Abstract：
:Antithrombin (AT) is a serine protease inhibitor that regulates the activity of coagulation proteases of both intrinsic and extrinsic pathways. We identified an AT-deficient patient with a heterozygous Thr90Ser (T90S) mutation who experiences recurrent venous thrombosis. To understand the molecular basis of the clotting defect, we expressed AT-T90S in mammalian cells, purified it to homogeneity, and characterized its properties in established kinetics, binding, and coagulation assays. The possible effect of mutation on the AT structure was also evaluated by molecular modeling. Results demonstrate the inhibitory activity of AT-T90S toward thrombin and factor Xa has been impaired three- to fivefold in both the absence and presence of heparin. The affinity of heparin for AT-T90S has been decreased by four- to fivefold. Kinetic analysis revealed the stoichiometry of AT-T90S inhibition of both thrombin and factor Xa has been elevated by three- to fourfold in both the absence and presence of heparin, suggesting that the reactivity of coagulation proteases with AT-T90S has been elevated in the substrate pathway. The anticoagulant activity of AT-T90S has been significantly impaired as analyzed in the AT-deficient plasma supplemented with AT-T90S. The anti-inflammatory effect of AT-T90S was also decreased. Structural analysis predicts the shorter side-chain of Ser in AT-T90S has a destabilizing effect on the structure of AT and/or the AT-protease complex, possibly increasing the size of an internal cavity and altering a hydrogen-bonding network that modulates conformations of the allosterically linked heparin-binding site and reactive center loop of the serpin. This mutational effect increases the reactivity of AT-T90S with coagulation proteases in the substrate pathway.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Lu Y,Villoutreix BO,Biswas I,Ding Q,Wang X,Rezaie ARdoi
10.1055/s-0040-1710590subject
Has Abstractpub_date
2020-07-01 00:00:00pages
1045-1055issue
7eissn
0340-6245issn
2567-689Xjournal_volume
120pub_type
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journal_title：Thrombosis and haemostasis
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更新日期：1997-04-01 00:00:00
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journal_title：Thrombosis and haemostasis
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journal_title：Thrombosis and haemostasis
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更新日期：2002-02-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究
doi：10.1160/TH09-10-0683
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
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更新日期：2002-05-01 00:00:00
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journal_title：Thrombosis and haemostasis
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
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更新日期：1987-08-04 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
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journal_title：Thrombosis and haemostasis
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更新日期：2008-11-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-04-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-02-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：10.1160/TH04-12-0814
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1055/s-0038-1629896
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1978-08-31 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1994-09-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1987-02-03 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1999-09-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1989-09-29 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1987-10-28 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究,随机对照试验
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journal_title：Thrombosis and haemostasis
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doi：
更新日期：1997-01-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1999-11-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-07-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH09-02-0127
更新日期：2009-09-01 00:00:00
abstract：:Magnesium (Mg) has shown the ability to inhibit arterial thrombus formation in some experimental animal studies. This effect may be due to an inhibition of platelet reactivity as in vitro studies have demonstrated that Mg inhibits platelet aggregation. In order to evaluate the in vivo effect of Mg in humans measuremen...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1996-06-01 00:00:00
abstract：:Haemostatic parameters were assessed before insulin induced hypoglycaemia and 0, 1 and 2 hr after discontinuation of insulin infusion in 7 non-diabetics, aged 28 (22-31) years (mean and range), and 8 juvenile diabetics, aged 31 (27-35) years, with a mean duration of diabetes of 4 years. The patients were normoglycaemi...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1982-06-28 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章
doi：10.1160/TH08-03-0172
更新日期：2008-07-01 00:00:00
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journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1979-08-31 00:00:00
abstract：:Antithrombin readily undergoes a spontaneous transition from its active five-stranded form to a six-stranded inactive latent form. The recognition of this change in plasma has been obscured by the immediate linkage of newly formed latent antithrombin to a molecule of active antithrombin to give a dimer with an electro...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：
更新日期：2001-07-01 00:00:00
