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Javier Corral - One of the best experts on this subject based on the ideXlab platform.
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Antithrombin Deficiency as a still underdiagnosed thrombophilia: a primer for internists.
Polish archives of internal medicine, 2020Co-Authors: Carlos Bravo-perez, María Eugenia De La Morena-barrio, Vicente Vicente, Javier CorralAbstract:Antithrombin is a key endogenous anticoagulant that also plays other roles in inflammation, immunity, and other processes. Congenital Antithrombin Deficiency is the most severe type of thrombophilia, yet characterized by a remarkable clinical heterogeneity. Here, as a primer for internists, we present a practical review of data regarding this disorder, focused on its molecular basis, diagnostic procedures, prognostic implications, and clinical management of patients suffering from this severe, and probably underdiagnosed, type of thrombophilia.
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Management of Antithrombin Deficiency: an update for clinicians
Expert review of hematology, 2019Co-Authors: Carlos Bravo-perez, Vicente Vicente, Javier CorralAbstract:Introduction. Antithrombin is a serpin that inhibits multiple procoagulant serine proteases and acts as an endogenous anticoagulant. Thus, congenital Antithrombin Deficiency constitutes a major thrombophilic state, the most severe so far. Areas covered. In the present work, we globally review the biology, genetics, diagnosis, and management of congenital Antithrombin Deficiency, and also discuss puzzling questions and future perspectives regarding this severe inherited thrombophilia. Expert opinion. Although this disorder exerts high clinical heterogeneity, many carriers will need careful and long-term anticoagulation and/or thromboprophylaxis, especially in high-risk situations, such as surgery and pregnancy. Notably, Antithrombin concentrates constitute a considerable arsenal for both treatment and prevention of acute venous thrombosis in subjects with Antithrombin Deficiency. Current evidences are based almost exclusively on retrospective case series, so an integrated functional, biochemical and molecular characterization will be of clinical relevance and guide hematologists' personalized decisions.
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Incidence and features of thrombosis in children with inherited Antithrombin Deficiency.
Haematologica, 2019Co-Authors: Belén De La Morena-barrio, María Eugenia De La Morena-barrio, Vicente Vicente, Christelle Orlando, Kristin Jochmans, Javier CorralAbstract:Pediatric thromboembolism (≤18 years) is very rare (0.07-0.14/10,000/year) but may be more prevalent in children with severe thrombophilia (protein C, protein S or Antithrombin Deficiency). The aim of this study was to define the prevalence and clinical characteristics of pediatric thrombosis in subjects with inherited Antithrombin Deficiency. Our observational retrospective multicentric study from two countries recruited 968 patients of any age from 441 unrelated families with genetically, biochemically and functionally characterized Antithrombin Deficiency. Seventy-three subjects (7.5%) developed thrombosis before 19 years of age. Two high-risk periods for thrombosis were identified: adolescence (12-18 years, n=49) with thrombus localization (lower limb deep venous thrombosis or pulmonary embolism) and triggering factors common to adults (oral contraceptives, surgery or pregnancy); and the neonatal period (
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MPI-CDG with transient hypoglycosylation and Antithrombin Deficiency.
Haematologica, 2018Co-Authors: María Eugenia De La Morena-barrio, Antonia Miñano, Javier Corral, Vicente Vicente, Ewa Wypasek, Danuta Owczarek, Anetta UndasAbstract:Antithrombin Deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness.[1][1]–[5][2] Most cases of Antithrombin Deficiency are explained by mutations in SERPINC1 , the gene encoding this anticoagulant, with detection rate ranging from 70–80%.[6
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Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent Antithrombin Deficiency.
Oncotarget, 2017Co-Authors: Wei Zeng, María Eugenia De La Morena-barrio, Mara Toderici, Liang Tang, Yan-yan You, Javier CorralAbstract:// Wei Zeng 1, 2, * , Bei Hu 1, * , Liang Tang 1, * , Yan-Yan You 3 , Mara Toderici 4 , Maria Eugenia de la Morena-Barrio 4 , Javier Corral 4 and Yu Hu 1 1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 2 Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China 3 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 4 Centro Regional de Hemodonaciόn, Universidad de Murcia, IMIB, CIBERER, Murcia, Spain * These authors have contributed equally to this work Correspondence to: Yu Hu, email: dr_huyu@126.com Javier Corral, email: javier.corral@carm.es Keywords: venous thromboembolism, Antithrombin Deficiency, SERPINC1 , thrombophilia, mutation Received: July 03, 2017 Accepted: September 04, 2017 Published: September 28, 2017 ABSTRACT Despite the essential anticoagulant function of Antithrombin and the high risk of thrombosis associated with its Deficiency, the prevalence of Antithrombin Deficiency among patients with venous thromboembolism (VTE) is very low. However, increasing evidence suggests that Antithrombin Deficiency may be underestimated. The analysis of SERPINC1 , the gene encoding Antithrombin, in 1,304 consecutive Chinese VTE patients and 1,334 healthy controls revealed a hotspot involving residues 294 and 295 that severely increases the risk of VTE. We detected the c.883G>A (p.Val295Met) (rs201381904) mutation in 11 patients and just one control (OR = 13.6; 95% CI: 1.7-107.1); c.881G>T (p.Arg294Leu) (rs587776397) in six patients but no controls; and c.880C>T (p.Arg294Cys) (rs747142328) in two patients but no controls. In addition, c.881G>A (p.Arg294His) (rs587776397) was identified in one control. These mutations were absent in a Caucasian cohort. Carriers of these mutations had normal Antithrombin levels and anticoagulant activity, consistent with results obtained in a recombinant model. However, mutation carriers had a significantly increased endogenous thrombin potential. Our results suggest the existence in the Chinese population of a hotspot in SERPINC1 that significantly increases the risk of VTE by impairing the anticoagulant capacity of the hemostatic system. This effect is not revealed by current antigen or in vitro functional Antithrombin assays.
Vicente Vicente - One of the best experts on this subject based on the ideXlab platform.
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Antithrombin Deficiency as a still underdiagnosed thrombophilia: a primer for internists.
Polish archives of internal medicine, 2020Co-Authors: Carlos Bravo-perez, María Eugenia De La Morena-barrio, Vicente Vicente, Javier CorralAbstract:Antithrombin is a key endogenous anticoagulant that also plays other roles in inflammation, immunity, and other processes. Congenital Antithrombin Deficiency is the most severe type of thrombophilia, yet characterized by a remarkable clinical heterogeneity. Here, as a primer for internists, we present a practical review of data regarding this disorder, focused on its molecular basis, diagnostic procedures, prognostic implications, and clinical management of patients suffering from this severe, and probably underdiagnosed, type of thrombophilia.
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Congenital Antithrombin Deficiency in patients with splanchnic vein thrombosis
'Wiley', 2020Co-Authors: Baiges Aznar Anna, María Eugenia De La Morena-barrio, Vicente Vicente, Turon Fanny, Miñano Antonia, Ferrusquía, José Alberto, Magaz Marta, Reverter Calatayud, Juan Carlos, Hernández Gea Virginia, Corral JavierAbstract:Splanchnic vein thromboses (SVT) are a rare condition that can be life-threatening. The most severe thrombophilia associated to SVT is Antithrombin (AT) Deficiency, usually caused by SERPINC1 mutations. Although transitory AT deficiencies and congenital disorders of the N-glycosylation pathways (CDG) have been recently reported as causes of AT Deficiency, the current AT clinical screening still only includes anti-FXa activity. This study aims to 1) improve the detection of Antithrombin Deficiency in SVT and 2) characterize the features of Antithrombin Deficiency associated with SVT.The study was performed in 2 cohorts: 1) 89 SVT patients with different underlying etiologies but in whom AT Deficiency had been ruled out by classical diagnostic methods; and 2) 271 unrelated patients with confirmed AT Deficiency and venous thrombosis. Antithrombin was evaluated by functional (anti-FXa and anti-FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed.In 4/89 patients (4.5%) additional alterations in AT were found (two had SERPINC1 mutations, one had a specific variant causing transient AT Deficiency and one patient had CDG). In 11 of the 271 patients (4.1%) with AT Deficiency and thrombosis, thrombosis was located at the splanchnic venous territory.AT Deficiency may be underdiagnosed by current clinical screening techniques. Therefore, a comprehensive AT evaluation should be considered in cases of rethrombosis or doubtful interpretation of anti-FXa activity levels. SVT is a relatively common localization of the thrombotic event in patients with congenital AT Deficiency.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Management of Antithrombin Deficiency: an update for clinicians
Expert review of hematology, 2019Co-Authors: Carlos Bravo-perez, Vicente Vicente, Javier CorralAbstract:Introduction. Antithrombin is a serpin that inhibits multiple procoagulant serine proteases and acts as an endogenous anticoagulant. Thus, congenital Antithrombin Deficiency constitutes a major thrombophilic state, the most severe so far. Areas covered. In the present work, we globally review the biology, genetics, diagnosis, and management of congenital Antithrombin Deficiency, and also discuss puzzling questions and future perspectives regarding this severe inherited thrombophilia. Expert opinion. Although this disorder exerts high clinical heterogeneity, many carriers will need careful and long-term anticoagulation and/or thromboprophylaxis, especially in high-risk situations, such as surgery and pregnancy. Notably, Antithrombin concentrates constitute a considerable arsenal for both treatment and prevention of acute venous thrombosis in subjects with Antithrombin Deficiency. Current evidences are based almost exclusively on retrospective case series, so an integrated functional, biochemical and molecular characterization will be of clinical relevance and guide hematologists' personalized decisions.
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Incidence and features of thrombosis in children with inherited Antithrombin Deficiency.
Haematologica, 2019Co-Authors: Belén De La Morena-barrio, María Eugenia De La Morena-barrio, Vicente Vicente, Christelle Orlando, Kristin Jochmans, Javier CorralAbstract:Pediatric thromboembolism (≤18 years) is very rare (0.07-0.14/10,000/year) but may be more prevalent in children with severe thrombophilia (protein C, protein S or Antithrombin Deficiency). The aim of this study was to define the prevalence and clinical characteristics of pediatric thrombosis in subjects with inherited Antithrombin Deficiency. Our observational retrospective multicentric study from two countries recruited 968 patients of any age from 441 unrelated families with genetically, biochemically and functionally characterized Antithrombin Deficiency. Seventy-three subjects (7.5%) developed thrombosis before 19 years of age. Two high-risk periods for thrombosis were identified: adolescence (12-18 years, n=49) with thrombus localization (lower limb deep venous thrombosis or pulmonary embolism) and triggering factors common to adults (oral contraceptives, surgery or pregnancy); and the neonatal period (
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MPI-CDG with transient hypoglycosylation and Antithrombin Deficiency.
Haematologica, 2018Co-Authors: María Eugenia De La Morena-barrio, Antonia Miñano, Javier Corral, Vicente Vicente, Ewa Wypasek, Danuta Owczarek, Anetta UndasAbstract:Antithrombin Deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness.[1][1]–[5][2] Most cases of Antithrombin Deficiency are explained by mutations in SERPINC1 , the gene encoding this anticoagulant, with detection rate ranging from 70–80%.[6
María Eugenia De La Morena-barrio - One of the best experts on this subject based on the ideXlab platform.
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Antithrombin Deficiency as a still underdiagnosed thrombophilia: a primer for internists.
Polish archives of internal medicine, 2020Co-Authors: Carlos Bravo-perez, María Eugenia De La Morena-barrio, Vicente Vicente, Javier CorralAbstract:Antithrombin is a key endogenous anticoagulant that also plays other roles in inflammation, immunity, and other processes. Congenital Antithrombin Deficiency is the most severe type of thrombophilia, yet characterized by a remarkable clinical heterogeneity. Here, as a primer for internists, we present a practical review of data regarding this disorder, focused on its molecular basis, diagnostic procedures, prognostic implications, and clinical management of patients suffering from this severe, and probably underdiagnosed, type of thrombophilia.
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Congenital Antithrombin Deficiency in patients with splanchnic vein thrombosis
'Wiley', 2020Co-Authors: Baiges Aznar Anna, María Eugenia De La Morena-barrio, Vicente Vicente, Turon Fanny, Miñano Antonia, Ferrusquía, José Alberto, Magaz Marta, Reverter Calatayud, Juan Carlos, Hernández Gea Virginia, Corral JavierAbstract:Splanchnic vein thromboses (SVT) are a rare condition that can be life-threatening. The most severe thrombophilia associated to SVT is Antithrombin (AT) Deficiency, usually caused by SERPINC1 mutations. Although transitory AT deficiencies and congenital disorders of the N-glycosylation pathways (CDG) have been recently reported as causes of AT Deficiency, the current AT clinical screening still only includes anti-FXa activity. This study aims to 1) improve the detection of Antithrombin Deficiency in SVT and 2) characterize the features of Antithrombin Deficiency associated with SVT.The study was performed in 2 cohorts: 1) 89 SVT patients with different underlying etiologies but in whom AT Deficiency had been ruled out by classical diagnostic methods; and 2) 271 unrelated patients with confirmed AT Deficiency and venous thrombosis. Antithrombin was evaluated by functional (anti-FXa and anti-FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed.In 4/89 patients (4.5%) additional alterations in AT were found (two had SERPINC1 mutations, one had a specific variant causing transient AT Deficiency and one patient had CDG). In 11 of the 271 patients (4.1%) with AT Deficiency and thrombosis, thrombosis was located at the splanchnic venous territory.AT Deficiency may be underdiagnosed by current clinical screening techniques. Therefore, a comprehensive AT evaluation should be considered in cases of rethrombosis or doubtful interpretation of anti-FXa activity levels. SVT is a relatively common localization of the thrombotic event in patients with congenital AT Deficiency.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Incidence and features of thrombosis in children with inherited Antithrombin Deficiency.
Haematologica, 2019Co-Authors: Belén De La Morena-barrio, María Eugenia De La Morena-barrio, Vicente Vicente, Christelle Orlando, Kristin Jochmans, Javier CorralAbstract:Pediatric thromboembolism (≤18 years) is very rare (0.07-0.14/10,000/year) but may be more prevalent in children with severe thrombophilia (protein C, protein S or Antithrombin Deficiency). The aim of this study was to define the prevalence and clinical characteristics of pediatric thrombosis in subjects with inherited Antithrombin Deficiency. Our observational retrospective multicentric study from two countries recruited 968 patients of any age from 441 unrelated families with genetically, biochemically and functionally characterized Antithrombin Deficiency. Seventy-three subjects (7.5%) developed thrombosis before 19 years of age. Two high-risk periods for thrombosis were identified: adolescence (12-18 years, n=49) with thrombus localization (lower limb deep venous thrombosis or pulmonary embolism) and triggering factors common to adults (oral contraceptives, surgery or pregnancy); and the neonatal period (
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MPI-CDG with transient hypoglycosylation and Antithrombin Deficiency.
Haematologica, 2018Co-Authors: María Eugenia De La Morena-barrio, Antonia Miñano, Javier Corral, Vicente Vicente, Ewa Wypasek, Danuta Owczarek, Anetta UndasAbstract:Antithrombin Deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness.[1][1]–[5][2] Most cases of Antithrombin Deficiency are explained by mutations in SERPINC1 , the gene encoding this anticoagulant, with detection rate ranging from 70–80%.[6
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High levels of latent Antithrombin in plasma from patients with Antithrombin Deficiency.
Thrombosis and Haemostasis, 2017Co-Authors: María Eugenia De La Morena-barrio, E. Sandoval, Pilar Llamas, Ewa Wypasek, Mara Toderici, José Navarro-fernández, Agustín Rodriguez-alén, Nuria Revilla, Raquel López-gálvez, Antonia MiñanoAbstract:Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of Antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma Antithrombin in healthy subjects. The analysis of latent Antithrombin in 141 unrelated patients with Antithrombin Deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42oC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent Antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin Deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent Antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of Antithrombin (and potentially of all serpins). High levels of endogenous latent Antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation.
Antonia Miñano - One of the best experts on this subject based on the ideXlab platform.
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MPI-CDG with transient hypoglycosylation and Antithrombin Deficiency.
Haematologica, 2018Co-Authors: María Eugenia De La Morena-barrio, Antonia Miñano, Javier Corral, Vicente Vicente, Ewa Wypasek, Danuta Owczarek, Anetta UndasAbstract:Antithrombin Deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness.[1][1]–[5][2] Most cases of Antithrombin Deficiency are explained by mutations in SERPINC1 , the gene encoding this anticoagulant, with detection rate ranging from 70–80%.[6
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High levels of latent Antithrombin in plasma from patients with Antithrombin Deficiency.
Thrombosis and Haemostasis, 2017Co-Authors: María Eugenia De La Morena-barrio, E. Sandoval, Pilar Llamas, Ewa Wypasek, Mara Toderici, José Navarro-fernández, Agustín Rodriguez-alén, Nuria Revilla, Raquel López-gálvez, Antonia MiñanoAbstract:Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of Antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma Antithrombin in healthy subjects. The analysis of latent Antithrombin in 141 unrelated patients with Antithrombin Deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42oC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent Antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin Deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent Antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of Antithrombin (and potentially of all serpins). High levels of endogenous latent Antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation.
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Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient Antithrombin Deficiency
Thrombosis and haemostasis, 2016Co-Authors: José Navarro-fernández, Irene Martínez-martínez, Antonia Miñano, Teresa Sevivas, Sonia Aguila, Jose Padilla, C De Cos, M.e. De La ,morena-barrio, Nataliya Bohdan, N. Fernández-mosteirínAbstract:The key haemostatic role of Antithrombin and the risk of thrombosis associated with its Deficiency support that the low incidence of Antithrombin Deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient Antithrombin Deficiency. SERPINC1 was sequenced in 214 cases with a positive test for Antithrombin Deficiency, including 67 with no Deficiency in the sample delivered to our laboratory. The p.Val30Glu mutation (Antithrombin Dublin) was identified in five out of these 67 cases, as well as in three out of 127 cases with other SERPINC1 mutations. Genotyping in 1593 patients with venous thrombosis and 2592 controls from two populations, revealed a low prevalent polymorphism (0.3 %) that moderately increased the risk of venous thrombosis (OR: 2.9; 95 % CI: 1.07–8.09; p= 0.03) and identified one homozygous patient with an early thrombotic event. Carriers had normal anti-FXa activity, and plasma Antithrombin was not sensitive to heat stress or proteolytic cleavage. Analysis of one sample with transient deficit revealed a type I Deficiency, without aberrant or increased latent forms. The recombinant variant, which lacked the two amino-terminal residues, had reduced secretion from HEK-EBNA cells, formed hyperstable disulphide-linked polymers, and had negligible activity. In conclusion, p.Val30Glu by affecting the cleavage of Antithrombin’s signal peptide, results in a mature protein lacking the N-terminal dipeptide with no functional consequences in normal conditions, but that increases the sensitivity to be folded intracellularly into polymers, facilitating transient Antithrombin Deficiency and the subsequent risk of thrombosis.
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Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency.
PloS one, 2016Co-Authors: Mara Toderici, María Eugenia De La Morena-barrio, Antonia Miñano, Vicente Vicente, Ana Isabel Antón, Jose Padilla, Juan A. Iniesta, María Teresa Herranz, Nuria Fernández, Javier CorralAbstract:Antithrombin is a crucial anticoagulant serpin whose even moderate Deficiency significantly increases the risk of thrombosis. Most cases with Antithrombin Deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with Antithrombin Deficiency but without known genetic defects. Three cases with moderate Antithrombin Deficiency (63–78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma Antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and Antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in Antithrombin Deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments.
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Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in Antithrombin Deficiency
Thrombosis and Haemostasis, 2013Co-Authors: Sonia Aguila, María Eugenia De La Morena-barrio, Irene Martínez-martínez, Antonia Miñano, Pilar Llamas, M. Collado, Ana Isabel Antón, C. Martinez-redondo, Jose Padilla, A. Garcia-avelloAbstract:Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in Antithrombin Deficiency -
Anetta Undas - One of the best experts on this subject based on the ideXlab platform.
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MPI-CDG with transient hypoglycosylation and Antithrombin Deficiency.
Haematologica, 2018Co-Authors: María Eugenia De La Morena-barrio, Antonia Miñano, Javier Corral, Vicente Vicente, Ewa Wypasek, Danuta Owczarek, Anetta UndasAbstract:Antithrombin Deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness.[1][1]–[5][2] Most cases of Antithrombin Deficiency are explained by mutations in SERPINC1 , the gene encoding this anticoagulant, with detection rate ranging from 70–80%.[6
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hypoglycosylation is a common finding in Antithrombin Deficiency in the absence of a serpinc1 gene defect
Journal of Thrombosis and Haemostasis, 2016Co-Authors: Ewa Wypasek, Anetta Undas, M E De La Morenabarrio, Irene Martinezmartinez, C De Cos, Vanessa Roldan, M Van Scherpenzeel, Dirk J LefeberAbstract:Essentials We investigated the molecular base of Antithrombin Deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to Antithrombin. Variations in genes involved in N-glycosylation underline this phenotype. These results support a new form of thrombophilia. Click here to listen to Dr Huntington's perspective on thrombin inhibition by the serpins SummaryBackground Since the discovery of Antithrombin Deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than Antithrombin Deficiency. Objective To identify new thrombophilic mechanisms. Patients/methods We studied 30 patients with Antithrombin Deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). Results A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of Antithrombin. All N-glycoproteins tested in these patients (α1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent Antithrombin Deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway. Conclusions Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient Antithrombin Deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation.
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Antithrombin Katowice: exon 1 deletion in the SERPINC1 gene associated with type I Antithrombin Deficiency.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 2015Co-Authors: Marek Cieśla, Javier Corral, Ewa Wypasek, Martine Alhenc-gelas, Anetta UndasAbstract:Type I Antithrombin Deficiency is an autosomal dominant disorder associated with thromboembolic complications mainly related to single-point mutations in SERPINC1, the gene encoding Antithrombin. Chromosomal rearrangements have been found in up to 10% of cases with type I Antithrombin Deficiency. We report here the first heterozygous deletion of SERPINC1 exon 1 identified in a 44-year-old man with type I Deficiency who developed deep vein thrombosis of the left leg complicated by pulmonary embolism. This study demonstrates that the search for large gene rearrangements in SERPINC1 can be a useful diagnostic approach, particularly in patients with type I Antithrombin Deficiency without mutations in SERPINC1.
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Recurrent ischemic cerebrovascular events in a patient with type I Antithrombin Deficiency caused by 9788 G>A splice site mutation: a case report.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 2013Co-Authors: Magdalena Szymańska, Martine Alhenc-gelas, Anetta UndasAbstract:Type I Antithrombin Deficiency is an autosomal dominant disorder associated with high risk for venous thromboembolism. Data on the association between Antithrombin Deficiency and arterial thromboembolism are inconsistent. We report here the case of AT Deficiency in a 43-year-old man free of cardiovascular risk factors who experienced venous thromboembolism and ischemic stroke followed by two transient ischemic attacks after interruption of oral anticoagulation due to colonoscopy. DNA sequencing of the Antithrombin gene revealed heterozygosity for the previously reported substitution G to A at nucleotide position 9788 in intervening sequence four. To our knowledge, this report is the first to show that this genetic abnormality can be associated with recurrent cerebrovascular ischemic events.
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Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 Antithrombin Deficiency (Antithrombin Krakow)
Thrombosis and haemostasis, 2011Co-Authors: Magdalena Celińska-löwenhoff, Martine Alhenc-gelas, Teresa Iwaniec, Jacek Musiał, Anetta UndasAbstract:Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 Antithrombin Deficiency (Antithrombin Krakow) -
