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PubMed1991

[Clinical and genetic aspects of antithrombin III deficiency and abnormal antithrombin III].

Antithrombin III (AT III) has been confirmed to play an important role as a serine protease inhibitor in the mechanism of blood coagulation, and its deficiency or abnormality is found to cause thromboembolic disorders by reducing the anticoagulant activity. In this paper AT III gene of patient with congenital AT III deficiency, which was suggested to have qualitative abnormality by isoelectric focusing, was investigated. Analysis of the genomic structure by Southern blot hybridization with a cDNA probe (pAT6) revealed no detectable changes indicating any deletions, rearrangements and translocations. Therefore, we focused to analyze the sequence of exon 6 of AT III gene by polymerase chain reaction (PCR) methods followed by direct sequencing analysis. Nucleotide sequencing of exon 6 of AT III gene showed a G to T transitional mutation resulting in the conversion of arginine-406 to methionine coexisted with normal allele which encodes arginine. The mutation is located near the reactive center of AT III molecule, which region has been proved to be highly conserved during the evolution of serine protease inhibitor (serpin) family. From these results, it is concluded that the new type of mutation at amino acid site 407, which is similar to AT III Utah, is important for maintaining the structural and biological function of this inhibitor.

Antithrombin III↗
PubMed1986

[Procedures for the isolation and characterization of human antithrombin III].

Antithrombin III, the most important inhibitor of activated coagulation factors (IIa, IXa, Xa, XIa, XIIa) was isolated from human plasma by affinity chromatography. The biochemical characterization of this highly purified inhibitor showed, that is was uniform by means of HPLC and PAA gradient gel electrophoresis. The molecular weight was determined to 70000 daltons and the isoelectric point was pH 4,5. The inhibition of factor Xa by AT III had been proofed as competitive by kinetic studies. AT III works as a "dead end inhibitor". Heparin seems to form a ternary complex with AT III and activated coagulation factors, so acting as a catalyst. The therapeutic value of AT III-concentrates will be discussed.

Antithrombin III↗
PubMed1998

The preparation of specific sorbents with polyclonal antibodies as a ligand for purification of human antithrombin III.

Antithrombin III (AT III) is a serine protease inhibitor active against thrombin, factor X and factor VII. Major hematolytic abnormalities such as disseminated intravascular closing, coagulative vein inflammation, embolism in lungs or brain etc. frequently occur when the level of AT III is low. As a drug AT III is separated from blood preparations by bioselective sorption on sorbents containing heparine as a complementary ligand interacting with AT III molecules. The present paper describes the preparation procedures and the properties of sorbents with chemically bonded AT III antigen. The chromatographic ability of the prepared sorbents to separate AT III from human plasma are discussed in relation to the bonding procedure which was used for AT III antigen immobilization.

Animals↗
PubMed1983

Purification and characterization of guinea pig antithrombin III.

Antithrombin III (AT III) is a serine esterase inhibitor which regulates the activity of a number of coagulation factors. In this report, a three-step procedure for the purification of guinea pig AT III is described. This method, which involves affinity chromatography with heparin-Sepharose, ion exchange chromatography using DEAE-Sepharose, and Sephadex G-100 gel chromatography, results in purified, functionally active AT III with a 39% yield. The potential role of this molecule in the regulation of lymphocyte activation is discussed.

Animals↗
PubMed1986

[Hereditary deficit of antithrombin III].

Antithrombin III is a well-known coagulation inhibitor. Its heterozygous deficit is demonstrated through concentrations reduced about by 50 p. 100. On a clinical level, about 40 p. 100 to 70 p. 100 patients present with deep venous thrombosis (visceral on the whole) and pulmonary embolisms from puberty. There are both qualitative and quantitative deficits, these appearing to be mostly frequent. Only calculation of activity in the presence of heparin (co-factor of heparin) enables to diagnose these two types of deficits. Treatment performed includes both AT III concentrated agents and heparin in severe cases. Recurrences prevention is performed thanks to antivitamins K. If surgical treatment or delivery, a prevention of any incidents thanks to a vicarious therapy (AT III concentrated agent) is to be used.

Adult↗
PubMed1984

Neonatal antithrombin III.

Antithrombin III (AT-III) heparin cofactor activity and its antigen levels have been determined in 106 plasma samples from 42 term and preterm neonates. In contrast to healthy adult controls, a reduced activity/antigen (act/ag) ratio (ranging from 0.26 to 0.86) was observed in 90% of the samples and was independent of the state of health of the infant. By modifying the routine assay techniques, laboratory artefacts were excluded as the cause of the observed discrepancy. The relative increase in antigenic AT-III could not be accounted for by circulating AT-III-thrombin complexes, or by increased heparin cofactor II plasma levels in neonates.

Adult↗
PubMed1980

Immunochemical analysis of active and inactive antithrombin III.

Antithrombin III (AT) levels from normal and AT deficiency persons were measured by electroimmunoassay (EIA) and the results compared with a chromogenic assay (S2238). Discrepant results were obtained when plasma and serum were compared using one antiserum, and therefore did not always relate to functional activity. Another antiserum, however, when used was capable of differentiating active AT from inactive AT complexed with its proteases and demonstrated close correlation with all samples tested (r=0.97). The specificity of the antisera and consequent anomalous results were elucidated when purified human thrombin was added to plasma samples and subsequently reanalysed. Quantitative differences observed when serum samples were compared by single radial immunodiffusion and electroimmunoassay with one antiserum, illustrates the fundamental principle differences between the two methods. These results give some insight as to why previous anomalies with AT immunoassays have occurred. They also indicate that plasma and not serum should be used as clinical test material. AT antisera should be capable of recognizing and distinguishing free AT from AT/protease complexes if the results obtained by electroimmunoassay are to correlate with functional activity.

Antithrombin III↗
PubMed1983

Isolation of a cDNA clone for human antithrombin III.

Antithrombin III (ATIII) is an important plasma protease inhibitor with a central role in the coagulation system. On the basis of its protein sequence, ATIII is one member of a "super family" of protease inhibitors that includes alpha 1-antitrypsin and chicken ovalbumin. An increased risk of thromboembolism is associated with inherited ATIII deficiency. To study the structure and expression of the human ATIII gene, we have isolated complementary (cDNA) clones for ATIII from human liver mRNA. ATIII cDNA clones were identified by hybridization to a mixture of synthetic oligodeoxynucleotides encoding amino acids 251-256 of the ATIII protein sequence. The largest cDNA clone (1.4 kilobases) included the coding region of ATIII mRNA from codon 10 through a 3'-untranslated region. Comparison of ATIII cDNA clones from two different sources revealed a sequence polymorphism at an internal PstI restriction site. Analysis of both total genomic DNAs and an ATIII gene cloned in a bacteriophage Charon 4A showed that the ATIII gene is present once per haploid genome and is distributed over 10-16 kilobases of DNA. Computer-assisted comparison of the cDNA sequence with those for baboon alpha 1-antitrypsin and chicken ovalbumin revealed homologies consistent with their inclusion in the protease inhibitor superfamily.

Amino Acid Sequence↗
PubMed1994

Amino acid sequence of porcine antithrombin III.

Antithrombin III (ATIII) is a member of the serine protease inhibitor (serpin) family. As a step towards a better understanding of the heparin-binding mechanism of mammalian ATIIIs, the amino acid sequence of porcine ATIII was established by sequence analysis of the peptides derived from cyanogen bromide cleavage and enzymatic digestion with lysyl endopeptidase, V8 protease, and trypsin. Porcine ATIII was found to consist of 431 amino acid residues, with a calculated molecular weight of 48,930 without carbohydrate. Its molecular weight with 16.4% carbohydrate was estimated as 56,955, which is in good agreement with the value determined by SDS-PAGE. Porcine ATIII showed high sequence similarity to other mammalian ATIIIs, including the reactive site, heparin-binding basic amino acid residues, and disulfide bonds. The most notable feature of porcine ATIII was that it possesses only three carbohydrate chains, at Asn136, 156, and 193, whereas other mammalian ATIIIs have four, additional chain being at Asn97; this is replaced by Asp in porcine ATIII. In the case of human ATIII, the chains are at Asn96, 135, 155, and 192. The heparin-binding affinities of human and porcine ATIIIs were compared using an immobilized heparin column. Porcine ATIII eluted from the column with a peak at an NaCl concentration of 924 mM while human ATIII eluted at 838 mM NaCl. Neuraminidase treatment of each ATIII enhanced the heparin-affinity to the same extent. These results suggest that in spite of the high degree of amino acid sequence identity between porcine and human ATIIIs (91% identical), porcine ATIII has a higher heparin-binding affinity than human, because it lacks a carbohydrate chain at Asp97.

Amino Acid Sequence↗
PubMed1997

Thrombin-antithrombin III complexes and antithrombin III in amniotic fluid.

We measured thrombin-antithrombin III (TAT) complexes and antithrombin III (AT III) in amniotic fluid and blood plasma of 39 parturient women. TAT was measured by ELISA. Partigen plates were used for measuring the antigen of AT III, and activity was determined using chromogenic substrate. While AT III activity and AT III antigen were below 20% of plasma values, TAT concentration was 2-4 times higher in amniotic fluid than in blood plasma (over twice at the onset of labour, i.e. 54.2 +/- 26.4 and 20.7 +/- 10.7 ng/ml, and approximately 4 times after childbirth, i.e. 108.9 +/- 49.2 ng/ml in amniotic fluid and 27.8 +/- 13.2 ng/ml in blood plasma, respectively). We have concluded that thrombin generation and TAT formation in amniotic fluid are are of significantly higher intensity than in plasma, and they increase during labour.

Adult↗
PubMed1985

Comparison between the effect of pentosan polysulphate heparin and antithrombin III injections in antithrombin III deficient patients.

Pentosan polysulphate is an heparin analogue which acts via an antithrombin III (AT III) independent pathway. We compared the effect of this drug to that of heparin and AT III infusions in AT III deficient patients. Four patients with AT III congenital deficiency received on three different occasions: (i) an infusion of human AT III concentrate (20 U/kg or 40 U/kg), (ii) an intramuscular injection of pentosan polysulphate (2 mg/kg), (iii) a subcutaneous calcium heparin injection (100 U/kg). AT III infusion inhibits the excessive thrombin generation (46% of inhibition) observed in the plasma of AT III deficient patients during at least 12 hours, but does not modify the factor Xa formation. On the contrary, pentosan polysulphate has a marked effect on both thrombin (62% of inhibition) and factor Xa generation (57% of inhibition) still present 8 hours after injection. Heparin injection has the same effect, more prolonged, as pentosan polysulphate on thrombin generation but is not so effective on impairing factor Xa generation (27% of inhibition). The marked effect of pentosan polysulphate on thrombin and factor Xa generation in these patients is due to its AT III independent mechanism of action.

Antithrombin III↗
PubMed1987

Interaction of antithrombin III and thrombin-antithrombin III complex with cultured aortic endothelial cells.

The binding of antithrombin III, thrombin, thrombin-antithrombin III complex to endothelial cells was investigated. While the rate of the binding of thrombin to these cells was very rapid, that of antithrombin III was relatively slow and the thrombin-antithrombin III complex was intermediate. Binding kinetics indicated that antithrombin III, like thrombin, showed high affinity to endothelial cells; with a Kd of 3 X 10(-8) M and with 5 X 10(4) binding sites per cell. The dissociation of the inhibitor molecule was also rapid, i.e., approximately 70% bound antithrombin III was released in 2 minutes. Heparin, in a 100-fold molar excess to antithrombin III, or the modification of lysine residues of the inhibitor involved in the interaction with heparin, did not influence the association of antithrombin III with endothelial cells. In addition, antithrombin III did not compete with thrombin blocked in its active center for binding to endothelial cells. It is suggested that the binding sites of endothelial cells are different for thrombin and antithrombin III, and antithrombin III does not bind to these cells through its heparin binding domain.

Animals↗
PubMedDate not supplied

Comparative behaviour of antithrombin III antigen and antithrombin III activity in cardiovascular patients.

Antithrombin III-functional (AT III F) and immunoprotein (AT III I) assessed by two comparative methods in various cardiovascular conditions, showed significant differences between the two parameters, namely: a simultaneous decrease of both AT III F and AT III I during acute embolic episodes of only AT III F in transient ischemic attacks (with normal level of AT III I) and increase of AT III I (with apparently normal AT III F) in patient with mitral valve prosthesis. It is considered that in condition of "hypercoagulability" various patterns of AT III F/AT III I ratio can be obtained: decompensated, compensated and hypercompensated consumption.

Adult↗
PubMed1991

[Plasma levels of antithrombin III, thrombin-antithrombin III complex, alpha 2 plasmin inhibitor and plasmin alpha 2 plasmin inhibitor complex in normal and sick newborn infants].

Both bleeding and thrombosis are commonly seen in newborn infants because of their imbalance of coagulation and fibrinolysis system. In order to clarify some aspects of the hemostatic characteristics during neonatal period, we measured the levels of antithrombin-III (AT-III), thrombin AT-III complex (TAT), alpha 2-plasmin inhibitor (alpha 2PI) and plasmin alpha 2PI complex (PIC) in 137 normal and sick newborn infants. The results were as follows 1) AT-III levels in normal neonates were significantly low as compared with them in normal adults, and further lower levels were found in sick neonates. 2) TAT levels in sick neonates were significantly higher than those in either normal neonates and adults. In sick neonates, the incidence of abnormally high TAT values increased with DIC score points. 3) No significant difference of alpha 2PI level was seen between normal term neonates and adults. However, alpha 2PI levels in sick neonates were significantly low as compared with them in normal term neonates and adults. 4) PIC levels in either normal and sick infants were significantly higher than those in adults, but there was no significant difference in PIC levels between normal and sick newborn infants.

Antifibrinolytic Agents↗
PubMed1989

[Study of serum level of antithrombin-III antigen, antithrombin activity, and its ratio of AT-III-heparin complex formation in maintenance hemodialysis patients].

The plasma level of Antithrombin-III (AT-III) antigen, antithrombin activity and the ratio of AT-III-heparin complex formation have been studied in 20 patients with chronic glomerulonephritis on regular hemodialysis at two occasions with 2 year interval (in 1986 and 1988), and studied as to each variation in each plasma levels, and compared with the period of length of hemodialysis-history of individual cases. A significant decrease was found not only in plasma level of AT-III antigen (25.7 +/- 4.1 mg/dl to 23.4 +/- 3.9 mg/dl), but also in antithrombin activity (90.8 +/- 11.8% to 85.2 +/- 16.8%). Moreover and ratio of AT-III-heparin complex formation was significantly reduced during two years, too (50.7 +/- 3.0% to 53.0 +/- 1.5%). Similarly, a significant negative correlation could be found on the comparison between the duration of hemodialysis and each plasma levels of AT-III antigen (r = -0.27), antithrombin activity (r = -0.33), and as well as ratio of AT-III-heparin complex formation (r = -0.34). Therefore, it was interestingly suggested the possibility that prolonged hemodialysis treatment induced a functional loss of AT-III, especially in a capacity to form a AT-III-heparin complex due to partial loss of the affinity for heparin.

Adult↗
PubMed1993

Acquired antithrombin III deficiency: replacement with antithrombin III concentrates in a patient with protein S deficiency accelerates response to therapy.

A 33-year-old man with inherited protein S deficiency and a 20-year history of deep and superficial venous thrombosis was admitted for treatment of extensive, acute, superficial venous thrombosis of the left lower extremity. Clinical response to intravenous heparin was very slow. After discovery of acquired antithrombin III deficiency superimposed on the protein S deficiency, he was given antithrombin III concentrates with the intravenous heparin. His response to therapy was accelerated. The development of acquired antithrombin III deficiency in patients with venous thrombosis may slow the response to standard anticoagulant therapy. Therapy of the thrombosis may be improved with administration of antithrombin III concentrates.

Adult↗
PubMed1993

Congenital antithrombin III deficient neonate treated with antithrombin III concentrates.

A patient with antithrombin III deficiency developed deep vein thrombosis during her first pregnancy. Her pregnancy and delivery were successfully treated with simultaneous administration of antithrombin III concentrates and low molecular weight heparin. She delivered a 2,412g girl at 39 weeks' gestation. The baby was administered with antithrombin III concentrates as prophylaxis for neonatal arterial and venous thrombosis because the antithrombin III level was extremely low to be 2%. Her second pregnancy was uneventful at 38 weeks' gestation, and she was treated with administration of antithrombin III concentrates prophylactically. She delivered a 3,256g boy at 42 weeks' gestation without any complications. The antithrombin III level of the second baby was normal. These results showed that in a neonate with congenital antithrombin III deficiency the antithrombin III concentrates would be administered to prevent neonatal arterial and venous thrombosis.

Adult↗