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[Antithrombin III in 86 patients with venous thrombosis (author's transl)].

Antithrombin III concentration was studied in 86 patients with recurrent or extensive venous thrombosis. Two of them were found to have an hereditary antithrombin III deficiency. 25 patients receiving heparin therapy had low antithrombin III concentration. After stopping heparin treatment antithrombin rose to a normal level. Pathological antithrombin III modifications are recalled (synthesis decrease in liver diseases, intra vascular consumption during active venous thrombosis). Antithrombin III decreased activity induced by heparin treatment is pointed out.

Antithrombin III↗

PubMed1990

The inactivation of antithrombin III by serum elastase in patients with surgical infections.

The relationship between serum elastase and antithrombin III was determined in septic surgical patients as a possible mechanism for intravascular thrombosis and hypercoagulability during sepsis. Eighteen patients with surgical infections and elevated white blood cell counts had their blood assayed daily for white blood cell count, serum elastase, and antithrombin III, until the patient's white blood cell count returned to normal. Antithrombin III was significantly lower (0.87%) when elastase was above the normal range (greater than 14.2 micrograms/ml). Elastase was significantly higher (30.6 micrograms/ml), when antithrombin III was less than normal. These data indicate that elevated serum elastase is associated with a significant reduction in circulating antithrombin III. Stimuli that increase serum elastase, i.e. surgery, trauma, or sepsis may promote intravascular thrombosis by the inhibition of antithrombin III at the blood-endothelial cell interface.

Antithrombin III↗

PubMed1989

Prevention of venous thrombosis after total hip arthroplasty. Antithrombin III and low-dose heparin compared with dextran 40.

The anticoagulant action of heparin is mediated through antithrombin III, and the postoperative decrease in the plasma concentration of antithrombin III may contribute to the relative ineffectiveness of prophylaxis with low-dose heparin in preventing venous thrombosis after total hip arthroplasty. We conducted a prospective, randomized trial to compare the effectiveness of a regimen of antithrombin III, given intravenously once daily, and low-dose heparin with a regimen of dextran 40, given intravenously, in preventing venographically documented venous thrombosis after total hip arthroplasty. The results demonstrated an incidence of venous thrombosis of 4.9 per cent in patients who received antithrombin III and heparin; this was significantly lower than the incidence (28.6 per cent) in patients who received dextran 40 (p less than 0.005). Venous thrombosis occurred only in patients who had total hip arthroplasty with a cemented prosthesis (fourteen of fifty-seven patients, or 24.6 per cent); none of the twenty-six patients in whom a non-cemented prosthesis was used had venous thrombosis (p less than 0.01). Of the patients in whom a cemented prosthesis had been inserted, the incidence of venous thrombosis was lower in those who were treated with antithrombin III and heparin (7.4 per cent) than in those who were treated with dextran 40 (40 per cent) (p less than 0.005). Postoperative levels of antithrombin III were maintained at more than 90 per cent of the baseline level in patients who received it; this was significantly higher than in patients who received dextran 40.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III↗

PubMed1989

Breed, age, and gender differences in plasma antithrombin-III activity in clinically normal young horses.

Plasma antithrombin-III activity was quantitated in plasma samples obtained from 165 clinically normal horses 3 years old or younger. In the horses as a group, antithrombin-III activity ranged from 63 to 131% of a species-specific reference plasma. Thoroughbred horses had significantly higher antithrombin-III activity (103.3 +/- 18.3; mean +/- SD) than did Standardbred horses (92.3 +/- 14.2). The plasma antithrombin-III activities were significantly lower in horses younger than 16 months old when compared with those in more mature horses (3 years old). There was no statistically significant gender-related effect on plasma antithrombin-III activity. Breed and age factors should therefore be taken into consideration when interpreting plasma antithrombin-III activity in horses.

Age Factors↗

PubMed1989

Histidine-rich glycoprotein does not interfere with interactions between antithrombin III and heparin-like compounds on vascular endothelial cells.

The role of histidine-rich glycoprotein in controlling heparin-like compounds on the endothelial cell surface is still unclear. The effects of this heparin-neutralizing protein on the interaction between antithrombin III and cultured porcine aortic endothelial cells were examined. Displacement of 125I-labeled antithrombin III specifically bound to endothelial cells by unlabeled histidine-rich glycoprotein was much less potent than that by unlabeled antithrombin III. One hundred-fold molar excess of histidine-rich glycoprotein displaced specific 125I-antithrombin III binding only by 20%. Furthermore, the endothelial cell-mediated acceleration of thrombin inactivation by antithrombin III was diminished by protamine sulfate, but was not affected by histidine-rich glycoprotein even at a histidine-rich glycoprotein/antithrombin III molar ratio of approximately 7:1. These data indicate that histidine-rich glycoprotein does not interfere with the interaction of endothelial cell heparin-like compounds with antithrombin III. Thus, it may not play an important role in the modulation of anticoagulant activity of endothelial cells in vivo, suggesting that the commonly accepted view of the probable function of this protein is erroneous.

Animals↗

PubMed1988

Biosynthesis of heparin. O-sulfation of the antithrombin-binding region.

The antithrombin-binding region in heparin is a pentasaccharide sequence with the predominant structure GlcNAc(6-OSO3)-GlcA-GlcNSO3(3,6-di-OSO3)-IdoA -(2-OSO3)-GlcNSO3(6-OSO3) (where GlcA and IdoA represent D-glucuronic and L-iduronic acid, respectively), in which the 3-O-sulfate residue on the internal glucosaminyl unit is a marker group for this particular region of the polysaccharide molecule. A heparin octasaccharide which contained the above pentasaccharide sequence was N/O-desulfated and re-N-sulfated and was then incubated with adenosine 3'-phosphate 5'-phospho[35S]sulfate in the presence of a microsomal fraction from mouse mastocytoma tissue. Fractionation of the resulting 35S-labeled octasaccharide on antithrombin-Sepharose yielded a high affinity fraction that accounted for approximately 2% of the total incorporated label. Structural analysis of this fraction indicated that the internal glucosamine unit of the pentasaccharide sequence was 3-O-35S-sulfated, whereas both adjacent glucosamine units carried 6-O-[35S]sulfate groups. In contrast, the fractions with low affinity for antithrombin (approximately 98% of incorporated 35S) showed no consistent O-35S sulfation pattern and essentially lacked glucosaminyl 3-O-[35S]sulfate groups. It is suggested that the 3-O-sulfation reaction concludes the formation of the antithrombin-binding region. This proposal was corroborated in a similar experiment using a synthetic pentasaccharide with the structure GlcNSO3(6-OSO3)-GlcA-GlcNSO3(6-OSO3)-Id oA (2-OSO3)-GlcNSO3(6-OSO3) as sulfate acceptor. This molecule corresponds to a functional antithrombin-binding region but for the lack of a 3-O-sulfate group at the internal glucosamine unit. The 35S-labeled pentasaccharide recovered after incubation bound with high affinity to antithrombin-Sepharose and contained a 3-O-[35S]sulfate group at the internal glucosamine residue as the only detectable labeled component. The use of this pentasaccharide substrate along with the affinity matrix provides a highly specific assay for the 3-O-sulfotransferase.

Animals↗

PubMed1988

Behavior of antithrombin III isoforms on immobilized heparins. Evidence that the isoforms bind to different numbers of low-affinity heparin sites.

Antithrombin III exists in plasma as major and minor isoforms differing in affinity for heparin. The nature of the binding of each purified isoform to immobilized heparins was investigated. Unfractionated, mixed-affinity heparin bound each isoform with both high affinity and concentration-dependent low affinity. The isoforms were resolved when filtered through low-affinity heparin (heparin repeatedly passed over immobilized antithrombin III) columns. Following chemical modification of a specific tryptophan residue required for heparin binding, each isoform failed to bind to either low-affinity or mixed-affinity heparin-agarose, but elution of the modified higher-affinity isoform was retarded on both gels. Because the modified lower-affinity isoform eluted with the similarly sized bovine serum albumin in these experiments, the difference in isoform affinity for heparin appears to be the result of a unique, secondary heparin-binding site in the higher-affinity isoform that can bind a heparin site with low affinity for antithrombin III. This interpretation was supported by the chromatographic behavior of the isoforms on mixed-affinity agarose during reverse gradient elution. Two other populations of each of the tryptophan-modified isoforms were identified. Since these isoforms bound tightly to mixed-affinity heparin-agarose but eluted at lower salt concentrations than the corresponding unmodified isoforms, both isoforms may contain additional secondary sites that interact weakly with heparin. A general model of heparin-antithrombin III interaction is proposed in which a high-affinity heparin site initially interacts with a primary site on antithrombin III. The subsequent conformational change leads to a cooperative, entropy-driven association between secondary sites on the protein and low-affinity sites on heparin, stabilizing antithrombin III in its activated form.

Antithrombin III↗

PubMed1985

The role of surface charge on the accelerating action of heparin on the antithrombin III-inhibited activity of alpha-thrombin.

We have compared surface charge and the surface charge density on the polyanions heparin and potassium polyvinyl sulfate (KPVS), as well as on hydrolyzed heparin and KPVS, with their accelerating effect on the inhibitory action of antithrombin III on thrombin. Polyelectrolyte titration of thrombin with KPVS or heparin at pH 7.4 clearly indicates an electrostatic interaction. In contrast, at the same pH no electrostatic interaction is observed between polyanions and antithrombin III. KPVS accelerates the inhibitory action of antithrombin III to the same extent as heparin on the basis of charge equivalence. Heparin and KPVS with a mean distance between two charged centers of less than 0.75 and 0.95 nm, respectively, accelerate strongly whereas hydrolysates with lower charge densities are far less active. The following observations are indicated. Intramolecular neutralization of oppositely charged residues occurs within thrombin, antithrombin III, and partially hydrolyzed heparin. Heparin acts on the antithrombin III-thrombin reaction through cooperative electrostatic binding to thrombin and nonelectrostatic interaction with antithrombin III. This indicates a quasi-catalytic action of the polyelectrolyte. Hydrolysis of only a few N-sulfate residues within the heparin molecule decreases the linear surface charge density to such an extent that the accelerating action is drastically reduced. The loss of accelerating capacity agrees with the sudden loss of counterion condensation due to the decrease of the linear surface charge density beyond limits postulated by Manning in a theory of polyelectrolytes.

Antithrombin III↗

PubMed1985

The prevalence of hereditary antithrombin-III deficiency in patients with a history of venous thromboembolism.

Antithrombin-III activity was determined in 752 patients with a history of venous thrombosis and/or pulmonary embolism. 54 patients (7.18%) had an antithrombin-III activity below the normal range. Among these were 13 patients (1.73%) with proven hereditary deficiency. 14 patients were judged to have probable hereditary antithrombin-III deficiency, because they had a positive family history, but antithrombin-III deficiency could not be verified in other members of the family. In the 27 remaining patients (most of them with only slight deficiency) hereditary antithrombin-III deficiency was unlikely. The prevalence of hereditary antithrombin-III deficiency was higher in patients with recurrent venous thrombosis.

Antithrombin III Deficiency↗

PubMed1983

Fate of thrombin and thrombin-antithrombin-III complex adsorbed to a heparinized biomaterial: analysis of the enzyme-inhibitor complexes displaced by plasma.

Heparin covalently-linked to polyvinyl alcohol (PVA) is a biomaterial which is of potential value as a non-thrombogenic coating. 125I-labelled thrombin adsorbed to heparin-PVA beads was not dislodged by phosphate-buffered saline, pH 7.4, although radioactivity was progressively displaced from the adsorbent by fibrinogen-free human plasma. Analysis by gel filtration and affinity chromatography showed that the released radioactivity was distributed between (thrombin-antithrombin-III) complex (approx. 70%) and, probably, (thrombin-alpha-2-macroglobulin) complex (approx. 30%). Less efficient thrombin displacement was obtained by either bovine serum albumin (5% w/v) or antithrombin-III-free human plasma: in the latter case, the dislodged enzyme was presumably associated with alpha-2-macroglobulin. Purified alpha-2-macroglobulin did not displace thrombin from heparin-PVA. The quantity of thrombin displaced by an alpha-2-macroglobulin-free plasma fraction compared well with fibrinogen-free plasma: The eluted enzyme was largely associated with antithrombin-III. Purified antithrombin-III did not displace thrombin from heparin-PVA despite causing greater than 70% inactivation of the bound enzyme. Subsequent treatment with fibrinogen-free plasma dislodged (thrombin-antithrombin-III) at a similar rate to that of bound thrombin. We conclude that plasma contains a component(s) which displaces (thrombin-antithrombin-III) complex from immobilised heparin: presumably this leaves the heparin sites free for further use in enzyme inactivation.

Antithrombin III↗

PubMed1984

Antithrombin III levels in term and preterm infants measured by rate nephelometry.

The plasma antithrombin III level was measured in term and premature newborns within the first 24 h of life; in addition to the authors', own immunological method utilizing rate nephelometry the assays of Laurell and Kabi Coatest were used. Antithrombin III concentration showed a linear correlation with the degree of maturity, in accordance with previous data. The lowest values were found in premature babies affected by idiopathic respiratory distress syndrome who later developed pulmonary haemorrhage. At all gestational ages the antithrombin III functional index was lower than 1.0, indicating antithrombin III consumption. Since both concentration and activity of antithrombin III are low in prematures, they are at an increased risk for coagulopathies, hence substitution therapy is indicated. Measurement of antithrombin III by rate nephelometry can also be used for following changes in inhibitor concentration.

Antithrombin III↗

PubMed1983

Purification of antithrombin III mRNA and cloning of its cDNA.

Antithrombin III mRNA was enriched from a baboon liver by specific polysome immunoprecipitation. The partially purified antithrombin III mRNA preparation was used for cDNA synthesis and cloning. Candidate antithrombin III cDNA clones were identified by differential hybridization using as probes [32P]cDNAs synthesized from the polysome-enriched and -depleted RNA fractions, respectively. The candidate clones were further analyzed by hybrid-selected translation. The authenticity of a cDNA clone positive to both tests was unambiguously confirmed by matching its nucleotide sequence with the known amino acid sequence of human antithrombin III. The baboon antithrombin III cDNA clone hybridized well with human antithrombin III mRNA and can be used as a probe to isolate the corresponding human gene.

Animals↗

PubMed1982

Heparin with two binding sites for antithrombin or platelet factor 4.

A new, highly discriminating affinity chromatographic technique has been developed which employs antithrombin and concanavalin A-Sepharose to fractionate heparin species of all molecular sizes. This methodology is able to subdivide the active mucopolysaccharide pools of molecular weight 6,000 to 8,000 (LMW) or 18,000 to 22,000 (HMW) into various species with descending affinities for antithrombin as well as decreasing anticoagulant potencies. The upper 10% of these two pools, either LMW or HMW highly active heparin, appears to be relatively homogeneous with respect to interactions with antithrombin and possessed anticoagulant potencies of 350 units/mg and 731 units/mg, respectively. The HMW highly active heparin has been examined by analytic ultracentrifugation. It exhibited a charge-connected weight-average molecular weight of 22,000 +/- 2,000 with minimal size heterogeneity. The stoichiometries of interaction of antithrombin and platelet factor 4 with HMW highly active heparin as determined by fluorescence spectroscopy indicated that 2 molecules of either protein are able to bind to 1 molecule of the mucopolysaccharide. These studies also reveal that the binding of antithrombin to HMW highly active heparin is characterized by KDISSHAT = 5.0 X 10(-8) M and KDISSHAT2 = 1.0 x 10(-7) M, respectively. The avidity of platelet factor 4 for HMW highly active heparin could not be quantitated but appears to be at least 10 to 100 times greater than that of antithrombin for mucopolysaccharide.

Antithrombins↗

PubMed1982

Effect of heparin on the inactivation rate of human factor XIa by antithrombin-III.

Factor XIa catalyzes an important reaction in the early phase of blood coagulation by converting factor IX to an active enzyme (factor IXa). Although antithrombin-III, an inhibitor of factor XIa, normally accounts for only one-sixth of the plasma inhibitory activity against factor XIa, its effectiveness has been reported to be enhanced by heparin. We have reinvestigated the ability of heparin to potentiate factor XIa inhibition by both purified antithrombin-III and plasma using synthetic tripeptide amide substrates as well as a coagulant assay. No increase in the inactivation rate of factor XIa amidolytic activity by purified antithrombin-III was observed in the presence of therapeutic heparin concentrations (1 U/ml), although inhibition of the amidolytic activity of thrombin by purified antithrombin-III was enhanced at least 20-fold by the same concentration of heparin. Furthermore, despite the ability of heparin (1 U/ml) to increase the inactivation rate of thrombin by plasma, no acceleration of the rate of inhibition of factor XIa by plasma was observed. Similar results were found when the inhibition of factor XIa was monitored with a coagulant assay after first removing the heparin. Only at heparin concentrations of 5 and 10 U/ml, was a 2- and 4-fold increase in the inactivation rate of factor XIa by purified antithrombin III observed. Therefore, in both purified systems as well as plasma, heparin, at concentrations observed in clinical practice, does not accelerate the inactivation rate of human factor XIa by antithrombin-III.

Amides↗

PubMed1982

Antithrombin III and dietary intake of polyunsaturated fatty acids.

Immunoreactive antithrombin III and antithrombin III activity was found to be significantly higher in 81 Greenland Eskimos than in 50 Caucasian Danes. Sixteen Eskimos who had emigrated to Denmark had significantly lower immunoreactive antithrombin III levels than the Greenland Eskimos, though higher than the Danes. The immunoreactive antithrombin III increased significantly while the increase in antithrombin III activity was insignificant in 20 male Caucasian Danes upon 3 weeks supplementation of the diet with 10 ml daily of a cod liver oil concentrate. The high antithrombin III level in the Eskimos may at least partly be a consequence of a high dietary intake of polyunsaturated fatty acids. It may also play a role for the low incidence of thrombosis apparently found in Greenland Eskimos.

Adult↗

PubMed1995

Cloning of an avian antithrombin: developmental and hormonal regulation of expression.

We present the complete amino acid sequence of a non-mammalian antithrombin together with a structural comparison to its mammalian homologs. In the majority of cases, but not all, the analyses indicate high degrees of primary structural identity within regions of predicted or demonstrated functional importance. We have also taken advantage of the avian model to define the ontogeny of antithrombin mRNA expression. Northern analyses indicate chicken antithrombin mRNA levels to be detectable in the liver early during development and increase to reach adult levels just prior to hatching. Although no sex-dependent differences in antithrombin mRNA levels were detected, the administration of estrogen to male roosters was observed to cause a 3-fold decrease in antithrombin mRNA levels, suggesting that the hormone may alter circulating antithrombin levels via a pre-translational mechanism.

Amino Acid Sequence↗

PubMed1977

Some properties of human progressive antithrombin.

The effect of some mono- and divalent cations was examined on thrombin--antithrombin reaction in vitro. It was found that 0--0.1 M sodium- or potassium chloride did not affect either thrombin or antithrombin activity; at higher concentrations thrombin activity decreased. Calcium chloride as well as magnesium chloride at concentrations from 0 to 0.5 M increased enzyme activity, whereas at higher concentrations the activity decreased. Thrombin inactivation by antithrombin was also accelerated at calcium or magnesium chloride concentrations above 0.04 M. Antithrombin was inactivated at pH 7.3 at 65 degrees C in some minutes and heparin failed to protect it against heat denaturation. Thrombin inactivation by antithrombin did not proceed at 0 degrees C in 60 min, but the interaction between thrombin and antithrombin was facilitated in the presence of heparin.

Antithrombin III↗

PubMed1994

Thrombogenicity of the injured vessel wall--role of antithrombin and heparin.

The thrombogenicity of the vessel wall after endothelial denudation is partly explained by an impaired inhibition of thrombin on the subendothelium. We have previously reported that thrombin coagulant activity can be detected on the vessel wall after balloon injury in vivo. The glycosaminoglycans of the subendothelium differ from those of the endothelium and have a lower catalyzing effect on antithrombin III, but inhibition of thrombin can still be augmented by addition of antithrombin III to the injured vessel surface. In this study the effect of antithrombin III and heparin on thrombin coagulant activity on the vessel wall was studied after in vivo balloon injury of the rabbit aorta using biochemical and immunohistochemical methods and thrombin was analysed after excision of the vessel. Continuous treatment with heparin, lasting until sacrifice of the animal, or treatment with antithrombin III resulted in significant reduction of thrombin coagulant activity on the injured aorta. Heparin given only in conjunction with the injury did not prevent thrombin coagulant activity or deposition of fibrin on the surface. The capacity of the injured vessel wall to inhibit thrombin in vitro was improved on aortic segments obtained from animals receiving antithrombin III but not from those given heparin. It is concluded that treatment with antithrombin III interferes with thrombin appearance on the vessel wall after injury and thereby reduces the risk for thrombosis.

Animals↗