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PubMed2002

Antithrombin III. Key factor in extracorporeal circulation.

Antithrombin III plays many different roles during cardiac operations with cardiopulmonary bypass. Basically, it acts as the natural inhibitor of thrombin, which, in presence of heparin, blocks the thrombin action and avoids gross thrombus formation inside the extracorporeal circulation circuit. By acting as a "suicide substrate", antithrombin III is consumed during cardiopulmonary bypass; at the same time, thrombin is extensively formed during and after cardiopulmonary bypass. As a result, at the end of the operation there is a potential imbalance in the antithrombin III-thrombin interaction, leading to a prothrombotic status. Moreover, patients pre-treated with heparin reach the operating theater with reduced levels of circulating antithrombin III; this may lead to the heparin resistance phenomenon and may further increase the risk for postoperative thrombotic complications. Finally, the anti-inflammatory properties of antithrombin III in the setting of the "whole body inflammatory reaction" induced by the cardiopulmonary bypass represents a new and unexplored field of research.

Anticoagulants↗

PubMed2003

Antithrombin III activity in cerebrovascular accidents.

UNLABELLED: Cerebrovascular accidents are commonly due to occlusive or haemorrhagic lesions. The present prospective study was planned to find out role of antithrombin in possible etiopathological process, which might predispose an individual for stroke. METHOD: Biological activity of antithrombin III was done by the method as described by Innerfield et al (1976). Immunological estimation of an antithrombin III was done by single radial immunodiffusion by the technique of Mancini et al modified by Fahey and Mckelvey. RESULTS: The biological and immunological activity of antithrombin III was measured in 98 patient of occlusive and 56 patients of haemorrhagic strokes. Significant depression in biological as well as immunological activity (p<0.001) was observed in occlusive stroke. In haemorrhagic stroke both, biological and immunological activity was increased. In follow up study, there was progressive normalization of both, biological as well as of immunological activity in both group. CONCLUSION: Decrease of antithrombin III in occlusive and increase in haemorrhagic stroke indicates that these changes have at least an additive role in the pathogenesis of stroke.

Adult↗

PubMedDate not supplied

[Antithrombin and protein C activity in the blood of premature newborns with intrauterine growth retardation].

UNLABELLED: Intrauterine growth retardation (IUGR) and prematurity are often correlated with higher mortality and morbidity in the first days of life especially due to complications such as: hypoglycemia, polycythemia, necrotizing enterocolitis, meconium aspiration syndrome. Disturbances in the haemostatic system could be responsible for poor outcome of these complications. AIM: To determine the activity of main inhibitor of coagulation-antithrombin, level of protein C, concentration of thrombin-antithrombin (TAT) complexes and fibrinogen in the blood of premature infants with intrauterine growth retardation (IUGR) in comparison with premature infants without IUGR. MATERIAL: 33 premature infants with symptoms of intrauterine growth retardation (IUGR) and 146 premature infants without IUGR were included in our trial. RESULTS: There were no statistical differences between the analyzed groups in the level of protein C, concentration of TAT and fibrinogen. Activity of antithrombin was higher within 1 hour after birth and lower on the third day of life in the group of children with IUGR. CONCLUSIONS: Higher activity of antithrombin after birth in the group of newborns with IUGR prevents excessive activation of coagulation. On the third or fourth day of life the activity of antithrombin decreases due to its higher consumption in the blood of newborns with IUGR.

Antithrombin III↗

PubMed2006

Performance goals for the laboratory testing of antithrombin, protein C and protein S.

To achieve a reliable analytical quality for both monitoring and diagnostic testing, laboratories need to fulfil the widely accepted analytical performance goals based on the biological variation of the analytes of testing. Not only is the short-term analytical performance, which regularly is assessed by internal quality control procedures, of importance, but also the long-term analytical performance. To assess the long-term analytical performance, data obtained from an external quality assessment programme can be used. In this study we have used the evaluation model designed by the ECAT Foundation for the assessment of the longterm analytical performance, including imprecision, bias and total analytical error. The model was applied to the data from 136 different laboratories for the assay of antithrombin (activity), protein C (activity and antigen) and protein S (activity, total and free antigen). The imprecision (median; range), reflected by the long-term analytical coefficient of variation (LCV (A) ), was the lowest for antithrombin (7.6%; 2.6 - 43.8%) and the highest for protein S activity (17.2%; 4.3 - 88.6%). For bias and total error the same pattern was observed (antithrombin: 3.8%; 0.3 - 17.1% and 9.1%; 3.4 - 34.3%, respectively; protein S activity: 12.8%; 3.1 - 34.8% and 24.5%; 9.9 - 87.0%, respectively). For the majority of the laboratories (70 - 85%) the imprecision contributes considerably more to the total error than the bias. However the effect of the bias on the analytical quality is not negligible. Assays for antithrombin, protein C and protein S are mainly used for diagnostic testing. About 70 - 100% of the laboratories can fulfil the desirable performance goal for imprecision. The desirable performance goal for bias was reached by 50 - 95% of the laboratories. In all cases the highest numbers of laboratories fulfilling performance goals was obtained for the protein C variables. To improve the analytical quality in assays of antithrombin, protein C and protein S it is highly recommended that primarily imprecision (non-systematic failures) be suppressed. However the effect of the bias (systematic failures) on the analytical quality should not be neglected. A useful tool for determining the imprecision (LCV (A) ) and bias is the long-term analytical performance evaluation model as used by the ECAT Foundation.

Antithrombin III↗

PubMedDate not supplied

The significance of low antithrombin III levels in cirrhosis.

Antithrombin III is an anticoagulant synthesized in the liver cells. The aim of this study was to estimate the serum level of antithrombin III in cirrhotics. Investigations were carried out in 32 patients with cirrhosis and in 20 healthy controls. Antithrombin III measured by radial immunodiffusion was found significantly lower (19.2 +/- 6.8 mg%) than in controls (28.0 +/- +/- 5.2 mg%) (p less than 0.01). The level of antithrombin III is positively correlated with pseudo-cholinesterase and, less significantly with blood albumin. Therefore decreased antithrombin III reflects liver cell disfunction in cirrhosis and its decrease may predispose to thrombotic events which occur sporadically in cirrhosis.

Antithrombin III↗

PubMed1990

Rat heparan sulphates. A study of the antithrombin-binding properties of heparan sulphate chains from rat adipose tissue, brain, carcase, heart, intestine, kidneys, liver, lungs, skin and spleen.

Adult male rats were given [35S]sulphate intraperitoneally. Heparan [35S]sulphate (HS) chains were recovered from adipose tissue, brain, carcase, heart, intestine, kidneys, liver, lungs, skin and spleen by digestion with Pronase, precipitation with cetylpyridinium chloride, digestion with chondroitin ABC lyase and DNAase and gradient elution from DEAE-Sephacel. Purity was confirmed by agarose-gel electrophoresis and degradation with HNO2. Fractionation by gradient elution from antithrombin-agarose indicated that the proportion of HS with high binding affinity for antithrombin (HA-HS) ranged from 4.7% (kidneys) to 21.5% (brain). On a mass basis the major sources of HA-HS were carcase, skin and intestine. HA-HS from intestine was arbitrarily divided into subfractions I-VI, with anticoagulant activities ranging from 1 to 60 units/mg [by amidolytic anti-(Factor IIa) assay] and from 4 to 98 units/mg [by amidolytic anti-(Factor Xa) assay], indicating that the antithrombin-binding-site densities of HA-HS chains covered a wide range, as shown previously for rat HA-heparin chains [Horner, Kusche, Lindahl & Peterson (1988) Biochem. J. 251, 141-145]. HA-HS subfractions II, IV and VI were mixed with samples of HA-[3H]heparin chains and rechromatographed on antithrombin-agarose. Affinity for matrix-bound antithrombin did not correlate with anticoagulant activity, e.g. HA-HS subfraction IV [38 anti-(Factor Xa) units/mg] was co-eluted with HA-heparin chains [127 anti-(Factor Xa) units/mg].

Adipose Tissue↗

PubMed1987

Neutralization and binding of heparin by S protein/vitronectin in the inhibition of factor Xa by antithrombin III. Involvement of an inducible heparin-binding domain of S protein/vitronectin.

The interference of the heparin-neutralizing plasma component S protein (vitronectin) (Mr = 78,000) with heparin-catalyzed inhibition of coagulation factor Xa by antithrombin III was investigated in plasma and in a purified system. In plasma, S protein effectively counteracted the anticoagulant activity of heparin, since factor Xa inhibition was markedly reduced in comparison to heparinized plasma deficient in S protein. Using purified components in the presence of heparin, S protein induced a concentration-dependent reduction of the inhibition rate of factor Xa by antithrombin III. This resulted in a decrease of the apparent pseudo-first order rate constant by more than 10-fold at a physiological ratio of antithrombin III to S protein. S protein not only counteracted the anticoagulant activity of commercial heparin but also of low molecular weight forms of heparin (mean Mr of 4,500). The heparin-neutralizing activity of S protein was found to be mainly expressed in the range 0.2-10 micrograms/ml of high Mr as well as low Mr heparin. S protein and high affinity heparin reacted with apparent 1:1 stoichiometry to form a complex with a dissociation constant KD = 1 X 10(-8) M as determined by a functional assay. As deduced from dot-blot analysis, direct interaction of radiolabeled heparin with S protein revealed a dissociation constant KD = 4 X 10(-8) M. Heparin binding as well as heparin neutralization by S protein increased significantly when reduced/carboxymethylated or guanidine-treated S protein was employed indicating the existence of a partly buried heparin-binding domain in native S protein. Radiolabeled heparin bound to the native protein molecule as well as to a BrCN fragment (Mr = 12,000) containing the heparin-binding domain as demonstrated by direct binding on nitrocellulose replicas of sodium dodecyl sulfate-polyacrylamide gels. Kinetic analysis revealed that the heparin neutralization activity of S protein in the inhibition of factor Xa by antithrombin III could be mimicked by a synthetic tridecapeptide from the amino-terminal portion of the heparin-binding domain. These data provide evidence that the heparin-binding domain of S protein appears to be unique in binding to heparin and thereby neutralizing its anticoagulant activity in the inhibition of coagulation factors by antithrombin III. The induction of heparin binding and neutralization may be considered a possible physiological mechanism initiated by conformational alteration of the S protein molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

Antithrombin III↗

PubMed1989

Characterization of recombinant human antithrombin III synthesized in Chinese hamster ovary cells.

Biochemical and physiochemical properties of recombinant human antithrombin III were examined. This protein, produced in Chinese hamster ovary cells, showed a conformation apparently identical with the natural product isolated from human plasma when examined by circular dichroism, UV absorbance, and fluorescence spectroscopy. Comparison of the NH2-terminal sequences of recombinant and human plasma-derived antithrombin III showed that on synthesis and secretion of the recombinant protein from Chinese hamster ovary cells the signal peptide is correctly cleaved by the corresponding endoplasmic signal peptidase. The recombinant antithrombin III has identical properties in heparin binding and biological activities as determined in vitro by two-dimensional immunoelectrophoresis, progressive inhibitor, and heparin cofactor assays. Analysis of the carbohydrate portion of recombinant antithrombin III synthesized in Chinese hamster ovary cells revealed glycosylation of the complex type. Characterization of the oligosaccharide chains present in the recombinant protein reveals three major fractions, A (20%), B (60%), and C (20%). Fraction A contains tri- and tetraantennary complex-type oligosaccharides, fraction B contains biantennary oligosaccharides, and fraction C partially truncated biantennary structures. Pharmacokinetic studies with recombinant and plasma-derived antithrombin III in rabbits showed that the clearance behavior of both proteins is very similar and can be described by a double exponential decrease with almost identical kinetic parameters.

Animals↗

PubMed1989

Transient kinetics of heparin-catalyzed protease inactivation by antithrombin III. Characterization of assembly, product formation, and heparin dissociation steps in the factor Xa reaction.

The kinetics of alpha-factor Xa inhibition by antithrombin III (AT) were studied in the absence and presence of heparin (H) with high affinity for antithrombin by stopped-flow fluorometry at I 0.3, pH 7.4 and 25 degrees C, using the fluorescence probe p-aminobenzamidine (P) and intrinsic protein fluorescence to monitor the reactions. Active site binding of p-aminobenzamidine to factor Xa was characterized by a 200-fold enhancement and 4-nm blue shift of the probe fluorescence emission spectrum (lambda max 372 nm), 29-nm red shift of the excitation spectrum (lambda max 322 nm), and dissociation constant (KD) of about 80 microM. Under pseudo-first order conditions [( AT]0, [H]0, [P]0 much greater than [Xa]0), the observed factor Xa inactivation rate constant (kobs) measured by p-aminobenzamidine displacement or residual enzymatic activity increased linearly with the "effective" antithrombin concentration (i.e. corrected for probe competition) up to 300 microM in the absence of heparin, indicating a simple bimolecular process with a rate constant of 2.1 x 10(3) M-1 s-1. In the presence of heparin, a similar linear dependence of kobs on effective AT.H complex concentration was found up to 25 microM whether the reaction was followed by probe displacement or the quenching of AT.H complex protein fluorescence due to heparin dissociation, consistent with a bimolecular reaction between AT.H complex and free factor Xa with a 300-fold enhanced rate constant of 7 x 10(5) M-1 s-1. Above 25 microM AT.H complex, an increasing dead time displacement of p-aminobenzamidine and a downward deviation of kobs from the initial linear dependence on AT.H complex concentration were found, reflecting the saturation of an intermediate Xa.AT.H complex with a KD of 200 microM and a limiting rate of Xa-AT product complex formation of 140 s-1. Kinetic studies at catalytic heparin concentrations yielded a kcat/Km for factor Xa at saturating antithrombin of 7 x 10(5) M-1 s-1 in agreement with the bimolecular rate constant obtained in single heparin turnover experiments. These results demonstrate that 1) the accelerating effect of heparin on the AT/Xa reaction is at least partly due to heparin promoting the ordered assembly of antithrombin and factor Xa in an intermediate ternary complex and that 2) heparin catalytic turnover is limited by the rate of conversion of the ternary complex intermediate to the product Xa-AT complex with heparin dissociation occurring either concomitant with this step or in a subsequent faster step.

Antithrombin III↗

PubMed1987

[Effect of rabbit thrombomodulin on the inhibition of thrombin by the antithrombin-heparin complex: role of the acid domain of thrombomodulin].

Acidic and non-acidic forms of rabbit thrombomodulin were studied with regard to their effects on the inhibition of thrombin by antithrombin in the presence of exogenous heparin. The non acidic form was obtained by proteolytic cleavage of a polyanionic component (presumably a sulfated polysaccharide) from the parent acidic form of thrombomodulin, and purified by ion-exchange chromatography. It was previously found that the acidic form of thrombomodulin increases the rate of thrombin inactivation by antithrombin. The present study showed that thrombin bound to acidic thrombomodulin was inactivated at a lower rate by antithrombin in the presence of exogenous heparin than was free thrombin or thrombin bound to the non-acidic form of thrombomodulin. The data suggest that the acidic component of thrombomodulin is primarily responsible for the retardation of thrombin-antithrombin complex formation in the presence of exogenous heparin. It is proposed that the polyanionic component of thrombomodulin blocks a site on thrombin required for heparin binding, thus rendering the antithrombin-heparin complex ineffective.

Animals↗

PubMedDate not supplied

Clinical studies on plasma antithrombin III using an antiserum prepared in our laboratories.

Using an antiserum obtained in rabbits injected with antithrombin III purified in our laboratories, the plasma level of this inhibitor of coagulation was found to be significantly (p less than 0.001) decreased in 8 patients with decompensated cirrhosis of the liver (15.66 mg/dl +/- 2.22) and in 18 nephrotic patients (21.74 mg/dl +/- 1.75). When compared to values noted in 22 normal-weight normolipidemic control subjects (31.54 mg/dl +/- 0.81), the plasma level of antithrombin III was slightly (p less than 0.05) higher in the 18 hyperlipidemic subjects (36.11 mg/dl +/- 1.9). Owing to an extremely wide dispersion of individual values, the mean level of antithrombin III noted in 16 critically ill postoperative patients (28.16 mg/dl +/- 2.98) did not significantly differ from control values, although this protease inhibitor was obviously decreased in those postoperative patients who developed multiple organ failure or disseminated intravascular-coagulation. Among the 11 patients with recurrent venous thrombosis, two subjects with familial deficiency in antithrombin III were detected. The results provide evidence that the antiserum prepared in our laboratories is a useful tool for detecting acquired and inherited antithrombin III deficiencies.

Adult↗

PubMed1986

Characterization of an abnormal antithrombin (Milano 2) with defective thrombin binding.

Four members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and half-normal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus' plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus' plasma to human alpha-thrombin immobilized on sepharose beads revealed defective binding of the antithrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

Adult↗

PubMed1987

Heparin binding defect in a new antithrombin III variant: Rouen, 47 Arg to His.

Antithrombin III (AT-III) Rouen is a hereditary abnormal antithrombin with normal progressive inhibitory activity and reduced heparin cofactor activity. It was isolated from the plasma of a woman who suffered a sudden idiopathic sensorineural hearing loss and balance impairment. There was no familial history of thrombosis. By heparin-Sepharose chromatography, AT-III Rouen was separated from the normal antithrombin on elution with increasing concentrations of NaCl. AT-III Rouen eluted earlier than is normal at both pH 7.4 and pH 6.0. At the lower pH, the antithrombins bound more avidly to the column, with the abnormal AT-III eluting closer to the normal than at the higher pH. Two-dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests of carboxymethylated antithrombins was performed on thin-layer silica plates. The abnormal peptide was located by tryptophan staining, and amino acid analysis and sequence studies demonstrated a substitution of an arginine at residue 47 for a histidine. Results from this study suggest that replacement of arginine 47 by a partially positively charged histidine has less effect on the heparin binding affinity than dose replacing it with a neutral cysteine side chain as in AT-III Toyama, in which no heparin binding was observed. In addition, heparin binding per se is not a sufficient condition to activate AT-III.

Adult↗

PubMed1987

Histidine-rich glycoprotein modulation of the anticoagulant activity of heparin. Evidence for a mechanism involving competition with both antithrombin and thrombin for heparin binding.

Heparin binding to rabbit histidine-rich glycoprotein (HRG) was studied in a purified system, allowing for determination of a heparin dissociation constant of approximately 5.5 X 10(-8) M for the interaction with HRG at pH 7.0. The strong interaction between heparin and HRG was demonstrated to be competitive with the binding of both antithrombin and thrombin to the heparin chain. HRG was further tested as a modulator of the anticoagulant activity of heparin by comparing rates of the heparin-catalyzed reaction between antithrombin and thrombin in the presence and absence of added HRG. The heparin-antithrombin-thrombin reaction was modeled using the formalism of a two-substrate enzyme-catalyzed reaction with heparin as the enzyme and HRG analyzed as an enzyme inhibitor. HRG was shown to compete with both antithrombin and thrombin for binding to heparin by this kinetic analysis. Thus, both the kinetic and heparin-binding data indicate that the mechanism by which HRG modulates heparin anticoagulant activity involves competition for heparin with both the inhibitor and the protease. Inhibition by HRG of the heparin-catalyzed reaction was found to be highly dependent on pH, with a sharp increase in inhibition from about 15% to greater than 90% observed as pH was lowered from 7.4 to 7.0. Since little change in the rate of the heparin-catalyzed inhibition of thrombin by antithrombin occurs in this pH region, the dramatic change in HRG inhibition seen upon pH titration may reflect increasing ionic interaction between heparin and HRG due to the protonation of histidine residues which occurs in this pH region.

Antithrombins↗

PubMed1985

Antithrombin deficiency in end-stage renal disease associated with paraplegia: effect of hemodialysis.

Plasma antithrombin III activity and concentration were determined in nine men with end-stage renal disease (ESRD) associated with spinal cord injury (SCI). To determine the possible effects of hemodialysis measurements were repeated following dialysis. Values obtained in the SCI-ESRD group were compared with those obtained in a group of healthy volunteers and a group of 10 ambulatory men with ESRD. A normal pooled plasma was used as the internal standard for all assays. While antithrombin deficiency was observed in both uremic groups it was most severe in the group with SCI. Results demonstrated the association of antithrombin deficiency with ESRD and its potentiation in the presence of SCI. The mechanisms by which SCI compounds the uremia-induced antithrombin deficiency were not known. A mild increase in antithrombin level was noted following dialysis and was thought to be in part due to fluid removal by dialysis.

Adult↗

PubMedDate not supplied

[Antithrombin III activity in relation to multiple administration of various doses of heparin to normal animals].

Heparin affected the content of antithrombin III and the thrombin time of blood plasma coagulation depending on the dose of the anticoagulant administered (eight intravenous administrations at single doses of 225, 150, 75, 37 or 18 IU/kg of body mass of healthy rats). High doses of heparin decreased more distinctly the content of antithrombin III as compared with low doses. 8 intravenous infusions of small doses of heparin (37 IU/kg) as well as intramuscular administration of the anticoagulant (10 injections) at a dose of 225 IU/kg caused a compensatory increase in content of antithrombin III. After 30 intramuscular administrations the compensatory reaction of antithrombin III disappeared. In this case the content of antithrombin III and the thrombin time of blood plasma coagulation exhibited stability towards the anticoagulant effect.

Animals↗

PubMed1984

Antithrombin, antitrypsin and antichymotrypsin activities of the salivary gland secretion and intestinal chyme of medicinal leeches. Antichymotrypsin activity of partially purified preparations of hirudin and pseudohirudin.

High antithrombin activity was maintained in the salivary gland secretion of starved medicinal leeches (Hirudo medicinalis) despite harvesting of the secretion twice in a month. However, after third or fourth harvesting every month antithrombin activity was no longer detectable. Moreover, in salivary gland secretion high antitrypsin activity was found but no antichymotrypsin activity. On the other hand, intestinal chyme of starved leeches exhibited high antichymotrypsin activity. Low antithrombin and antitrypsin activities were due to contamination by salivary gland secretion. There was a correlation between antichymotrypsin and antithrombin activities of hirudin preparations purified from bdellins and fractionated by isoelectric focusing. Pseudohirudin preparations exhibited neither antithrombin nor antichymotrypsin activities.

Animals↗

PubMed1978

Human antithrombin III. Carbohydrate components and associated glycolipid.

Human antithrombin III was found to contain covalently linked N-acetylglucosamine, mannose, galactose, and sialic acid in a molar ratio of approximately 1:1:0.6:1. Sialic acid was released upon treatment with neuraminidase. The modified glycoprotein retained the capability to inhibit thrombin and to bind with heparin. Antithrombin III isolated by different procedures was also found to contain glucose in an approximately equimolar ratio with N-acetylglucosamine. Th" glucose-containing component was extractable with lipid solvents and shown to be beta-glucosylceramide. This glycolipid is tightly complexed with antithrombin III and could not be separated by fractional precipitations or ion exchange gels. Although it remains to be established whether the inhibitory actions of antithrombin III are affected by glucosylceramide, the relative amounts which are bound suggest that antithrombin III may be a significant carrier of the glycolipid.

Antithrombins↗