Antithrombin: The Principal Inhibitor of Thrombin

Olds, R.J.; Lane, David A.; Mille, B.; Chowdhury, Vijoy; Thein, Swee Lay

doi:10.1055/s-2007-1001927

Cited by 51 publications

(24 citation statements)

References 91 publications

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“…These data suggested that both mutations would likely cause a type I AT deficiency in such patients. AT has two important functional domains, one is to inhibit clotting protease while the other is to bind heparin, by which the inhibition of protease can be accelerated by *1000 fold [4]. In the case of thrombin, heparin accelerates the protease inhibitor activity of AT via both approximation effects and conformational changes, while in the case of factor Xa and other clotting proteases, it enough activates via only conformational changes [15].…”

Section: Resultsmentioning

confidence: 99%

“…The inhibition of thrombin by AT, forming a covalent complex in a 1:1 molar ratio, is relatively slow, but is dramatically enhanced in the presence of glycosaminoglycan, heparin [4]. The plasma AT plays a key role in the natural hemostatic balance to maintain blood fluidity, and patients with AT deficiency are susceptible to thromboembolic diseases, particularly deep vein thrombosis of lower limb and pulmonary embolism [5].…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations

et al. 2007

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We analyzed the antithrombin (AT) gene in four unrelated Japanese patients with an AT deficiency, and individually identified four distinct mutations in the heterozygous state. There were two novel mutations, 2417delT leading to a frameshift with a premature termination at amino acid -3 (FS-3Stop) and C2640T resulting in a missense mutation (Ala59Val). Previously reported mutations, T5342C (Ser116Pro) and T72C (Met-32Thr), were also found in the other two patients. To understand the molecular basis responsible for the AT deficiency in these patients, in vitro expression experiments were performed using HEK293 cells transfected with either wild type or respective mutant AT expression vector. We found that -3Stop-AT and -32Thr-AT were not secreted into the culture media, whereas 116Pro-AT and 59Val-AT were secreted normally. We further studied the heparin cofactor activity and the binding to heparin of each recombinant AT molecule. Ser116Pro mutation significantly impaired the binding affinity to heparin resulting in a reduced heparin cofactor activity. In contrast, we found that Ala59Val mutant AT unexpectedly showed a normal affinity to heparin, but severely impaired the heparin cofactor activity. Our findings suggested that FS-3Stop and Met-32Thr mutations are responsible for type I AT deficiency, whereas Ser116Pro and Ala59Val mutations contribute to type II AT deficiency, confirming that there were diverse molecular mechanisms of AT deficiency depend upon discrete AT gene abnormalities as reported previously. Am. J. Hematol. 82:702-705, 2007. V

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations

et al. 2007

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“…Antithrombin (AT) is one of the most important protease inhibitors in plasma-regulating blood coagulation [1,2]. In healthy subjects, AT circulates in two isoforms, AT-· (90-95%) and AT-ß (5-10%).…”

Section: Introductionmentioning

confidence: 99%

Quantification of Antithrombin Isoform Proportions in Plasma Samples of Healthy Subjects, Sepsis Patients, and in Antithrombin Concentrates

Römisch¹,

Dönges²,

Stauss³

et al. 2002

Pathophysiol Haemos Thromb

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Antithrombin (AT) circulates in plasma in two isoforms, AT-α (90–95%) and AT-β (5–10%). AT isoform proportions were measured in plasma samples of 17 healthy subjects and 26 posttraumatic or postoperative septic patients, as well as in 4 commercially available AT concentrates. Total AT was immune-purified from plasma and concentrates. Micellar electrokinetic chromatography was used to analytically separate and quantify the isoforms. Compared with plasma samples of healthy donors, septic plasmas revealed significantly reduced AT activity (p < 0.001) and β-isoform content (p < 0.05). AT-β correlated inversely with urea and creatinine serum concentrations (p < 0.01), indicating a relationship between better renal function and higher β-isoform content. β-Isoform neither correlated with age, gender, and 28-day mortality, nor with plasma concentrations of various inflammatory and organ function parameters. The commercial AT concentrate, which is equivalent to the current WHO standard, had an AT-β content close to that found in plasma of healthy subjects. The availability of this novel quantitative AT isoform assay allows, for the first time, a closer look at the role of AT isoforms in hemostasis and sepsis pathophysiology.

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“…Antithrombin III (AT III) represents the most important physiological regulator of thrombin and other coagulation factors and it acts as an inhibitor of serine proteases (Olds et al, 1994). Human AT III (hAT III) is a single stranded glycoprotein with a molecular weight of approximately 58,000 Da, comprising a carbohydrate content of about 15%.…”

Section: Introductionmentioning

confidence: 99%

Production of recombinant human antithrombin III on 20-L bioreactor scale: Correlation of supernatant neuraminidase activity, desialylation, and decrease of biological activity of recombinant glycoprotein

Munzert

Heidemann²,

Lehmann³

et al. 1997

Biotechnol. Bioeng.

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Antithrombin: The Principal Inhibitor of Thrombin

Cited by 51 publications

References 91 publications

Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations

Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations

Quantification of Antithrombin Isoform Proportions in Plasma Samples of Healthy Subjects, Sepsis Patients, and in Antithrombin Concentrates

Production of recombinant human antithrombin III on 20-L bioreactor scale: Correlation of supernatant neuraminidase activity, desialylation, and decrease of biological activity of recombinant glycoprotein

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