Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency

Navarro-Fernández, José; Morena‐Barrio, María Eugenia de la; Padilla, José; Miñano, Antonia; Bohdan, Nataliya; Águila, Sonia; Martínez‐Martínez, Irene; Sevivas, Teresa; Cos, Carmen de; Fernández‐Mosteirín, Nuria; Llamas, Pilar; Asenjo, Susana; Medina, Pilar; Souto, Juan Carlos; Overvad, Kim; Kristensen, Søren Risom; Corral, Javier; Vicente, Vicente

doi:10.1160/th15-11-0871

Cited by 22 publications

(25 citation statements)

References 42 publications

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“…Congenital thrombophilia is caused by a wide variety of genetic abnormalities (being antithrombin deficiency the strongest one) and results in permanent risk for recurrent thrombosis1. Moreover, the presence of an acquired factor at specific time-points may further disturb the already unbalanced hemostatic system or trigger the pathological effects of certain mutations that can lead to thrombotic events2. Unfortunately, to date only a small number of genetic and acquired factors involved in thrombosis have been identified.…”

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confidence: 99%

Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy

Revilla

Morena‐Barrio

Miñano

et al. 2017

Sci Rep

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An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.

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confidence: 99%

Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy

Revilla

Morena‐Barrio

Miñano

et al. 2017

Sci Rep

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“…Afterwards, since mutations that are not usually detected by current functional assays and that are responsible for transient AT deficiencies are usually located in exons 2 and 7, these exons were sequenced in the whole cohort of 89 patients. One mutation was found: Patient 3 was a 51 year‐old‐woman with a known MPN that during follow‐up developed a portal and splenic vein thrombosis.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, it has been reported that the pathogenic effect of some SERPINC1 mutations might be exacerbated by environmental factors, leading to transient AT deficiency that would only be detected by functional methods. This would be the case of SERPINC1 mutation p.Val30Glu . Patients with this mutation would have normal levels and function of AT in baseline conditions but with a higher conformational susceptibility to stress, which would lead to deficiency of AT .…”

Section: Introductionmentioning

confidence: 99%

“…This would be the case of SERPINC1 mutation p.Val30Glu . Patients with this mutation would have normal levels and function of AT in baseline conditions but with a higher conformational susceptibility to stress, which would lead to deficiency of AT . Similarly, post‐traslational defects such as alterations and reduction of the N‐glycosylation pathways caused by congenital disorders of glycosylation (CDG), which might be not detected by conventional functional methods, are also known to impair AT function …”

Section: Introductionmentioning

confidence: 99%

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Congenital antithrombin deficiency in patients with splanchnic vein thrombosis

Baiges

Morena‐Barrio

Turón

et al. 2020

Liver International

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Background and aims 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 (a) improve the detection of AT deficiency in SVT and (b) characterize the features of AT deficiency associated with SVT. Methods The study was performed in 2 cohorts: (a) 89 SVT patients with different underlying etiologies but in whom AT deficiency had been ruled out by classical diagnostic methods; and (b) 271 unrelated patients with confirmed AT deficiency and venous thrombosis. AT was evaluated by functional (anti‐FXa and anti‐FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed. Results 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. Conclusions Antithrombin 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.

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“…Most of the associated conditions cause multiple abnormalities of the coagulation cascade and alter levels of both pro and anti-coagulants [9–11]. Table 3 outlines some of the common causes of acquired ATIII deficiency.…”

Section: Introductionmentioning

confidence: 99%

To be or not to be a case of heparin resistance

Durrani

Malik

Ali

et al. 2018

Journal of Community Hospital Internal Medicine Perspectives

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Heparin resistance can be defined as high doses of unfractionated heparin (UFH), greater than 35,000 IU/day, required to raise the activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) to within therapeutically desired ranges or the impossibility of doing so. The most common pathology responsible is the deficiency of anti-thrombin III (ATIII) deficiency. Other clinically relevant conditions that can present with heparin resistance are congenital deficiencies; use of high doses of heparin during extracorporeal circulation, use of asparaginase therapy and disseminated intravascular coagulation (DIC). Most of these conditions effect the ATIII levels. Patients are typically identified in an acute phase, when determination of the cause of resistance is challenging. We present a case where a patient presented with suspected heparin resistance in an acute phase of sickness, where timely intervention was able to prevent a potentially fatal situation.Abbreviations: Neuroendocrine tumors (NETs), World health Organization (WHO), Radiation therapy (RT)

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Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency

Cited by 22 publications

References 42 publications

Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy

Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy

Congenital antithrombin deficiency in patients with splanchnic vein thrombosis

To be or not to be a case of heparin resistance

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