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At least 19 recordsLinked to original sources
PubMed1977

Crossed immunoelectrophoresis as applied to studies on complex formation. The binding of heparin to antithrombin III and the antithrombin III--thrombin complex.

A two-dimensional immunoelectrophoretic method has been used to obtain information on the binding of heparin to purified antithrombin III and the antithrombin III--thrombin complex. The difference in mobility of the components in a gel containing heparin enables distinction between free and complexed forms of antithrombin III. The results obtained with purified preparations show that heparin is bound more strongly to antithrombin III than to the antithrombin III--thrombin complex. In plasma heparin is bound to several components, only a fraction being bound to antithrombin III. Several components containing antithrombin III are detectable in serum.

Animals↗
PubMed1976

Hereditary antithrombin III deficiency. Effect of antithrombin III deficiency on platelet function.

Antithrombin III (AT III) is the main physiologic inhibitor of thrombin, and activated factors X and IX as well. Normal levels of AT III appear to be necessary to maintain blood fluidity and to prevent thrombosis. Four families with AT III deficiency and recurrent venous thromboembolism have been reported on. We present an additional family with AT III deficiency and a high incidence of thromboembolism. AT III levels were determined by both a functional and an immunologic assay. Results of platelet function tests, not previously reported in persons with AT III deficiency, were found to be normal. Following gel filtration, the platelets were very sensitive to thrombin. Thrombin-induced platelet aggregation appears to be dependent on a balance between the amount of thrombin and AT III present.

Adolescent↗
PubMed1978

Microheterogeneity of human antithrombin III.

Antithrombin purified from normal human plasma has been separated into two fractions by isoelectric focusing in a pH 4-6 gradient. These fractions were homogeneous by polyacrylamide gel electrophoresis, had similar amino acid composition and the same specific activity. Both of them cross reacted with antiserum against antithrombin. They were found to contain different amounts of sialic acid and aminosugars. After neuraminidase treatment only a single, homogeneous peak was found by isoelectric focusing--with unchanged antithrombin activity--suggesting that the microheterogeneity is due to a difference in glycosylation.

Antithrombins↗
PubMed1976

Effect of various estrogen treatment schedules on antithrombin III levels.

Antithrombin III levels were determined in 18 normal indiviuals of both sexes, 24 pregnant women (at term), 20 patients treated with oral contraceptives and 21 postmenopausal patients treated with Premarin. There was no sex difference in antithrombin III levels in the untreated control group. Pregnant women at term had the lowest levels of antithrombin III. The second lowest values were exhibited by women on oral contraceptives. Both of these groups differed significantly (p less than 0.05) from the controls. Premarin treated postmenopausal women had somewhat lower levels of antithrombin III than controls but these were statistically not significant.

Adolescent↗
PubMed1978

Study of the activity of antithrombin-III in latent cholestasis. (A clinico-pharmacological study of the relationship between antithrombin-III activity and steroid cholestasis).

The relationship between steroid cholestasis and antithrombin-III activity were examined in users of oral contraceptives (Infecundin or Bisecurin) and in patients receiving anabolic hormone therapy (Nerobol). The control group for the oral contraceptive users consisted of patients with spontaneous anovulation. The untreated control group consisted of healthy women in the reproductive age. The increase in antithrombin-III activity was found to be directly related to the decline of anion excretion. Latent cholestasis in itself is not associated with an increased antithrombin-III activity, nor is the activity of antithrombin-III affected by long-continued use of those anabolic steroids which produce no decrease in anion excretion.

Adult↗
PubMed1979

Purification and properties of guinea pig antithrombin III.

Guinea pig antithrombin III has been purified from plasma by sequential heparin-Sepharose affinity chromatography, DE-52 cellulose chromatography, isoelectric focussing, and Sephadex G-100 gel filtration chromatography. The final product was homogeneous as judged by sodium dodecyl sulfate disc gel electrophoresis. Purification was 202-fold with a yield of 41%. Antiproteinase activity of antithrombin III was determined by progressive inactivation of thrombin coagulant and amidolytic activity. Heparin cofactor activity was demonstrated by immediate inactivation of thrombin by antithrombin III in the presence of minute quantities of heparin. It also could be demonstrated that thrombin inactivation by antithrombin III occurs by formation of a bimolecular complex whose rate of formation is markedly enhanced by minute quantities of heparin.

Animals↗
PubMed1979

Dissociation of complexes and their derivatives formed during inhibition of bovine thrombin and activated factor X by antithrombin III.

The complexes formed by antithrombin III with activated bovine Factor X and thrombin have been studied by gel electrophoresis in dodecyl sulfate. When subjected to electrophoresis at pH 7, the complexes remain intact, whereas electrophoresis at pH 9 in the presence of Tris results in their dissociation. Dissociation of both the Factor Xa-antithrombin III complex and the thrombin-antithrombin III complex in dodecyl sulfate produces a modified form of antithrombin III which, unlike the native inhibitor, apparently consists of two chains. Gel electrophoresis of the dissociated complexes has also been used to study the sites where the complexes are cleaved by the respective enzymes. The cleavage of the Factor Xa-inhibitor complex by Factor Xa apparently results from hydrolysis of a single bond in the enzyme part of the complex and releases a 15,000-dalton NH2-terminal fragment of the heavy chain, with the light chain attached. Cleavage of the thrombin-inhibitor complex by thrombin involves several cleavages of the heavy (B) chain of the thrombin part of that complex. Neither enzyme-inhibitor complex is subject to cleavage by free enzyme in the inhibitor part of the complex under the conditions used.

Animals↗
PubMed1979

Antithrombin III in uremia.

Antithrombin III (AT-III) was measured immunologically in 20 uremic patients on maintenance hemodialysis and in 10 non-dialysed uremic patients. The dialysed patients had slightly elevated AT-III levels. The non-dialysed patients had significantly elevated AT-III levels. A negative correlation was found between AT-III and serum creatinine and between AT-III and serum albumin. AT-III did not correlate to the heparin amount required for hemodialysis. A negative correlation was found between the heparin requirement and serum albumin. It is suggested, that serum albumin might facilitate the action of AT-III and heparin. It is also suggested, that AT-III levels may be high in active renal disease, decreasing as uremia advances.

Adult↗
PubMed1979

Heparin-antithrombin III binding. In vitro and in vivo studies.

Heparin antithrombin III binding was studied by crossed immunoelectrophoresis. In plasma and purified antithrombin III standard, multicomponent patterns were obtained with low concentrations of mucosal heparin. There is evidence that antithrombin III may bind more than one heparin molecule. At high heparin concentration (greater than 16 U/ml), single symmetrical peaks were obtained. Serum samples showed two antithrombin III peaks due to a decreased heparin binding of the slower peak (2.1-3.9 times), which was probably antithrombin III-activated procoagulant complexes. Heparin analogue (A 73025) also bound antithrombin III in vitro but the mobility of the peak was slower than with mucosal heparin and only a single peak was obtained in serum samples. Radioimmunoassay showed a decreased binding of antithrombin III antibody to heparin-antithrombin III complex. Venous occlusion to the forearm resulted in a slow second peak in the plasma. Heparin therapy gave rise to a double peak in the plasma antithrombin III profile and with continuous infusion, quantitative decreases were noted in all subjects studied, two of whom rethrombosed at the end of 7 days therapy.

Animals↗
PubMed1977

Heparin-induced decrease in circulating antithrombin-III.

Plasma-antithrombin-III (AT-III) concentrations were measured throughout therapy in 24 patients receiving continuous intravenous heparin infusion and in 2 patients treated with repeated intravenous heparin injections. In all patients, including 1 with congenital AT-III deficiency, heparin therapy was associated with a considerable progressive reduction in AT-III-binding capacity and antigenic protein. The net individual decrease in plasma-AT-III was 0-31 +/- 0-05 units/ml (normal plasma-AT-III was 1-00 units/ml) or 9-5 +/- 2-0 mg/dl and the decrease was independent of initial concentration. Plasma-AT-III returned to normal two to three days after heparin was stopped. There was no decrease in plasma-AT-III after a single dose of intravenous heparin. When present in blood for long periods heparin significantly reduced AT-III, the proteinase inhibitor that is responsible for the anticoagulant effect of this drug. The finding is very relevant to the interpretation of clinical data in patients treated with heparin and suggests that AT-III depletion may underly the thromboembolic complications sometimes encountered during heparin therapy.

Antigens↗
PubMed1978

Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome.

Antithrombin III levels were studied in relation to the occurrence of thromboembolism in 48 patients with various degrees of proteinuria. Nine of these patients had clinical signs of thrombosis, including four with renal vein thrombosis. In eight of these nine patients, antithrombin III concentrations were below 70 per cent. There was a significant negative correlation between the antithrombin III concentration and the urinary protein excreation (P less than 0.001). Antithrombin III was found in the urine of 32 of 42 patients. There was a significant correlation between the renal clearance and the degree of antithrombin III serum deficiency (P less that 0.001). The clearance and serum level of albumin closely paralleled these changes. We conclude that thrombosis in patients with severe proteinuria is associated with a deficiency of antithrombin III due to urinary excretion of this protein.

Adolescent↗
PubMed1978

Antithrombin III. Theory and clinical applications. H. P. Smith Memorial Lecture.

Antithrombin III is one of the main inhibitors in the blood coagulation mechanisms. Thrombin and factor Xa are slowly inactivated by it, as well as other serine proteinases of the coagulation mechanisms. Heparin tremendously accelerates the inhibitory function of antithrombin III. In the process antithrombin III activity is also reduced. Heparin retards the thrombin-fibrinogen reaction, but otherwise the effectiveness of heparin as an anticoagulant depends on antithrombin III in laboratory experiments, as well as in therapeutics. The activation of prothrombin is inhibited, and any thrombin or other vulnerable protease that might generate becomes inactivated. The measurement of antithrombin III concentration in blood is now achieved by research methods, as well as by methods that are practical for routine use. The tests require either thrombin or factor Xa as substrate, and could be specific for antithrombin III. There are congenital as well as acquired deficiencies of antithrombin III. The inhibitor is also found in tissues.

Antithrombins↗
PubMed1979

Studies on the mechanism of the rate-enhancing effect of heparin on the thrombin-antithrombin III reaction.

The rate of the reaction between thrombin and antithrombin III is greatly increased in the presence of heparin. Several mechanisms for this effect are possible. To study the problems commercial heparin was fractionated into one fraction of high anticogulant activity and one of low anticoagulant activity by affinity chromatography on matrix-bound antithrombin III. The strength of the binding of the two heparin fractions to antithrombin III and thrombin, respectively, was determined by a crossed immunoelectrophoresis technique. As was to be expected, the high activity fraction was strongly bound to antithrombin III while the low activity fraction was weakly bound. In contrast, thrombin showed equal binding affinity for both heparin fractions. The ability of the two heparin fractions to catalyse the inhibition of thrombin by antithrombin III was determined and was found to be much greater for the high activity heparin fraction. A mechanism for the reaction between thrombin and antithrombin III in the presence of small amounts of heparin is suggested, whereby antithrombin III first binds heparin and this complex then inhibits thrombin by interaction with both the bound heparin and the antithrombin III.

Antithrombin III↗
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↗
PubMed1977

Effect of collagen on thrombin inactivation by antithrombin-III and heparin.

Thrombin inactivation by antithrombin-III and heparin has been found to decrease in the presence of collagen, whereas thrombin activity and the rate of thrombin inactivation by antithrombin-III alone are not affected. Albumin, at the same concentration as collagen, does not influence either thrombin activity or thrombin inactivation by antithrombin-III or by antithrombin-III plus heparin.

Animals↗