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At least 1,117 records · Page 62Linked to original sources
PubMed2001

Separation of native and latent forms of human antithrombin by hydrophobic interaction high-performance liquid chromatography.

Hydrophobic interaction high-performance liquid chromatography (HIC-HPLC) was utilized for the separation of native human antithrombin (AT) and a partially denaturated form of AT, known as the latent form (L-AT). The AT used in this study is commercially available (Atenativ, Pharmacia & Upjohn, Sweden) and contains albumin as the main stabilizer. The AT was reconstituted and heat treated in order to generate L-AT. This latent form of AT has been shown to exhibit a strong antiangiogenic activity and also to suppress tumor growth. The HPLC system included a TSK Phenyl 5PW column and a segmented gradient, 4.5-0 mol/L sodium chloride. Antithrombin was eluted at about 13 min, and L-AT, at 30 min, corresponding to about 4.2 and 1.6 mol/L sodium chloride, respectively. A reference sample gave 42% L-AT when analyzed by the HIC method and 41% L-AT when analyzed by the heparin affinity chromatography method. The resolution between AT and L-AT was higher with the HIC method than with the heparin affinity method. Incubation of Atenativ at 45 degrees C for 15 h gave about 18% L-AT and was shown by native polyacrylamide gel electrophoresis to contain only monomeric AT. A good resolution between AT and L-AT, but not between albumin and L-AT, was also achieved by a linear gradient of 2-0 mol/L ammonium sulfate, in 25 mmol/L Tris/HCl, pH 8.0.

Antithrombins↗
PubMed1993

Immobilization of the slime mould Dictyostelium discoideum for the continuous production of recombinant human antithrombin III.

Recombinant vegetative Dictyostelium discoideum cells were immobilized inside a porous matrix by an inorganic membrane that was permeable to nutrients but not to cells, in order to produce recombinant human antithrombin III. Cells so entrapped could reach up to 15 times higher biomass densities compared with organisms growing freely in suspension. The high cell concentration maintained in the immobilized cell bioreactor caused an increase in specific and volumetric productivity. In continuous operation a maximum volumetric antithrombin productivity of 56 ng h-1 ml-1 catalyst bulk volume was attained at a dilution rate of 0.016 h-1. In addition, the good retention of metabolic activity for several weeks as well as the convenient form of storage and regeneration of the catalytic system were shown.

Animals↗
PubMed1991

Hepatocarcinoma in cirrhosis. Is antithrombin III a neoplastic marker?

It has been reported that hepatoma (HCC) cells produce abnormal proteins such as erytropietin, fibrinogen, prothrombin, and, recently, antithrombin III (AT III). In a preliminary report, we reported increased AT III levels in patients bearing HCC independent of their clinical liver status. The present study was performed to assess antithrombin III levels and other serological data present in patients with cirrhosis and in patients with cirrhosis and clinical findings of neoplastic disease. In 70 well-matched patients (47 with cirrhosis and 23 with cirrhosis and proven HCC) serum total cholesterol, albumin, prothrombin, alkaline phosphatase, AFP, aminotransferases, and AT III were determined. Together with AFP and alkaline phosphatase, patients with HCC had higher values of AT III (88 +/- 7%) and total cholesterol (184 +/- 17 mg/100 ml), as compared with cirrhotic patients (AT III 56 +/- 3.6%; total cholesterol 113 +/- 5 mg/100 ml) (P less than 0.001). No difference was observed between these two groups for albumin, prothrombin, and aminotransferases. In HCC patients, AT III levels were related to the total cholesterol level (R2 = 0.317), whereas in the cirrhotic patients it correlated with the prothrombin level (R2 = 0.274). These data suggest that in HCC patients a greater rate of synthesis of AT III occurs, whereas in cirrhotic patients lower levels of AT III occur due to impaired synthesis or increased catabolism of the protein. The serial determination of AT III in cirrhotic patients as a means of detecting neoplastic transformation is suggested.

Adult↗
PubMed1991

Elevated thrombin-antithrombin III complex concentrations in patients with gynaecological malignancy.

In patients with malignant tumors a high incidence of haemostatic disorders occurs. The reaction of thrombin with its major inhibitor antithrombin III (AT III) leads to the formation of a stable complex, which represents a sensitive marker for the activation of intravascular coagulation. In 153 patients suffering from different kinds of gynaecological malignancy thrombin-antithrombin III-complex (TAT) levels were measured. In 21 cases the course of the disease was studied. Of 153 patients with gynaecological malignancy 102 (67%) showed TAT plasma concentrations above the normal range before therapy. Seven patients with elevated TAT levels before treatment showed a decrease of TAT concentrations to the normal range when no evidence of disease was obvious. In 5 cases TAT levels were in the normal range before and after successful therapy, 4 patients with tumor progression and 5 patients with tumor recurrence showed an increase of TAT levels. The TAT plasma concentrations correlated with the presence or absence of the tumor. Measurement of TAT plasma concentrations in gynaecologic malignancies can detect any thromboembolic risk for the patient and in addition can reveal information about the course of the disease.

Aged↗
PubMed1997

Plasma levels of protein C, protein S, and antithrombin III in patients with subarachnoid haemorrhage.

This study was designed to evaluate the clinical value of consecutive measurements of the levels of the anticoagulation factors protein C. protein S and antithrombin III in the plasma of patients with subarachnoid haemorrhage (SAH). Sequential samples of plasma were obtained from 34 patients at days 0 to 3, 5, 8, 14, and 20 days after SAH. Their levels of protein C, protein S and antithrombin III were measured by specific immuno-assays, and the symptomatic vasospasm and clinical states of the patients were monitored. Based on the retrospective comparisons between the measured levels of the three factors and the levels in pooled plasma from normal volunteers, the time course of changes in the levels allowed the classification of the patients into five groups as follows: A, the levels of the three factors decreased suddenly at 5 days after SAH, then increased again (n = 6); B, the three factors increased continuously (n = 13); C, the three factors remained below the normal range (n = 3); D, the three factors remained within the normal range (n = 6); and E, the three factors decreased continuously (n = 6). In group A patients, temporary deficiencies in the three factors occurred that coincided with the occurrence of delayed neurological deficit (DND). Twelve patients (92%) in group B had a favourable outcome (good and moderate disability) without DND. The patients in group C had low levels of anticoagulation factors and mild DND followed by a favourable outcome. Five patients (83%) in group D had a favourable outcome. In group E, five patients (83%) had a poor outcome (severe disability and death) due to DND. When clinical outcomes were compared by patient group, the patients in group E had significantly more unfavourable outcomes than did the other groups (P < 0.01). Although the mechanism responsible for the decrease in anticoagulation factor levels remained unclear, the results suggested that the decrease in anticoagulation factors may indicate hypercoagulability and cerebral ischaemia after SAH.

Adult↗
PubMed1997

Are prothrombin fragment 1 + 2 and thrombin-antithrombin complexes useful in the management of oral anticoagulant therapy?

We investigated the behavior of prothrombin fragment F1 + 2 and thrombin-antithrombin complexes in 70 patients treated with chronic anticoagulant therapy. Moreover, in a longitudinal study 37 patients were evaluated twice and 16 patients three times. Twenty-eight age- and sex-matched healthy subjects were also studied as a control group. Prothrombin fragment F1 + 2 or thrombin-antithrombin values among patients with different International Normalized Ratios, nor in the same patients studied two or three times. Our results confirm that oral anticoagulant treatment can effectively reduce thrombin activity. However, strong anticoagulation does not induce a further significant decrease in fragment F1 + 2 values. Therefore, we feel measurement of fragment F1 + 2 might be less useful than thought in optimizing oral anticoagulant therapy.

Administration, Oral↗
PubMed1989

Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism.

A small fraction of plasma antithrombin is normally bound to a specific population of heparan sulfate proteoglycans synthesized by macrovascular and microvascular endothelial cells. This permits the protease inhibitor to be selectively activated at blood-surface interfaces where enzymes of the intrinsic coagulation cascade are commonly generated. Thus, antithrombin is critically placed to neutralize these hemostatic enzymes and thereby protect natural surfaces against thrombus formation. Furthermore, the catalytic nature of this specific set of heparan sulfate proteoglycans ensures the continual regeneration of the nonthrombotic properties of the endothelial cell layer. Alterations in the synthesis and/or placement of the anticoagulantly active heparan sulfate proteoglycans on the surface of microvascular and macrovascular endothelial cells could be responsible for arterial and venous thrombotic disease in humans.

Animals↗
PubMed1989

Congenital antithrombin III deficiency: insights into the pathogenesis of the hypercoagulable state and its management using markers of hemostatic system activation.

Hereditary antithrombin III (ATIII) deficiency predisposes patients to venous thrombosis. The prothrombin fragment F1+2 radioimmunoassay demonstrates that many asymptomatic patients with this disorder not receiving antithrombotic therapy have elevated plasma factor Xa activity. The hemostatic system hyperactivity as measured by this assay could be specifically corrected by rising plasma ATIII levels of several persons into the normal range. This indicates that the prethrombotic state can be defined as an imbalance between the production and inhibition of factor Xa enzymatic activity. The effects of warfarin on factor Xa enzymatic activity in persons with congenital ATIII deficiency have also been evaluated. At equivalent intensities of oral anticoagulation, the mean plasma F1+2 level in patients with ATIII deficiency was significantly elevated as compared with anticoagulated persons without this inherited thrombotic disorder. It is concluded that the effect of warfarin on hemostatic system activation is modulated by the endogenous heparan sulfate-ATIII mechanism. This suggests that the F1+2 radioimmunoassay can be employed to improve the understanding of the hypercoagulable state associated with antithrombin III deficiency as well as to develop more effective treatment strategies to prevent thromboembolic events in patients with this disorder.

Antithrombin III Deficiency↗
PubMed1978

The increase in human antithrombin III tryptophan fluorescence produced by heparin.

The increase in fluorescence of human antithrombin III has been used to study the binding of a semi-synthetic heparin analogue. One molecule of heparin were found to bind with an association constant of 8.9 . 10(4) M-1. The intrinsic fluorescence of antithrombin III exhibits a fluorescence quantum yield of 0.17. Upon addition of heparin a marked increase in the protein fluorescence quantum yield is observed.

Antithrombins↗
PubMed1980

Effects of the reduction and S-carbamidomethylation on the conformation, activity and heparin-binding capacity of human antithrombin III.

Antithrombin III has been shown to contain three disulphide bridges. They can be broken by reduction under non-denaturing conditions. The completely reduced and S-carbamidomethylated protein is devoid of thrombin-inhibiting activity and does not bind heparin. However, the immunological reactivity as determined by electroimmunoassay is almost unchanged, indicating that no large conformational changes occur upon cleavage of the disulphide bonds. This is also supported by the observation that the reduced and S-carbamidomethylated protein has the same fluorescence properties as the native protein dichroic spectrum of the native protein shows a pronounced pattern in the near-ultraviolet region, indicating restricted rotation of the aromatic amino acid side chains. This is drastically changed by the reduction and carbamidomethylation. The character of the far-ultraviolet circular dichroic spectrum is similar in the native and reduced S-carbamidomethylated protein. The reduction and S-carbamidomethylation of antithrombin III induces some local changes in the tertiary structure affecting the inhibitor activity, heparin binding and near-ultraviolet circular dichroic spectrum, but do not seem to induce any substantial general conformation change.

2,2'-Dipyridyl↗
PubMed1987

Antithrombin III mRNA in adult rat liver and kidney and in rat liver during development.

Using Northern blots the size of antithrombin III (AT III) mRNA in rat liver was found to be 1650 nucleotides. Adult rat kidney also contained a slightly smaller mRNA at about 20% the level in liver. The ontogeny of AT III mRNA in the liver was assessed by dot blot hybridization. The mRNA was detectable at the earliest age examined (14th day of gestation) at about 15% of the adult levels. After the 17th day of gestation the levels of antithrombin III mRNA rise reaching 50% of adult levels at birth. After birth the mRNA levels rise to 75% of adult levels by the 5th day and reach adult levels by 40 days after birth. We suggest that foetal AT III is produced by both the foetal liver and by placental transfer of the maternal inhibitor.

Animals↗
PubMed1989

Examination, by 1H-n.m.r. spectroscopy, of the binding of a synthetic, high-affinity heparin pentasaccharide to human antithrombin III.

Binding of a synthetic, high-affinity heparin pentasaccharide and of intact heparin to both native and elastase-modified human antithrombin III have been examined by 1H-n.m.r. spectroscopy. The pentasaccharide perturbs many protein resonances in the same way as does intact heparin. There are, however, differences that seem to arise both from fewer contacts in the heparin binding-site when the pentasaccharide binds and from dissimilar conformational changes in the protein. The resonance of the H-2 atom of the histidine, considered to be the N-terminal residue and to be located in the heparin binding-site, is strongly perturbed by heparin binding both to native and modified antithrombin. The pentasaccharide has little effect on this histidine in either protein. Resonances from two of the remaining four histidine units are sensitive to longer-range conformational changes, and show differences between binding of the two heparin species both in native and modified ATIII. It is concluded that the pentasaccharide only partly fills the heparin binding-site and does not produce a conformational change identical to that caused by intact heparin. This is particularly significant as regards the mechanism of action of heparin, because the synthetic pentasaccharide activates ATIII towards Factor Xa, but not towards thrombin.

Antithrombin III↗
PubMed1990

Conformation of the pentasaccharide corresponding to the binding site of heparin for antithrombin III.

The conformation in solution of the pentasaccharide methyl glycoside (As-G-A*-Is-AM; 1), which represents the binding site of heparin for Antithrombin III, has been investigated using molecular mechanics and 1H-n.m.r. spectroscopy. The pentasaccharide has a rather rigid (As-G-A*) and a more flexible (Is-AM) region. A simplified model of 1, comprising two conformations, corresponding to the 1C4 and the 2S0 forms of the iduronate residue, and modified at the G-A* glycosidic linkage with respect to the energy minimum, reproduces most of the observed 3J values and n.O.e. enhancements. The possible role in the binding to Antithrombin III of a low-energy conformer, not observed in solution, is discussed.

Antithrombin III↗
PubMed1981

Practical requirements for immunochemical analysis of antithrombin III in agarose gels.

This report emphasizes the importance charged groups affixed to the agarose gel matrix have on immunoprecipitation of antithrombin III (AT) and of its protease complexes. Plasma and serum samples were analyzed for antithrombin III by electroimmunoassay and single radial immunodiffusion in different types of agarose. The results were compared with the amount of functionally active AT contained in the samples. A high correlation between the results was obtained provided the following criteria were fulfilled: (1) agarose with a sulphate content of 0.2% or more was used; (2) the antiserum should contain antibodies directed to AT plus antigenic determinant(s) that emerge(s) during the AT-protease interaction; (3) a gel buffer of about 75 mmol/l was used. Heparin added to the test system competed with sulphate groups affixed to the agarose gel matrix and inhibited immunoprecipitation of AT.

Antithrombin III↗
PubMed1982

A sensitive colorimetric assay for thrombin, prothrombin and antithrombin III in human plasma using a new synthetic substrate.

Benzoyl-L-leucyl-L-alanyl-L-arginine-alpha-naphthylester (Bz-Leu-Ala-Arg-NE) was synthesized as a new substrate for use in the assay of thrombin. In the assay alpha-naphthol released by the enzyme reaction was measured colorimetrically. With Bz-Leu-Ala-Arg-NE as substrate, the minimum detectable concentration of human thrombin was 0.0025 U. This assay using Bz-Leu-Ala-Arg-NE is a highly sensitive method for detecting prothrombin, thrombin and antithrombin III in human plasma. Prothrombin could be determined with 0.2 microliter of human plasma using Echis carinatus venom (ECV) as activator. Antithrombin III activity could be determined with 2 microliter of human plasma using human thrombin and heparin as cofactor. A zymogram of human prothrombin was prepared with Bz-Leu-Ala-Arg-NE as substrate. The preparation gave one band (pI 4.9) on polyacrylamide disc gel isoelectrophoresis.

Antithrombin III↗
PubMed1983

Effect of protamine sulfate on antithrombin III activity.

When protamine sulfate was added to heparinized plasma in vitro for neutralization of heparin, the activities on both thrombin and Xa known as heparin cofactor in antithrombin action were completely abolished. However, progressive activities on thrombin and Xa both recovered within 30 minutes after protamine sulfate addition. When equivalent heparin was again added, heparin cofactor activity was immediately restored. Based on the fact that protamine sulfate did not show any direct action on the antithrombin III molecule, the presence of AT III with progressive activity was considered to play an important role in the rebound phenomenon of heparin after heparin neutralization with protamine sulfate.

Antithrombin III↗