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PubMed1983

Effect of antithrombin III, alpha 1-proteinase inhibitor and heparin on amidolytic activity of nerve growth factor (7S-NGF).

Amidolysis catalysed by nerve growth factor (7S-NGF) and by a glandular kallikrein, unlike that catalysed by thrombin, was not inhibited by antithrombin III, either in the presence or absence of heparin. Inhibition by alpha 1-proteinase inhibitor of thrombin-, but not of 7S-NGF- or kallikrein-catalysed amidolysis was alleviated by incubation of enzyme and heparin before addition of inhibitor. These data are discussed in terms of a possible control of growth factor activity by antiproteinases and glycosaminoglycans.

Animals↗
PubMed1985

Mono- and bidimensional 500 MHz 1H-NMR spectra of a synthetic pentasaccharide corresponding to the binding sequence of heparin to antithrombin-III: evidence for conformational peculiarity of the sulfated iduronate residue.

1H-NMR spectra of the synthetic pentasaccharide (N-sulfate-6-0-sulfate-alpha-D-glucosamine) 1----4 (beta-D-glucuronic acid) 1----4 (N-sulfate-3,6-di-0-sulfate-alpha-D-glucosamine) 1----4 (2-0-sulfate-alpha-L-iduronic acid) 1----4 (N-sulfate-6-0-sulfate-alpha-D-glucosamine), corresponding to the active site of heparin for antithrombin (AT-III), have been resolved at 500 MHz and assigned by mono- and bidimensional techniques. Vicinal proton coupling constants of the D-glucosamine residues are similar to those in the regular sequences of heparin, indicating that the 4C1 conformation of the ring, and preference for the g,g conformation of the sulfated hydroxymethyl groups of these residues are neither affected by the unique 3-0-sulfo group nor by sequence effects. By contrast, an unusually large coupling between H-2 and H-3 of the sulfated L-iduronic acid residue suggests a greater departure from the 1C4 conformation of this residue. when present in the binding sequence to AT-III than in the regular sequences. Such a departure, leading to different orientation and spacing of essential sulfate groups, may have implications for high-affinity binding to AT-III.

Antithrombin III↗
PubMed1988

Isolation of heparan sulfates with antithrombin III affinity and anticoagulant potency from BALB/c 3T3, B16.F10 melanoma, and cutaneous fibrosarcoma cell lines.

The heparan sulfates synthesized in vitro by three cell lines were isolated by proteolysis and preparative anion exchange chromatography and purified free of other glycosaminoglycans by selective enzymatic degradation. The isolates from the medium of BALB/c 3T3 fibroblasts, B16.F10 melanoma cells, and a cutaneous fibrosarcoma line, along with that from the detergent-extracted cell layer of the fibroblasts, were affinity-fractionated on columns of matrix-immobilized human antithrombin III. Each heparan sulfate contained subfractions with high affinity for the proteinase inhibitor, ranging from 3-34% of the starting material. The high affinity species possessed measurable anticoagulant activities by a clotting assay (6 to 30 units/mg). Since none of the lines were derived from cell types having any known biological role in vascular homeostasis, we suggest that anticoagulant activity of the glycosaminoglycan is a random property of its primary structure.

Animals↗
PubMed1989

Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells.

Prostacyclin (PGI2) is a potent vasodilator and an inhibitor of platelet aggregation. We found that antithrombin III (AT III), an anticoagulant present in circulating blood, stimulated PGI2 production by cultured bovine aortic endothelial cells in a dose- and time-dependent manner. The stimulation of PGI2 production by AT III was observed at physiological concentrations and was inhibited by the addition of anti-AT III antiserum and heparin. These results suggest that AT III may stimulate PGI2 production by binding to heparin-like molecules on the endothelial cell membrane.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Rat protein SV-IV (seminal vesicle protein No. 4) accelerates human blood coagulation in vitro by selective inhibition of antithrombin III.

The seminal vesicle protein No. 4 (SV-IV) secreted from the rat seminal vesicle epithelium, possesses immunosuppressive and anti-inflammatory properties and it is a potent inhibitor of platelet aggregation both in vivo and in vitro. This research aimed to investigate the possible effect of SV-IV on the process of human blood coagulation. Preliminary experiments showed that the recalcification time (RT) of platelet-poor plasma (PPP) samples, obtained from both normal subjects and patients affected by some hemorrhagic disorders, was found to be markedly reduced in the presence of micromolar amounts of SV-IV. It was demonstrated that the concentration of free antithrombin III (AT III) occurring in blood sera obtained from PPP samples recalcified in the presence of SV-IV was significantly decreased in comparison with sera obtained from PPP recalcified in the absence of SV-IV. It was also shown that PPP treatment with SV-IV significantly reduced the concentration of free AT III without affecting the levels of other plasma serine protease inhibitors, such as alpha 2-macroglobulin, alpha 1-antitrypsin and C1-inhibitor. In addition, the RT of PPP treated with a specific rabbit anti-AT III polyclonal antiserum (anti-AT III treated PPP) was not modified by SV-IV. These findings were confirmed by the observation that the addition of SV-IV into an in vitro coagulation system, containing pure fibrinogen, alpha-thrombin and AT-III, resulted in complex suppression of thrombin inhibition by AT III. No other steps of the blood clotting process (prothrombinase complex, factor XIII, fibrinogen concentration) were affected by SV-IV.

Animals↗
PubMed1988

Binding of heparin to antithrombin III: a chemical proof of the critical role played by a 3-sulfated 2-amino-2-deoxy-D-glucose residue.

Known methyl (prop-1-enyl 2,3-di-O-benzyl-alpha-D-glucopyranosid)uronate was first converted into methyl (prop-1-enyl 2,3-di-O-benzyl-4-O-levulinyl-alpha-D-gluco-pyranosid)uro nat e. Acid hydrolysis, followed by treatment with (bromomethylene)-dimethylammonium bromide, gave methyl (2,3-di-O-benzyl-4-O-levulinyl-alpha-D-glucopyranosyl bromide)uronate. Condensation of this bromide with 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranose gave 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O- levulinyl-beta-D-glucopyranosyluronate)-beta-D-glucopyranose. Acetolysis, followed by selective anomeric O-deacetylation and treatment with (bromomethylene)dimethylammonium bromide then gave 6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O-levulinyl -beta-D-glucopyranosyluronate)-alpha-D-glucopyranosyl bromide. Condensation of this bromide with benzyl 6-O-acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-4- O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-alpha-D- glucopyranoside provided benzyl O-(methyl 2,3-di-O-benzyl-4-O-levulinyl-beta-D- glucopyranosyluronate)-(1----4)-O-(6-O-acetyl-2-azido-3-O-benzyl-2-deoxy - alpha-D-glucopyranosyl)- (1----4)-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-(1----4)- 6-O-acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glu copyranoside. Removal of the levulinyl group followed by condensation with 6-O-acetyl-2-azido-3,4-di-O -benzyl-2-deoxy-alpha-D-glucopyranosyl bromide provided benzyl O-(6-O-acetyl-2- azido-3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2,3-di- O-benzyl-beta-D-glucopyranosyluronate)-(1----4)-O-(6-O-acetyl-2-azido-3- O- benzyl-2- deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L- idopyranosyluronate)-(1----4)-6-O-acetyl-3-O-benzyl-2-benzyloxycarbon ylamino-2- deoxy-alpha-D-glucopyranoside in 78% yield. O-Deacetylation followed by re-esterification, O-sulfation, catalytic hydrogenolysis, saponification, and N-sulfation gave the non-sodium salt of O-(2-deoxy-6-O-sulfo-2-sulfoamino-alpha-D-glucopyranosyl)-(1----4) -O- (beta-D-glucopyranosyluronic acid)-(1----4)O-(2-deoxy-6-O-sulfo-2-sulfoamino- alpha-D-glucopyranosyl)-(1----4)-O-(2-O-sulfo-alpha-L-idopyranosyluronic acid)- (1----4)-2-deoxy-6-O-sulfo-2-sulfoamino-D-glucopyranose. This synthetic pentasaccharide neither binds to antithrombin III nor induces anti-factor Xa activity.

Alcohols↗
PubMed1995

Dynamics in aqueous solutions of the pentasaccharide corresponding to the binding site of heparin for antithrombin III studied by NMR relaxation measurements.

1H NMR and 13C NMR relaxation measurements at different magnetic field strengths were used to study the nature of overall and internal motions, in aqueous solution, of the synthetic pentasaccharide (A-G-A*-I-AM) corresponding to the binding site of heparin for antithrombin III. Two-dimensional double INEPT spectra were recorded at 11.7 T with and without suppression of cross-correlation effects between dipolar and chemical shift anisotropy relaxation mechanisms in measurements of spin-lattice and spin-spin relaxation times. Moreover, longitudinal relaxation times were collected at 7 T with the inversion recovery method. One dimensional NOESY spectra were recorded at 11.7 T and 9.4 T with various mixing times when spins of the A1* and A4* protons were inverted in the central residue of the pentasaccharide. Differences in the T1 relaxation times, as well as in the cross-relaxation rates between protons relaxing through fixed distances in the A* residue, indicated that the molecule tumbles anisotropically in solution. However, in order to achieve agreement between the spectral and the model data, the presence of internal motions had to be also considered, in addition to the assumption of a symmetric top model for the description of overall tumbling. The changes in the longitudinal and transversal relaxation times, collected with and without suppression of interference effects, supported the assumption that the cross-correlation between dipolar and chemical shift anisotropy relaxation mechanisms cannot be neglected in this medium-sized molecule. In fact, the influence of these effects was 10-15% in T1 and 20-25% in T2 relaxation times. The experimental data were analyzed using model free formalism and the computed order parameters indicate a decrease in spatial restriction from the central residue (S2 approximately 0.9) towards both ends of the pentasaccharide (S2 approximately 0.7). The anisotropy ratio found was approximately 3.3 with correlation times tau parallel = 450 ps and tau perpendicular = 1480 ps. The values of effective correlation time were within the range of tens of picoseconds. Thus, for a more precise interpretation of the experimental data for the pentasaccharide, in addition to internal motions and anisotropic tumbling, the effect of cross-correlation must be taken into account as well.

Antithrombins↗
PubMed1977

Identification of alpha1-acid glycoprotein, alpha2-macroglobulin and antithrombin III as components of normal and malignant human tissues.

alpha1-Acid glycoprotein, alpha2-macroglobulin, and antithrombin III have been identified, by immunological means, as components of the 90000 X g supernatant fraction of malignant and adjacent normal human breast, colon, and anal tissues, as well as malignant stomach and ileum. Malignant lung tissue only contained alpha1-acid glycoprotein. These protease inhibitors are immunologically equivalent to those present in human plasma.

Antithrombins↗
PubMed1984

Characterization of the biological activity of antithrombin III in patients with hepatic cirrhosis.

A discrepancy was found in hepatic cirrhosis patients between two forms of biological activities, i.e. progressive antithrombin activity (prog AT) and heparin cofactor activity (heparin AT). A reduced level of heparin AT was obtained in comparison with that of prog AT, despite the fact that both activities correlated well in normal controls. The binding ability of AT III to heparin was observed by crossed immunoelectrophoresis, and showed a reduced second peak of AT III with a faster AT III with a qualitative defect in its binding ability to heparin due to impaired protein synthesis.

Antithrombin III↗
PubMed1985

Location of two of the introns in the antithrombin-III gene.

At least two of the introns in the antithrombin-III (AT-III) gene are located in positions different from those of the other three proteins in this superfamily for which the gene structures are known, namely, ovalbumin, alpha 1-antitrypsin and angiotensinogen. In another part of the 3'-portion of the AT-III gene there is no intron where each of the other three gene structures has one.

Amino Acid Sequence↗
PubMed1986

The heparin-binding site(s) of histidine-rich glycoprotein as suggested by sequence homology with antithrombin III.

A high degree of sequence homology has been found between the N-terminal region of histidine-rich glycoprotein (HRG) and that of antithrombin III (AT III) where the putative heparin-binding site of AT III is located. The amino acid residue at the position corresponding to Arg-47 of AT III that is essential for the heparin-binding was also arginine (Arg 23 and 78) in the homologous sequences of HRG. These observations strongly suggest that the heparin-binding sites of HRG and AT III are evolutionarily related. There was no apparent sequence similarity between the remaining about 70% portions of the two proteins.

Amino Acid Sequence↗
PubMed1989

Antithrombin Cambridge, 384 Ala to Pro: a new variant identified using the polymerase chain reaction.

An antithrombin III variant was identified in the plasma of a female patient with a history of recurrent thromboses. The variant was shown to have normal antigenic levels but reduced heparin and progressive inhibitory activity consistent with an abnormality affecting function at the reactive centre. Polymerase chain reaction amplification of exon 6 of the gene with direct sequencing showed a point mutation resulting in the substitution of a proline for alanine at position 384. This substitution will predictably alter the conformation of the peptide loop containing the reactive centre of the molecule.

Adult↗
PubMed1994

Artificial ultraviolet whole-body radiation does not modify serum lipoprotein, plasma fibrinogen, plasminogen or antithrombin III concentrations in post-myocardial infarction patients.

The relationship of ischaemic heart disease (IHD) to seasonal and latitude variation has prompted speculation that exposure to the ultraviolet component of solar radiation may reduce IHD risk. This hypothesis was partially tested by exposing 14 post-myocardial infarction patients to a 6 week course of artificial whole-body ultraviolet radiation (UVR). Serum lipoprotein and plasma coagulation factor concentrations were measured before and after the course of UVR. Results were compared with similar measurements from a placebo-controlled group of 13 post-myocardial patients. Despite a more than two-fold rise in mean serum 25-OHD, serum lipoprotein and plasma fibrinogen, antithrombin III and plasminogen concentrations did not change significantly in the UVR group. Significant but minor change in prothrombin time and thrombin time in the placebo group appear unlikely to be of biological significance. Seasonal and latitude variation in these IHD risk factors appear unrelated to corresponding variation in solar UVR exposure.

Antithrombin III↗
PubMed1994

Control of the cultivation process of antithrombin III and its characterization by capillary electrophoresis.

The production by baby hamster kidney cells of recombinant antithrombin III (r-AT III), the main inhibitor of thrombin, factor Xa and other proteases of the clotting cascade, was monitored by capillary isotachophoresis using mixtures of continuous spacers. The results were compared with those obtained by capillary zone electrophoresis (CZE). The downstream process, which incorporated anion-exchange and heparin affinity chromatography, was monitored by CZE under acidic conditions and voltage ramping. The purified product was characterized by its isoelectric point and molecular mass. Isoelectric points of the three major and three minor isoforms of AT III were evaluated by capillary isoelectric focusing using a pH range of 4-6 and various mobilization procedures. The molecular mass of AT III was investigated by capillary gel electrophoresis (CGE), applying removable dextran gels. Both parameters could be determined within 30 min using only one coated capillary. The results showed an excellent correspondence with those achieved with conventional slab gels. The affinity complex between AT III and thrombin could also be detected by CGE and the heparin dependence of the affinity reaction could be investigated.

Animals↗
PubMed1989

Crystallization and preliminary crystallographic data for bovine antithrombin III.

Crystals of bovine antithrombin III were obtained in the presence of metal ions with ammonium sulphate as precipitating agent. Crystals belong to space group P4(1)2(1)2 or P4(3)2(1)2 with cell parameters a = b = 91.4 A, c = 383.1 A; there are two molecules per asymmetric unit. Electrophoresis experiments and amino acid sequence analysis of the N-terminal part of redissolved crystals suggest that the protein molecules are cleaved at the active site.

Animals↗
PubMed1984

Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery.

Prophylactic treatment of two asymptomatic antithrombin III (AT III) -deficient women with oral anticoagulants and heparin during pregnancy and after delivery appeared to be feasible. Oral anticoagulants caused no change in plasma AT III levels in either woman. A high dose of heparin intravenously in one of them caused a strong reduction in the AT III level which was corrected by infusion of AT III concentrate during delivery. A low dose of heparin subcutaneously in the other caused no significant change in plasma AT III levels. There is probably no need for AT III substitution during an uncomplicated pregnancy.

Adult↗
PubMedDate not supplied

Synergy of antithrombin III concentrate and antivenom in preventing coagulopathy in a rat model of Malayan pit viper envenoming.

The effects of unrefined equine antivenom and antithrombin III (AT-III) concentrate on the coagulopathy induced by systemic envenomation by Malayan pit viper (Calloselasma rhodostoma; MPV) venom were investigated in a rat model. 37 rats received an intramuscular injection of MPV venom and serial blood samples were taken from the femoral vein for simple whole blood clotting tests and measurement of AT-III activity. 30 min after venom injection, treatment (antivenom, AT-III or both) was given intravenously. 6 rats were untreated and all developed uncoagulable blood and AT-III depletion 90-210 (median 180) min after venom injection. A combination of high dose AT-III concentrate (0.5 units/g) and antivenom (20 micrograms/g) prevented abnormal clotting (P less than 0.001), whereas AT-III alone, antivenom alone, or a combination of low dose AT-III (0.25 units/g) and antivenom did not (P less than 0.05). These results suggest that the coagulation abnormality in MPV envenomation is secondary to activation of the coagulation cascade at several levels, and that treatment with antivenom alone may not be sufficient to reverse or prevent this phenomenon.

Animals↗