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PubMed1985

Substitution of antithrombin III in shock and DIC: a randomized study.

In 51 shock patients with DIC Antithrombin III (AT III) substitution, heparin or a combination of both substances respectively was administered. In the two groups which had been given AT III substitution the concentration of AT III rose considerably higher than the activity. There was a drop of the platelet count in both groups which had received heparin. C1 esterase inhibitor was diminished in the beginning but spontaneously increased in all groups. This increase was slowest in the group without substitution of AT III. The blood loss in cases of traumatic shock was considerably higher in the group which had received both substances. The consumption of AT III concentrates was slightly higher in the combined therapy group than in the AT III group. The duration of symptoms of DIC was considerably shorter in the two substituted groups than in the heparin group. It is concluded that additional administration of heparin does not improve the effect of AT III substitution in patients with DIC and that side effects such as thrombocytopenia and an increased blood loss are likely to develop when both substances are given simultaneously.

Antithrombin III↗
PubMed1985

Antithrombin III in renal transplant recipients.

Antithrombin III (AT III) is increased in situations where there is increased platelet turnover. Plasma AT III levels measured in 39 renal transplant recipients were significantly higher than in 20 healthy subjects (p less than 0.001) and 20 patient controls (p less than 0.025). AT III levels were significantly correlated with the patients' platelet counts (r = 0.4, p less than 0.02). Transplant patients with less than 1 year follow up had significantly higher AT III levels than patients with more than 1 year follow up (p less than 0.01). All 5 patients with transplant rejection in the study had elevated plasma AT III levels. The data suggest that elevation of plasma AT III may be related to graft rejection.

Adult↗
PubMed1985

Chloroquine and primary amines inhibit the internalization of antithrombin III.trypsin complex in cultured cells.

Bovine corneal endothelial (BCE) cells have been shown to specifically bind, internalize and degrade antithrombin III (AT III).protease complexes as well as thrombin. Previous studies have indicated that chloroquine has no effect on the internalization of thrombin or other cell surface-bound ligands, but it inhibits their subsequent degradation. In contrast, the present study demonstrates the unique inhibitory effect of chloroquine on the internalization of 125I-AT III.trypsin complex by BCE cultures. Similarly, the primary amines, monodansylcadaverine and methylamine, inhibit the internalization of 125I-AT III.trypsin complex, but not the internalization of 125I-thrombin. The various amines used in this study revealed: (1) differences in the process of cellular binding and internalization between AT III.protease complex and thrombin, although the degradation of both internalized ligands proceed in an analogous manner; and (2) the unique sensitivity to chloroquine of 125I-AT III.trypsin complex internalization by cultured cells. These results might indicate that AT III.protease complexes are internalized via a distinct receptor and/or a different mechanism from thrombin.

Amines↗
PubMed1985

Antithrombin III in mesangial IgA nephritis.

Plasma Antithrombin III (A T III) was measured in 97 patients with IgA nephritis, 30 patients with non IgA idiopathic mesangial proliferative glomerulonephritis and 40 healthy subjects. The mean plasma A T III levels in the patients with IgA nephritis (105 +/- 10%) was significantly higher than those of normal controls (96 +/- 5%) (p less than 0.0005). The mean plasma A T III levels in the patients with non IgA nephritis (101 +/- 10%) was not different from those of the normal controls or the patients with IgA nephritis. A T III levels were significantly correlated with proteinuria (p less than 0.0001), segmental sclerosis (p less than 0.001), crescents (p less than 0.01), medial hypertrophy (p less than 0.001) and intensity of IgA staining on IMF (p less than 0.02). Patients with IgA nephritis with raised A T III levels had significantly more proteinuria (p less than 0.003), more segmental sclerosis (p less than 0.007) as well as a greater intensity of IgA staining on IMF (p less than 0.02) when compared to patients with normal A T III levels. The data suggest that raised plasma A T III levels may serve as a prognostic marker in IgA nephritis.

Antithrombin III↗
PubMed1985

Analysis of antithrombin III microheterogeneity by isoelectric focusing in polyacrylamide gels and immunoblotting.

Microheterogeneity of antithrombin III (ATIII) was examined in pooled normal human plasma and serum by IEF/PA and immunoblotting techniques. A pattern consisting of 8 bands varying in isoelectric point from 4.7 to 5.2 was observed in citrated plasma following IEF in a pH range of 4-6. A similar pattern was observed in all 149 healthy adults examined. The reactivity of ATIII with heparin or, thrombin was investigated using this technique. Characteristic shifts of the banding pattern to the anode or, cathode respectively were observed.

Antithrombin III↗
PubMed1986

Factor IX concentrate therapy and thrombosis: relation to changes in plasma antithrombin III.

Commercial factor IX (fIX) concentrate therapy has been associated with thrombogenic complications, the cause of which is uncertain. We have previously reported that infusion of these fIX concentrates led to a decrease in antithrombin III (ATIII) functional activity, but not antigen, from pre-infusion levels. The patient plasmas also showed a cathodal shift in ATIII antigen by crossed immunoelectrophoresis (CIEP). We chose to characterize these ATIII changes more extensively in additional patients, by functional assays, radial immunodiffusion (RID), and CIEP. The effects of commercial fIX concentrate therapy on plasma ATIII levels appear to be dose-related, with most pronounced effects at 100 U/Kg; the effects are also cumulative, with a persistence of ATIII changes 24 hours after infusion in patients on daily therapy. We also studied pre- and post-infusion ATIII levels in patients who received 100 U/Kg of a more purified fIX concentrate (American Red Cross), which contains little or no activated clotting factors and has been shown to be non-thrombogenic in animal models. These patients showed no change post-infusion in ATIII levels by clotting, amidolytic, or RID assays, nor any significant change by CIEP. These data suggest that the ATIII changes that occur predictably after commercial fIX concentrate therapy are caused by a contaminating protein or proteins other than fIX and that the ATIII changes observed are related to the thrombotic complications of these commercial concentrates.

Antigens↗
PubMed1986

Reaction of thrombins with human antithrombin III. I. Enzyme activity losses unrelated to the inhibitory reaction and their prevention.

Adsorption loss of thrombin may produce considerable systematic error when quantitative evaluation of its reaction with antithrombin III is based on measurements of changes in enzyme activity with time. At 25 degrees C, pH 7.8 (0.1 M NaCl, 0.01 M TRIS, 0.01 M HEPES) glass, siliconized glass, polypropylene and polystyrene surfaces adsorb thrombin in a similar manner. Its adsorption is a saturation reaction reaching an equilibrium after about three hours. At initial concentrations of enzyme convenient for assay with chromogenic substrate (10 nM or less) a large fraction of activity is lost. Binding of alpha thrombin to polypropylene is very tight. The association constants (Ka) were found to be 12.6 X 10(9) M-1 and 4.0 X 10(9) M-1 for human and bovine alpha thrombin respectively. The adsorbed enzyme has hardly any ability to hydrolyze chromogenic substrate. A small part of its activity can be recovered by displacement with PEG 6000, more when the substrate is present. The addition of non-ionic detergents and continuous stirring allows recovery of up to 30% of the enzyme activity and accelerates this process. Complete and long term (more than 20 hours at 25 degrees C) prevention of adsorption loss of human alpha and bovine alpha and beta thrombin at pH between 7.0-8.3 is achieved by the addition of 0.1% PEG 6000 to the buffer and use of tubes precoated with PEG 20,000. Alternative use of non-ionic detergents (BRIJ-35, TRITON X-100) to modify the solvent also appears effective but their possible interference with reactions studied should be borne in mind.

Adsorption↗
PubMed1986

Heparin fractions with high and low affinities to antithrombin III are cleared at different rates.

The clearance characteristics of standard heparin (SH) and its fractions with high and low affinity to antithrombin III (HAH and LAH respectively) were studied by injecting 125I-labelled SH, HAH and LAH intravenously into the rabbits in increasing doses. Serial blood samples were then collected from an indwelling cannula for measurement of clearance, based both on radioactivity and anticoagulant activity. For equivalent weights injected, the radioactivity of HAH was cleared more slowly from the circulation than that of either SH or LAH. The radioactivity of SH, in turn, was cleared more slowly than that of LAH. The clearance of HAH, measured both by radioactivity and by anticoagulant activity were similar, whereas the clearance of the radioactivity of SH was more rapid than its anticoagulant activity (i.e. anti-factor Xa activity). These observations suggest that the radioactivity clearance curves of SH reflect a "net" estimation of the more complex clearance curves of the different heparin moieties whereas the anticoagulant clearance curves of SH reflects the clearance of the anticoagulant activity of a specific heparin fraction, in this case, the clearance of the anti-factor Xa activity of HAH. These differences suggest that the HAH:LAH ratio is, at any given time, greater in vivo than the same ratio measured in vitro.

Animals↗
PubMed1986

Effect of NaC1 on inactivation of bovine thrombin by antithrombin III in the presence of low affinity-heparin or dextran sulfate.

Heparin with low affinity (LA-heparin) to antithrombin III (AT III) enhanced the rate of inactivation of thrombin by AT III. The enhancement of the rate was saturable with AT III and was proportional to the LA-heparin concentration. Although the rate-enhancement in the presence of LA-heparin decreased with increase in NaC1 concentration, it was comparable with that in the presence of high affinity-heparin (HA-heparin) in the absence of NaC1. Inactivation of thrombin by AT III in the presence of dextran sulfate (DS) was also sensitive to NaC1 concentration. These findings indicate that free AT III is favorable for binding to the complexes of thrombin and highly sulfated polysaccharides having low affinities to AT III in the absence of NaC1.

Animals↗
PubMed1986

Effects of different ions on the interactions of heparin with bovine antithrombin III and thrombin.

Of four Tris-salts tested (chloride, sulfate, phosphate and acetate), chloride caused complete elution of antithrombin III (AT III) from a heparin-Sepharose column and sulfate caused partial elution. AT III was also partially eluted from the column with sodium acetate, but not Tris acetate. On the other hand, thrombin was eluted from the column with the Tris-salts in the order chloride greater than sulfate greater than acetate, but was not eluted with Tris-phosphate. Thrombin was also eluted from the column with sodium acetate. These findings indicate that the affinity of heparin to AT III was influenced only by strongly electronegative ions, whereas its affinity to thrombin was affected by both strongly electropositive and strongly electronegative ions.

Acetates↗
PubMed1986

The macrophage-mediated regulation of hepatocyte synthesis of antithrombin III and alpha 1-proteinase inhibitor.

Antithrombin III (ATIII) is an anticoagulant protein which binds and inactivates thrombin and other serine proteinases. Little is known about regulation of its synthesis. We confirm that ATIII is synthesized by isolated rat hepatocytes, and that its synthesis is not altered by direct feedback of its complexes with proteinases. Neither is hepatocyte synthesis of ATIII altered by supernatants from macrophages cultured in the presence of ATIII-proteinase complexes. However, culture of macrophages with fibrinogen fragment D results in production of a factor(s) in the macrophage supernatants which stimulates hepatic fibrinogen synthesis, as previously described, and also stimulates the synthesis of ATIII and alpha 1-proteinase inhibitor (alpha 1PI). Synthesis of albumin and rat alpha 2-macroglobulin (alpha 2M) is not (alpha 2M) is not altered. Culture of macrophages in the presence of bacterial endotoxin also results in release of a factor(s) into the medium which stimulates the same changes in hepatocyte protein synthesis. These results show for the first time a mechanism by which synthesis of ATIII can be regulated during coagulation and fibrinolysis.

Animals↗
PubMed1986

Comparative study of antithrombin III.protease complex metabolism by fibroblasts and vascular endothelial cells.

125I-labeled human antithrombin III (125I-AT III).protease complexes are specifically bound to both cultured human skin fibroblast (HSF) cells and adult bovine aortic endothelial (ABAE) cells; however, there is a significant difference in the rate and degree of metabolism of the complexes by these two cell types. HSF cells appear to internalize the complexes at a rate of about 2.5 pmole/1 X 10(6) cells/h and subsequently degrade them at a rate of 0.6 pmole/1 X 10(6) cells/h. ABAE cells internalize and degrade the complexes at rates approximately 100 and 30 times lower, respectively. Neither cell type interacts with free 125I-AT III but only with its combined form with either thrombin or trypsin. These data indicate the major role of HSF cells in the removal of AT III.protease complexes from extravascular spaces in the body, in contrast to the inert vascular surface with regard to AT III.protease complexes provided by the vascular endothelium.

Animals↗
PubMed1987

The relative contributions of antithrombin III during heparin treatment, and of clinically recognisable risk factors, to early recurrence of venous thromboembolism.

The influence of antithrombin III (ATIII) level and ATIII activity, measured during intravenous heparin treatment for venous thromboembolism (VTE), on 'heparin requirement' (the heparin dose required to prolong the activated partial thromboplastin time (APTT) into its designated therapeutic range), and on the likelihood of recurrent VTE during the first month of anticoagulant therapy, were examined in a prospective study of 232 patients with VTE treated according to a standard protocol. 15 patients with recurrent VTE (6.5%) had a lower mean APTT during heparin treatment than patients without recurrence; a finding due partly to their heparin requirement. However, there was no measurable relationship between ATIII level or ATIII activity and either heparin requirement or recurrence of VTE. By contrast, both the presence of disseminated malignancy and the development of heparin induced thrombocytopenia were powerful, clinically recognisable, risk factors for recurrence during or soon after heparin therapy.

Adolescent↗
PubMed1987

Affinity of antithrombin III for insoluble modified polystyrene.

In previous papers we described insoluble polystyrenes grafted with L-arginyl methyl ester (PAOM) which exhibit a high affinity for thrombin. Based on their specific interaction with the protease, the resin has been used as stationary phases for affinity chromatographic procedure of thrombin in affinity chromatography (AC) and high performance liquid affinity chromatography (HPLAC). A slight adsorption of antithrombin III (AT III) was shown in AC. In this paper we study the interaction of AT III for PAOM resin in batch procedure. The adsorption is measured using purified protein and corresponds to a monolayer adsorbed on the surface of the polymer. The affinity constant is evaluated kAT = 3.10(5) 1.M-1. Furthermore, insoluble sulfonated polystyrenes grafted with different amino acid were shown to possess an heparin-like behaviour and catalyse the generation of thrombin-AT III complex. So, compared to one of the resin previously mentioned, it could be concluded that PAOM is not heparin-like. When thrombin is adsorbed on the surface of the polymer, AT III cannot interact with the specific seryl residue of the enzyme.

Adsorption↗
PubMed1987

Monitoring of heparin therapy: should heparin assays also reflect the patient's antithrombin concentration?

Chromogenic substrate (CS) assay of heparin may be performed with or without addition of antithrombin (AT) to the test plasma. Both types of assay are used for monitoring of heparin therapy, reflecting either heparin activity (heparin act), or heparin concentration (heparin conc) when AT is added. In plasma samples from 43 patients treated with intravenous heparin for DVT, the ratio between heparin act and heparin conc varied from 0.36 in patients with AT plasma concentration below 0.50 U/ml, to 0.85 in patients with AT above 1.00 U/ml (mean ratio 0.61). A formula expressing heparin act as a function of AT and heparin concentration in the test plasmas of the patients was used to calculate heparin act of the total material comprising 280 patients. Mean heparin act and heparin conc were both significantly correlated to clinical outcomes (bleeding complications, pulmonary embolism and phlebography score). For monitoring heparin therapy, guidelines for plasma heparin activity or concentration ("therapeutic ranges") are requested. When using a heparin act assay, the heparin dose needed in patients with low plasma AT concentration to reach a fixed therapeutic range, may imply undue risk of bleeding. On the other hand, when a heparin conc assay indicate plasma heparin conc within therapeutic range, antithrombotic activity may still be inadequate in patients with low plasma AT concentration.

Antithrombins↗
PubMed1987

Consumption of heparin cofactor II (dermatan sulfate cofactor) and antithrombin during coagulation.

In vitro coagulation produces a consumption of heparin co factor II (HC II) of 8-10% both in plasma from normal individuals and patients whereas antithrombin (AT) consumption ranges 40-50%. In blood from heparin treated patients consumption is similar or greater. In blood from warfarin treated patients, consumption is decreased. Addition of heparin prior to clotting has little effect on HC II consumption, but high heparin concentration reduces AT consumption. Addition of dermatan sulfate has no effect on AT consumption, but increases HC II consumption dramatically. In consumption coagulopathy, the HC II levels are as low as AT, possibly reflecting intravascular consumption accelerated by vascular glycosaminoglycans.

Antithrombins↗
PubMed1988

Neutralization of thrombin by antithrombin III in the presence of cultured human fibroblasts.

Recent evidence suggests that heparan sulfate on endothelial cell surfaces acts as a catalyst for the neutralization of thrombin by antithrombin III (AT III). Fibroblasts also produce heparan sulfate which is present on the cell surface and secreted into the extracellular matrix. We evaluated the ability of cultured human fibroblasts to catalyze the interaction between thrombin and AT III and found that heparan sulfate produced by post-confluent fibroblasts was anticoagulantly active. Furthermore, after initial binding of thrombin to cells, thrombin-heparan sulfate appeared in the fluid phase above the cells; this thrombin could be rapidly neutralized by AT III independent of the further presence of cells. These results indicate that fibroblasts do produce an anticoagulantly active species of heparan sulfate and that the normal interaction between AT III and thrombin may be driven by initial release of heparan sulfate from the cell surface by thrombin followed by AT III interaction with the soluble thrombin-heparan sulfate complex.

Antithrombin III↗