The genetics of antithrombin

Corral, Javier; Morena‐Barrio, María Eugenia de la; Vicente, Vicente

doi:10.1016/j.thromres.2018.07.008

Cited by 88 publications

(88 citation statements)

References 44 publications

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“…Regarding the potential applications of this method, future binding studies with various pentasaccharide or even non-pentasaccharide AT activators could aid the design of novel AT-dependent anticoagulant drugs. Furthermore, the biochemical consequences of several pathogenic variants affecting the heparin binding of AT can be investigated by this method (Corral, de la Morena-Barrio, & Vicente, 2018;Dinarvand et al, 2018;Muszbek et al, 2010). Finally, such simulations could potentially serve as an in silico tool for investigating interactions between numerous GAG-binding proteins with diverse biological functions and sulfated glycosaminoglycans.…”

Section: Resultsmentioning

confidence: 99%

The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations

Balogh

Komáromi

Bereczky

2019

Journal of Biomolecular Structure and Dynamics

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The activity of antithrombin (AT), a serpin protease inhibitor, is enhanced by heparin and heparin analogs against its target proteases, mainly thrombin, factors Xa and IXa. Considerable amount of information is available on the multistep mechanism of the heparin pentasaccharide binding and conformational activation. However, much of the details were inferred from 'static' structures obtained by X-ray diffraction. Moreover, limited information is available for the early steps of binding mechanism other than kinetic studies with various ligands. To gain insights into these processes, we performed enhanced sampling molecular dynamics (MD) simulations using the Gaussian Accelerated Molecular Dynamics (GAMD) method, applied previously in drug binding studies. We were able to observe the binding of the pentasaccharide idraparinux to a 'non-activated' AT conformation in two separate trajectories with low root mean square deviation (RMSD) values compared to X-ray structures of the bound state. These trajectories along with further simulations of the AT-pentasaccharide complex provided insights into the mechanisms of multiple conformational transitions, including the expulsion of the hinge region, the extension of helix D and the conformational behavior of the reactive center loop (RCL). We could also confirm the high stability of helix P in non-activated AT conformations, such states might play an important role in heparin binding. 'Generalized correlation' matrices revealed possible paths of allosteric signal propagation to the binding sites for the target proteases, factors Xa and IXa. Enhanced MD simulations of ligand binding to AT may assist the design of new anticoagulant drugs.

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Section: Resultsmentioning

confidence: 99%

The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations

Balogh

Komáromi

Bereczky

2019

Journal of Biomolecular Structure and Dynamics

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“…Based on the recent discovery of mutations causing transient AT deficiency and the finding of N‐glycosylation related AT deficiencies, as well as the doubtful accuracy and reliability of AT anti‐FXa activity as a diagnostic test, we hypothesized that these new diagnostic techniques could play a role in facilitating the diagnosis of masked AT deficiencies in the setting of SVT. In Cohort 1 we identified that 4.5% of patients previously considered to have a normal AT function presented an underlying AT disorder, which is especially significant when contrasted with the general population prevalence of AT deficiency of 1/500‐5000 .…”

Section: Discussionmentioning

confidence: 99%

“…Antithrombin deficiencies have been classified into two types: in type I, levels of AT are low; in type II, AT levels are within the normal range but the AT molecule has impaired or null anticoagulant activity . Several AT deficiency mechanisms have been described, being the most frequent genetic variants in SERPINC1 (the gene encoding antithrombin) that account for up to 80% of the cases of AT deficiencies.…”

Section: Introductionmentioning

confidence: 99%

“…However, from a clinical point of view, it is striking that despite the high prothrombotic risk of AT deficiency, the reported incidence of this alteration is very low among patients with splanchnic venous thrombosis, thus suggesting that AT deficiencies might be underestimated. There are increasing evidences on the low sensitivity of the current functional diagnostic tests to detect pathogenic mutations causing AT deficiency . 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.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Current molecular analysis is mainly restricted to Sanger sequencing of exons and flanking regions of SERPINC1 , the gene encoding antithrombin, as this approach renders positive findings (mainly point mutations) in up to 70–80% of cases. Multiplex ligation‐dependent probe amplification (MLPA) detects gross gene defects, mainly deletions, in 2–5% of cases with antithrombin deficiency (Corral et al , ). However, these methods failed to detect any genetic defect in up to 20–30% of cases.…”

Section: Oligonucleotides Conditions and Length Of Pcr Productsmentioning

confidence: 99%