cytoplasm by altering local residue hydrophobicity. The c.318_319insT could eliminate aberrant transcripts by triggering nonsense-mediated mRNA degradation. Both mutations resulted in type I AT deficiency.


Assuntos
Deficiência de Antitrombina III , Antitrombina III , Trombofilia , Adulto , Humanos , Masculino , Antitrombina III/genética , Deficiência de Antitrombina III/genética , Células HEK293 , Mutação , Linhagem , Proteínas Recombinantes/genética , RNA Mensageiro , Trombina
8.
Neurol India ; 71(5): 984-986, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37929439

RESUMO

Hereditary antithrombin (AT) deficiency is a rare thrombophilia associated with cerebral vein thrombosis (CVT). We report a case study of hereditary AT deficiency causing CVT in three members of a family. A 29-year-old female presented with features of CVT. Her mother and a sister had CVT in the past and investigation for hereditary thrombophilia revealed low blood AT activity in all of them. The index patient (proband) was positive for the SERPINC1 gene mutation confirming the diagnosis of hereditary AT deficiency. She recovered well with anticoagulation and was advised to continue it lifelong. Diagnosing hereditary thrombophilia like AT deficiency is important in planning anticoagulation and proper counseling of asymptomatic family members regarding prophylaxis for venous thromboembolism (VTE) in high-risk situations.


Assuntos
Deficiência de Antitrombina III , Trombose Intracraniana , Trombofilia , Trombose Venosa , Humanos , Feminino , Adulto , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/genética , Trombofilia/tratamento farmacológico , Trombofilia/genética , Trombose Intracraniana/etiologia , Trombose Venosa/etiologia , Anticoagulantes/uso terapêutico
10.
Clin Lab ; 69(10)2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37844053

RESUMO

BACKGROUND: We present the case study of a 28-year-old pregnant woman with antithrombin deficiency who was treated with low-molecular-weight heparin (LMWH). METHODS: Due to severe homozygous type II antithrombin heparin binding site (HBS) deficiency, the thrombin generation (TG) was monitored in this woman via the Thrombin Generation Assay (TGA). We used Siemens diagnostic kits Berichrom® Antithrombin III (IIa) and INNOVANCE® Antithrombin (Xa) to determine antithrombin activity. We used a chromogenic method for determination of factor Xa (FXa) inhibition. RESULTS: There were no thrombotic complications during the whole pregnancy of the observed woman. Antithrombin was administered before and after delivery, which was significantly reflected in the decrease in thrombin generation. CONCLUSIONS: Consistent monitoring of thrombin generation with LMWH anticoagulant therapy administration during pregnancy together with antithrombin administration before and after delivery can improve the overall condition of pregnant women and the quality of their care.


Assuntos
Deficiência de Antitrombina III , Antitrombinas , Feminino , Humanos , Gravidez , Adulto , Antitrombinas/uso terapêutico , Antitrombina III/farmacologia , Trombina , Gestantes , Heparina de Baixo Peso Molecular/uso terapêutico , Anticoagulantes/farmacologia , Heparina/farmacologia , Deficiência de Antitrombina III/diagnóstico , Deficiência de Antitrombina III/tratamento farmacológico
11.
Sci Rep ; 13(1): 16734, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37794095

RESUMO

Antithrombin (AT) deficiency increases the risk for venous thromboembolism, therefore, a highly sensitive assay to identify this condition is crucial. The aim of this paper was to perform a meta-analysis comparing AT activities measured by different AT activity assays in patients with heparin binding site AT deficiency. In addition, the diagnostic sensitivity of selected assays was compared depending on the available data. An extensive literature search was performed considering results with publication date up to July 10, 2021. Seven relevant English-language observational studies, comparing AT activity measured by different AT activity assays in Caucasian Europeans with either the AT Budapest III or AT Padua I mutation were included in meta-analyses. There was no significant difference in AT activity between Labexpert and Innovance in patients with AT Budapest III (P = 0.567) and AT Padua I (P = 0.265), while AT activity determined by HemosIL was significantly higher compared to Innovance for both mutations (AT Budapest III: P < 0.001; AT Padua I: P < 0.001). These results are in line with the results of comparison of diagnostic sensitivity. In patients with AT Budapest III, the AT activity was also higher when measured with Berichrom compared to Innovance (P = 0.002), however, the results of comparison of diagnostic sensitivity across studies were variable. No significant difference (P = 0.117) in AT activity as well as diagnostic sensitivity was observed between Sta-Stachrom and Innovance. The results of our study suggest that Innovance, Labexpert and Sta-Stachrom are the most sensitive activity assays for detection of AT Budapest III and AT Padua I, whereas HemosIL showed considerably lower sensitivity for these two variants. As revealed in our study, the diagnostic sensitivity of AT activity assays to type II heparin binding site AT deficiency is different, and in some assays mutation dependent.


Assuntos
Deficiência de Antitrombina III , Heparina , Humanos , Heparina/metabolismo , Anticoagulantes , Testes de Coagulação Sanguínea/métodos , Deficiência de Antitrombina III/diagnóstico , Deficiência de Antitrombina III/genética , Sítios de Ligação , Antitrombinas/química
12.
Clin Appl Thromb Hemost ; 29: 10760296231205279, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37822179

RESUMO

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.


Assuntos
Deficiência de Antitrombina III , Antitrombinas , Gravidez , Feminino , Humanos , Antitrombinas/uso terapêutico , Células Endoteliais , Anticoagulantes/uso terapêutico , Antitrombina III , Coagulação Sanguínea , Deficiência de Antitrombina III/tratamento farmacológico
13.
Clin Appl Thromb Hemost ; 29: 10760296231197174, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37670493

RESUMO

The cases of antithrombin (AT)-deficient pregnant women with a homozygous HBS II mutation are relatively rare and are accompanied by an increased thrombophilic risk, which is manifested by increased thrombin generation (TG). It is very difficult to ensure their prophylactic treatment during pregnancy. We aimed to determine the utility of the thrombin generation assay (TGA) and anti-factor Xa (anti-FXa) test to monitor the effects of a prophylactic dose of low-molecular-weight heparin (LMWH) in a 28-year-old woman with homozygous AT deficiency caused by mutation c.391C > T#, (p.Leu131Phe†) in the SERPINC1 gene and to compare the findings with those from a group of pregnant and non-pregnant women also treated with LMWH. TG monitoring was chosen due to severe AT deficiency that was manifested by low levels of anti-FXa activity when monitoring the efficacy of LMWH treatment. A significant decrease in TG was detected in all monitored groups (P < .05). There were no thrombotic complications during the whole pregnancy of the woman with AT deficiency. Consistent monitoring of TG with LMWH anticoagulant therapy administration during pregnancy together with AT administration before and after delivery may improve the overall condition of pregnant women and the quality of their care.


Assuntos
Deficiência de Antitrombina III , Heparina de Baixo Peso Molecular , Feminino , Humanos , Gravidez , Adulto , Gestantes , Trombina/uso terapêutico , Antitrombinas/uso terapêutico , Anticoagulantes/uso terapêutico , Antitrombina III , Deficiência de Antitrombina III/tratamento farmacológico , Deficiência de Antitrombina III/genética , Mutação
14.
Thromb Res ; 230: 18-26, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37607435

RESUMO

INTRODUCTION: Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known abnormal variant in two unrelated Japanese families with venous thrombosis. In this study, we analyzed the mechanism by which these abnormal variants cause type I AT deficiency. MATERIALS AND METHODS: Wild-type and variant AT expression vectors were constructed and transiently expressed in human embryonic kidney 293 cells, and AT antigen levels and N-glycosylation of cell lysates and culture medium were evaluated by western blot analysis. Subcellular co-localization of AT was also examined using confocal microscopy, and chase experiments with cycloheximide and MG132 were performed to investigate the degradation pathway of AT variants. RESULTS: Genetic analysis identified a novel variant, c.613delC (p.Leu205Trpfs⁎79), and the known variant c.283T>C (p.Tyr95His). These AT variants exhibited significantly reduced extracellular secretion compared with the wild-type; N-glycosylation of the AT protein was normal. Co-localization analysis suggested that the transport of these abnormal AT proteins to the Golgi apparatus was impaired. The c.613delC variant was degraded early by the proteasome, suggesting that the c.283T>C variant is stored in the endoplasmic reticulum (ER). CONCLUSIONS: The AT variants identified here synthesize abnormal AT proteins that exhibit suppressed secretion and impaired transport from the ER to the Golgi apparatus. These results provide clues that could help elucidate the mechanism of type I AT deficiency and facilitate therapy development.


Assuntos
Deficiência de Antitrombina III , Trombose Venosa , Humanos , Antitrombinas , Proteínas Antitrombina , Antitrombina III/genética , Deficiência de Antitrombina III/genética , Trombose Venosa/genética
16.
J Thromb Haemost ; 21(5): 1248-1257, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36764659

RESUMO

BACKGROUND: The natural history and genotype-phenotype correlation of congenital antithrombin (AT) deficiency in children are unknown. OBJECTIVES: To describe the clinical presentation of congenital AT deficiency in children and evaluate its correlation to specific mutations in SERPINC1. METHODS: In 2017, a prospective pediatric database and DNA biorepository for congenital AT deficiency was established. During the pilot phase, the database was opened at 4 tertiary care centers in Canada and US. Approval from research ethics board was obtained at each participating center. Written consent/assent was obtained from guardians/subjects who met eligibility. Demographic/clinical data were uploaded into a database. DNA extraction and SERPINC1 sequencing were centralized for US centers. Standard statistical methods were used to summarize parameters. Probability of VTE-free survival was assessed using the Kaplan-Meier method. RESULTS: Overall, 43 participants (25 females) from 31 unique kindreds were enrolled. Median age (range) at enrollment was 14.8 years (1-21 years). Median AT activity was 52% (24%-87%), and median AT antigen (n = 20) was 55% (38%-110%). Nineteen (44%) participants had a history of venous thromboembolism (VTE). Median age at VTE diagnosis was 12.8 years (0.1-19.2 years). SERPINC1 sequencing was completed for 31 participants and 21 unique mutations were identified, including 5 novel variants. Probability of 5-year VTE-free survival (95% CI) for carriers of missense mutations (92.0% [95% CI: 71.6%-97.9%]) was significantly higher compared with carriers of null mutations (66.7% [95% CI: 19.5%-90.4%]); p = .0012. CONCLUSION: To our knowledge, this is the first pediatric study to document a severe thrombotic phenotype in carriers of null mutations in SERPINC1, when compared with carriers of missense mutations; underscoring the importance of genetic testing.


Assuntos
Deficiência de Antitrombina III , Trombose , Feminino , Humanos , Antitrombina III/genética , Deficiência de Antitrombina III/diagnóstico , Deficiência de Antitrombina III/genética , Antitrombinas , Hemostasia , Mutação , Fenótipo , Estudos Prospectivos , Trombose/diagnóstico , Trombose/genética , Bases de Dados Factuais
18.
Blood Coagul Fibrinolysis ; 34(3): 211-214, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36440804

RESUMO

Literature regarding the management of thrombus refractory to first-line treatment in the setting of pregnancy is limited, and management is made even more complicated in the context of thrombophilia. This case reviews the management of a patient with antithrombin deficiency who developed a massive thrombus during pregnancy, which was complicated by May-Thurner syndrome, lack of improvement with heparin, and preterm labor. The patient received multidisciplinary care throughout the pregnancy. At 35 weeks, anticoagulation was paused as she underwent induction of labor and delivery followed by postpartum placement of inferior vena cava filter and restarting heparin. Successful management of our pregnant patient with thrombus refractory to heparin hinged on individualized treatment for medical optimization with anticoagulation and antithrombin concentrate prior to labor followed by immediate postpartum placement of inferior vena cava filter.


Assuntos
Deficiência de Antitrombina III , Síndrome de May-Thurner , Filtros de Veia Cava , Trombose Venosa , Gravidez , Feminino , Recém-Nascido , Humanos , Trombose Venosa/complicações , Trombose Venosa/tratamento farmacológico , Síndrome de May-Thurner/complicações , Período Periparto , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/tratamento farmacológico , Heparina/uso terapêutico , Anticoagulantes/uso terapêutico , Antitrombinas , Filtros de Veia Cava/efeitos adversos , Veia Cava Inferior
19.
Int J Hematol ; 117(4): 523-529, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36526880

RESUMO

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.


Assuntos
Deficiência de Antitrombina III , Antitrombina III , Trombofilia , Humanos , Antitrombina III/genética , Antitrombina III/metabolismo , Deficiência de Antitrombina III/genética , Códon sem Sentido , Células HEK293 , Trombofilia/genética
20.
Tohoku J Exp Med ; 258(4): 327-332, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36351615

RESUMO

Antithrombin deficiency is a high-risk factor for venous thromboembolism during pregnancy, whereas cerebral venous thrombosis is rare. Cerebral venous thrombosis related to coronavirus disease 2019 (COVID-19) vaccines has been reported; however, there are a few reports of cerebral venous thrombosis after a messenger RNA (mRNA) vaccination. A 25-year-old female in her sixth week of pregnancy presented with headache 24 days after BNT162b2 mRNA COVID-19 vaccination. The following day, she presented with altered sensorium and was diagnosed with severe cerebral venous thrombosis. She demonstrated heparin resistance and was found to have an inherited antithrombin deficiency. A heterozygous missense variant in SERPINC1 (c.379T>C, p.Cys127Arg, 'AT Morioka') was detected by DNA analysis. Despite intensive care with unfractionated heparin, antithrombin concentrate, and repeated endovascular treatments, she died on the sixth day of hospitalization. Cerebral venous thrombosis in pregnant women with an antithrombin deficiency can follow a rapid and fatal course. Treatment with unfractionated heparin and antithrombin concentrate may be ineffective in severe cerebral venous thrombosis cases with antithrombin deficiency. Early recognition of antithrombin deficiency and an immediate switch to other anticoagulants may be required. Although the association between cerebral venous thrombosis and the vaccine is uncertain, COVID-19 vaccinations may require careful evaluation for patients with prothrombic factors.


Assuntos
Deficiência de Antitrombina III , COVID-19 , Trombose Venosa , Humanos , Feminino , Gravidez , Adulto , Gestantes , COVID-19/complicações , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , Heparina , RNA Mensageiro , Deficiência de Antitrombina III/complicações , Deficiência de Antitrombina III/genética , Antitrombinas/uso terapêutico , Anticoagulantes , Trombose Venosa/etiologia , Vacinação/efeitos adversos
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