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PubMed2003

Life-threatening thrombosis in mice with targeted Arg48-to-Cys mutation of the heparin-binding domain of antithrombin.

Antithrombin (AT) inhibits thrombin and some other coagulation factors in a reaction that is dramatically accelerated by binding of a pentasaccharide sequence present in heparin/heparan-sulfate to a heparin-binding site on AT. Based on the involvement of R47 in the heparin/AT interaction and the frequent occurrence of R47 mutations in AT deficiency patients, targeted knock-in of the corresponding R48C substitution in AT in mice was performed to generate a murine model of spontaneous thrombosis. The mutation efficiently abolished the effect of heparin-like molecules on coagulation inhibition in vitro and in vivo. Mice homozygous for the mutation (AT(m/m) mice) developed spontaneous, life-threatening thrombosis, occurring as early as the day of birth. Only 60% of the AT(m/m) offspring reached weaning age, with further loss at different ages. Thrombotic events in adult homozygotes were most prominent in the heart, liver, and in ocular, placental, and penile vessels. In the neonate, spontaneous death invariably was associated with major thrombosis in the heart. This severe thrombotic phenotype underlines a critical function of the heparin-binding site of antithrombin and its interaction with heparin/heparan-sulfate moieties in health, reproduction, and survival, and represents an in vivo model for comparative analysis of heparin-derived and other antithrombotic molecules.

Amino Acid Substitution↗

PubMed1996

The interactions between antithrombin III, thrombin and surface immobilized heparin.

The interactions between antithrombin III (ATIII), thrombin, and surface immobilized heparin were investigated. Carboxylated polystyrene modified with covalently immobilized albumin-heparin conjugate contain sites which can bind ATIII from buffer and plasma solutions. Approximately 65% of the ATIII molecules present at the heparinized surface either adsorbed from a buffer or plasma solution, exchanged with ATIII in buffer solution. The exchange between surface bound ATIII and ATIII in solution was repeated several times on the same heparinized surface. The number of binding sites that could bind and release ATIII was much higher when the heparinized surface was exposed to an ATIII containing buffer solution than to a plasma solution. The reduction in binding sites available for ATIII using plasma solutions as compared to buffer solutions could be explained by the competition of other plasma proteins with ATIII for the heparinized surface. It was observed that heparin binding proteins were able to compete with ATIII for binding to the immobilized heparin. Furthermore adsorption of proteins on the heparinized surface significantly reduced the availability of binding sites for ATIII. Exposure of thrombin to the heparinized surface resulted in thrombin activity at the surface. The thrombin activity on the heparinized surfaces was lower on surfaces with a higher ATIII concentration. The activity of surface bound thrombin was not affected by the presence of other plasma proteins. Enzymatically active thrombin molecules present at the heparinized surface were completely inactivated when the surface was exposed to a solution containing ATIII. The inactivation rate of surface bound thrombin by ATIII was higher than the rate of the uncatalyzed inactivation of thrombin in solution. Part of the Thrombin-Antithrombin III (TAT) complexes (10-20%) that were formed upon inactivation of thrombin remained bound to the heparinized surface. In general it was concluded that only the surface immobilized heparin molecules that can bind ATIII in a reversible way determine the anticoagulant properties of the surface. The mechanism of inactivation of a protease on a heparinized surface depends either on the catalytic effect of heparin on the inactivation rate of proteases by ATIII or on an increased uncatalytic inactivation due to increased concentrations of ATIII near the surface as compared to the concentration of ATIII in the bulk phase.

Adsorption↗

PubMed1983

Protection of factor Xa from neutralization by the heparin-antithrombin complex.

We have studied the accessibility of Factor Xa to neutralization by the heparin-antithrombin complex within plasma and whole blood. This serine protease was detected by measuring the concentrations of activation fragments (F2/F1+2) cleaved from prothrombin. The levels of F2/F1+2) were quantitated by means of a sensitive and specific radioimmunoassay. Our findings indicate that the binding of Factor Xa to "activated" platelets but not to phospholipid micelles results in the protection of the above enzyme from inactivation by the heparin-antithrombin complex. This sequestration of Factor Xa is not affected by the liberation of platelet release proteins or the molecular heterogeneity of the mucopolysaccharide preparations used. The magnitude of enzyme protection is strongly correlated with the extent of prothrombin activation at the time of heparin addition. On this basis, we suggest that high in vivo rates of thrombin generation may lead to the sequestration of Factor Xa on the platelet surface and hence allow this serine protease to resist the action of heparin until the complex is cleared from the circulation.

Antithrombins↗

PubMed1989

Molecular characterization of antithrombin III (ATIII) variants using polymerase chain reaction. Identification of the ATIII Charleville as an Ala 384 Pro mutation.

The genes of seven structural mutants of antithrombin III (ATIII), presenting either defective serine protease reactivity or abnormal heparin binding, were analyzed. The polymerase chain reaction (PCR) was used to amplify the corresponding gene exon and the mutation was identified by either dot blot analysis using a battery of allele-specific oligonucleotide probes or sequencing. Variants Paris and Paris 2 were identified as Arg 47 Cys mutations, and Clichy, Clichy 2, and Franconville were found to be Pro 41 Leu mutations. All five are heparin binding-site variants. ATIII Avranches is an Arg 393 His mutation and ATIII Charleville is an Ala 384 Pro mutation. These two mutations impair the reactive site of the molecule. ATIII Charleville is a new mutation of the reactive center, as predicted by previous biochemical data. The position of this new mutation, together with the other previously described mutations of the reactive center, sheds light on the molecular function of this site in inhibiting thrombin. Finally, genomic amplification by PCR is a powerful technique for the fast identification of antithrombin III mutations and their homozygous/heterozygous status, and should be useful for predicting thrombotic risk.

Adult↗

PubMed1992

Congenital antithrombin III deficiency causing mesenteric venous infarction: a lesson to remember--a case history.

Congenital antithrombin III deficiency is an uncommon but important cause of venous thrombosis, usually presenting with recurrent or atypical venous thromboembolism. Its importance lies in the fact that early recognition can lead to treatment in the acute stage, which can prevent propagation of the disease, and further prophylactic treatment may reduce the incidence of further episodes. The authors present a case of mesenteric venous infarction associated with congenital antithrombin III deficiency and briefly discuss the diagnosis, surgical implications, and treatment of this disorder.

Antithrombin III Deficiency↗

PubMed1995

Portal vein thrombosis due to antithrombin III deficiency. A case report.

The authors report a case of intrahepatic portal vein thrombosis in a sixty-four-year-old Japanese man with antithrombin III deficiency who successfully underwent cholecystectomy and common bile duct exploration. To their knowledge, this is the first report of portal vein thrombosis due to primary antithrombin III deficiency.

Antithrombin III Deficiency↗

PubMedDate not supplied

Antithrombin III, protein C and protein S plasma levels in patients with Behçet's disease.

The association between natural inhibitors of coagulation and thrombophilia was investigated in 35 patients with Behcet's disease. Antithrombin III and protein C levels were measured using synthetic chromogenic substrate methods, and protein S levels by quantitative enzyme-linked immunosorbent assay. There were no significant differences between patients and controls in plasma antithrombin III, protein C and free protein S concentrations. We conclude that there was no evidence of a primary coagulation inhibitor abnormality in patients with Behçet's disease.

Adolescent↗

PubMedDate not supplied

Attenuation of leukocyte beta 2-integrin expression by antithrombin-III.

Antithrombin-III exerts antiinflammatory effects via ligation of heparan sulfate proteoglycans. Here we show in vitro that recombinant human antithrombin-III attenuates CD11b/CD18 expression of activated neutrophils and monocytes in whole blood ex vivo. As leukocyte integrin expression is triggered by extracorporeal circulation, this observation may be of relevance for pharmacological treatment during cardiopulmonary bypass.

Adult↗

PubMed1997

Effect of 15-hydroperoxyeicosatetraenoic acid on the fibrinolytic factor release and the antithrombin binding of vascular endothelial cells.

15-Hydroperoxyeicosatetraenoic acid (15-HPETE), an arachidonate lipoxygenase product, is reported to induce severe endothelial injury. In this study, we examined the effect of 15-HPETE on the release of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) from cultured human umbilical vein endothelial cells (HUVEC). The addition of 15-HPETE to the serum-free medium reduced the release of t-PA antigen from HUVEC, while the release of PAI-1 antigen was significantly enhanced. However, treatment of the cultured HUVEC with alpha-tocopherol or nordihydroguaiaretic acid completely suppressed the 15-HPETE-induced change in t-PA and PAI-1 antigen release. 15-Hydroxyeicosatetraenoic acid (15-HETE) had no effect on the release of either antigen from cultured HUVEC. The HUVEC surfaces exposed to 15-HPETE decreased the potency for binding antithrombin III. In a reconstituted system with heparin and phosphatidylcholine, 15-HPETE decreased the ability of heparin to inactivate thrombin activity. These results suggest that the fibrinolytic factor release and the antithrombin binding of vascular endothelial cells are impaired by the attack of 15-HPETE, and that the presence of antioxidants prevents the injurious action of lipid hydroperoxide.

Antioxidants↗

PubMed1989

Application of thrombin-antithrombin III complex for detecting a latent hypercoagulable state in patients with coronary artery disease.

It is thought that a hypercoagulable state contributes to the pathogenesis of coronary artery disease (CAD), but few sensitive markers have been available for detecting the state. In the present study the plasma level of thrombin-antithrombin III complex (TAT), a specific indicator of thrombin generation in blood, was investigated before and after a submaximal exercise test in 18 patients with CAD and in 12 healthy controls. The mean (+/- SEM) value of plasma TAT before the exercise was 3.30 (0.81) ng/ml in the patient group and 1.49 (0.08) ng/ml in controls, and its level increased to 29.22 (5.74) ng/ml and 12.07 (2.89) ng/ml after the exercise, respectively. Thus, the TAT value in the patient group was higher than that in the controls both before and after the exercise. However, no differences could be found between the groups in the following parameters; prothrombin time, activated partial thromboplastin time, antithrombin III, fibrinogen, FDP, plasminogen, alpha 2-plasmin inhibitor, and alpha 2-macroglobulin. Through these results it was concluded that plasma TAT level could be a sensitive marker for latent activation of blood coagulation, and also that the results of these experiments showed that patients with CAD were in a latent hypercoagulable state.

Adolescent↗

PubMed2005

Development of a fed-batch culture process for enhanced production of recombinant human antithrombin by Chinese hamster ovary cells.

Antithrombin is a serine protease inhibitor that inactivates several coagulation proteases, primarily thrombin and factor Xa. The Chinese hamster ovary (CHO) cell line transfected with a vector expressing recombinant human antithrombin (rAT) and a selectable marker, glutamine synthetase (GS), was cultivated in a 2-l fed-batch culture process using serum-free, glutamine-free medium. To maximize the rAT yield, effects of culture pH, balanced amino acid feeding, and an increased glutamate concentration on cell metabolism and rAT production were investigated. When cells were grown at pH values of 6.6, 6.8, 7.0, and 7.2, the maximum cell density and maximum lactate concentration decreased with decreasing pH. The highest production level of rAT was obtained at culture pH 6.8 due to the extended culture lifetime. Compared to the imbalanced amino acid feeding at culture pH 6.8, the balanced amino acid feeding increased the amount of rAT activity by 30% as a result of an increased viable cell number. A decrease in the specific glucose consumption rate (q(Glc)) with increasing culture time was observed in all the above-mentioned experiments, while the glucose concentration was maintained above 0.7 g l(-1). In addition, a decrease in the specific rAT production rate (q(rAT)) was observed after the depletion of lactate in the late cultivation stage. Taken together, these results suggest that the reduced availability of cellular energy caused by the decrease in q(Glc) and depletion of lactate led to the decrease in q(rAT). This decrease in q(rAT) was partially prevented by increasing the residual glutamate concentration from 1 mM to 7 mM, thus resulting in an additional 30% increase in the amount of rAT activity. The optimized fed-batch culture process yielded 1.0 g l(-1) rAT at 287 h of cultivation.

Animals↗

PubMed2005

Production of recombinant human antithrombin by Pichia pastoris.

This paper deals with the production of recombinant human antithrombin (rAT) by the methylotrophic yeast Pichia pastoris. In preliminary methanol-limited fed-batch fermentation, the rAT concentration reached 324 mg/l at 192 h of cultivation, but the specific heparin cofactor (HC) activity of rAT in the culture supernatant was 10% of that of plasma-derived antithrombin (pAT). To improve the specific HC activity of rAT, effort was first focused on the optimization of culture pH and media composition, resulting in protection of rAT against pH-dependent instability and proteolytic degradation. However, even in the optimized methanol-limited fed-batch fermentation, the specific HC activity of rAT in the culture supernatant was still 20% that of pAT. To investigate the unknown mechanisms involved in the decreased specific HC activity of rAT, the culture supernatant of mock-transfected cells was prepared by methanol-limited fed-batch fermentation. When pAT was added to this supernatant, a rapid decrease in HC activity was observed; the residual HC activity was 26% after 24 h of incubation at 25 degrees C. The loss of pAT activity was prevented by addition of a formaldehyde scavenger, amino urea, to the supernatant. In addition, alcohol oxidase activity was observed in the supernatant, resulting in the accumulation of formaldehyde in the culture broth. These results suggest that the formaldehyde produced by methanol oxidation in the culture broth of P. pastoris might decrease the HC activity of rAT during fermentation. Replacing the methanol with glycerol as the carbon source improved the specific HC activity of rAT from 20% to above 40% of that of pAT. In the glycerol-limited fed-batch fermentation, rAT is expressed at 100 mg/l under the control of the truncated mutated AOX2 promoter.

Antithrombins↗

PubMed1980

The determination of antithrombin III, alpha 2-macroglobulin and alpha 2-antiplasmin in plasma by laser nephelometry.

Specific assay procedures were developed to determine antithrombin III, alpha 2-macroglobulin, and alpha 2-antiplasmin in plasma with the aid of a Laser nephelometer. About 100 normal and pathological plasmas were examined and the results compared with those obtained by conventional immunological methods, such as radial immunodiffusion or rocket electrophoresis. Nephelometry proved to be a very rapid, precise, and reproducible method for the determination of antithrombin III and alpha 2-macroglobulin. The reproducibility of the alpha 2-antiplasmin assay was poor, probably as a consequence of the low concentration of this inhibitor in normal plasma.

Antithrombin III↗

PubMed1995

Catastrophic secondary antiphospholipid syndrome with concomitant antithrombin III deficiency.

The association between thrombotic events and primary or secondary antiphospholipid/anticardiolipin syndrome is now well recognized. A spectrum of renal involvement ranging from glomerular thrombosis to renal infarction has been described. A case of systemic lupus erythematosus with immunoglobulin G and M antiphospholipid/anticardiolipin antibodies is reported. The patient developed catastrophic thrombosis in multiple organs, and glomerular thrombosis was documented by renal biopsy. The patient had an acquired antithrombin III deficiency, and the combination of secondary antiphospholipid syndrome with accompanying antithrombin III deficiency predisposed to thrombosis. Several mechanisms by which antiphospholipid/anticardiolipin antibodies cause thrombosis have been proposed and are briefly reviewed.

Adult↗

PubMed2000

Effects of an antithrombin drug in patients with subacute exacerbations of Binswanger disease.

The blood coagulation system has been shown to be activated in subacute exacerbations of Binswanger disease (BD). In our previous study, the antithrombin drug argatroban t ameliorated the neurological exacerbations in a BD patient with antiphospholipid antibody syndrome. We have further examined the therapeutic efficacy of argatroban in 3 BD patients with subacute exacerbations, but without any immune-mediated prothrombotic complications. In 1 out of these 4 patients, treatment with sodium ozagrel, an antiplatelet drug was applied, but was ineffective. In all patients, argatroban treatment reduced the levels of the hemostatic markers, with a corresponding improvement in cognitive dysfunction and gait disorders. These results suggest that the antithrombin effect is true also for BD patients not compromised by the immune-mediated prothrombotic condition.

Acute Disease↗

PubMed1998

Activated protein C resistance and deficiencies of antithrombin III, protein C or protein S and the risk of thromboembolic disease in users of oral contraceptives.

The objective of this paper was to assess the risk of thrombosis in users of oral contraceptives. Furthermore, the sensitivity, specificity and predictive values of potential screening tests for the prediction of thromboembolic complications in users of oral contraceptives were calculated for the approximately six million German pill users. Despite high specificity, the predictive values of a positive family history, or evidence of either antithrombin III, protein C or protein S deficiency or resistance to activated protein C, are low due to the very low absolute risk of thrombosis among pill users. More than half of the 840 annual cases would pass the screening protocol undetected. A two-step screening protocol is suggested using family history as a selection criterion (thus reducing the need for laboratory screening by 85%) for laboratory investigation of activated protein C sensitivity and deficiencies of antithrombin III, protein C or protein S. Genotyping for factor V Leiden mutation is useful in cases with equivocal activated protein C sensitivities or to confirm a homozygous genotype.

Antithrombin III Deficiency↗

PubMedDate not supplied

The effects of varying dietary n-6 to n-3 fatty acid ratios on platelet reactivity, coagulation screening assays, and antithrombin III activity in dogs.

Thirty beagles were placed on diets containing ratios of n-6 to n-3 fatty acids ranging from 5:1 to 100:1 for 12 weeks to determine the effects of these diets on platelet reactivity, coagulation screening assays, and antithrombin III activity. Although small changes were observed in adenosine diphosphate (ADP)-, collagen-, and arachidonic acid-induced platelet aggregation and 14C-serotonin release, fibrinogen concentrations, and antithrombin III activities during the 12-week study, these changes were not of clinical significance and did not correlate with the varying ratios of n-6 to n-3 fatty acids.

Adenosine Diphosphate↗

PubMedDate not supplied

[Effect of antithrombin III on anticoagulating system function in animals intravenously injected with tissue thromboplastin].

In experiments with rats, antithrombin III (a natural inhibitor of fibrinolysis) was shown to decrease the activation of the anticoagulation system either in prophylactic administration or during the development of thrombogenesis, caused by intravenous administration of tissue thromboplastin. The phenomenon led to the maintaining of the more high content of fibrinogen in blood of experimental animals, to the shortening of the thrombin time and to the increase in content of alpha2-macroglobulin and alpha1-antitrypsin (in-hibitors of fibrinolysis) as compard with control animals, administered with the only thrombolastin. Effect of antithrombin III depended on periods of administration of the prearation and on injection of tissue thromboplastin.

Afibrinogenemia↗