SEARCH · PubMed Health

Results for “ANTITHROMBIN”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,099 records · Page 61Linked to original sources

PubMed1995

Antithrombin III concentrates--are they clinically useful?

Treatment with AT III concentrates is a good example for the discrepancy between the optimistic expectations based on theoretical considerations or animal experiments and the result of clinical studies. 15 years after the introduction into clinical practice, a benefit for patients treated with AT III concentrates has not been proven. In hereditary antithrombin III deficiency, randomized clinical trials are completely lacking and only few and small sized randomized studies were performed in patients with acquired AT III deficiency. In none of these trials, a significant clinical benefit with regard to reduction of morbidity or mortality was detectable. Based on the published data, one can state that AT III concentrates may be beneficial in some special clinical situations in patients with hereditary antithrombin III deficiency (such as delivery, acute serious thromboembolic complications and postoperative thromboprophylaxis). In acquired AT III deficiency, there is no proven indication for the use of AT III concentrates.

Antithrombin III↗

PubMed1994

Homozygous or compound heterozygous qualitative antithrombin III deficiency.

A male patient of 24 years who had experienced thrombotic episodes since the age of 15 displayed an unusually low antithrombin III (AT III) activity measured as heparin cofactor (13% of the normal), while a similarly decreased value (16% of normal) was found in a 26 year old brother who had suffered from thrombotic events since the age of 12 years. AT III heparin cofactor activities were close to 50% of normal in the father, mother, another brother and a sister, none of whom had experienced thrombotic episodes. Since all available members of the family, including the patient, displayed near normal AT III antigen levels (73-85%) normal total progressive antithrombin activities (92-110%) as assessed by the thrombin agarose diffusion technique and normal total progressive anti-Xa activities, the propositus and his brother could be considered to be homozygotes or compound heterozygotes for a qualitative familial AT III deficiency probably caused by an abnormality of the heparin binding site. Molecular techniques would be required to elucidate the precise mutation giving rise to the deficiency.

Adolescent↗

PubMed1994

Different incidence of venous thrombosis in patients with inherited deficiencies of antithrombin III, protein C and protein S.

A cohort study was undertaken to compare the incidence of thrombosis in patients with inherited deficiency of Antithrombin III (n = 9), Protein C (n = 36) and Protein S (n = 36). The patients were stratified for schedule of antithrombotic prophylaxis and followed for a total period of 160 patient-years. Seven venous thrombosis were observed for a total incidence of 4.3% pts.-ys. The incidence of thrombosis was not significantly different in patients of different age, sex and schedule of prophylaxis, although there was a trend to a lower incidence in young individuals and in those receiving long-term oral anticoagulation. Patients with AT III deficiency had an higher incidence of thrombosis than patients with Protein C or Protein S deficiency (12 vs. 2.8 vs. 3.3% pts.-ys, p < 0.05), despite the fact that they were, on average, younger and more prophylaxed. This study suggests that congenital Antithrombin III deficiency constitutes a greater risk of thrombosis than congenital deficiencies of Protein C and Protein S.

Administration, Oral↗

PubMed1993

Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with defective heparin binding associated with thrombosis.

A novel variant of antithrombin III (AT III) that lacks affinity for heparin was found in a 33-year-old man who suffered from recurrent cerebral infarction. The propositus had a history of recurrent ischemic attacks from the age of 28. He was obese and had a smoking habit (30 to 40 cigarettes/day), low high-density lipoprotein cholesterol, and a mild glucose intolerance as the possible risk factors for thrombosis. No family history of thromboembolic episodes was observed. Coagulation studies found low heparin cofactor activity (55%) of AT III, with a normal immunoreactive level (109.7%) and progressive antithrombin activity (117%). Other factors capable of predisposing him to hereditary thrombophilia were within normal ranges. Analysis by crossed immunoelectrophoresis in the presence of heparin and affinity chromatography on heparin-Sepharose demonstrated that the propositus' AT III was composed of two populations, one having no affinity for heparin and the other binding heparin normally. Nucleotide sequencing of 7 exons of the propositus' AT III gene using polymerase chain reaction and subcloning disclosed a transition of thymine to cytosine in exon 3a (codon 116) of the AT III gene leading to a Ser116-Pro conversion. Allele-specific oligonucleotide hybridization procedures confirmed the presence of the mutation in the propositus' genomic DNA. Using the same technique, the mutation was also found in his father's genomic DNA, but not in that of his mother. These findings indicate that Ser116 is an important amino acid residue in heparin binding and that the propositus is heterozygous for the abnormality. Furthermore, the fact that the propositus suffered from recurrent cerebral infarction suggested that being heterozygous for a heparin-binding defect would lead to a predisposition to thrombosis when associated with various risk factors. The name AT III Nagasaki is proposed for this variant AT III containing a novel Ser116-Pro mutation.

Adult↗

PubMed1993

[Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complex(TAT) and thrombophilia parameters in orally anticoagulated patients with inferior vena cava filters].

Prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin-III-complex (TAT) levels were compared in 31 orally anticoagulated patients with inferior vena caval filters and a control group of 31 orally anticoagulated patients without caval filters and the incidence of markers of thrombophilia (deficiency of antithrombin-III, protein C, protein S and factor XII, presence of lupus anticoagulants) was determined. 8 of 31 patients (26%) from the group of caval filter carriers showed markers of thrombophilia (3 protein S deficiencies, 1 protein C deficiency, 2 factor XII deficiencies and 2 patients with lupus anticoagulants). In all orally anticoagulated patients a significant interdependence (p < 0.05) between F1 + 2- and TAT-levels and intensity (INR) of the oral anticoagulation could be observed. Comparison of F1 + 2- and TAT-levels of caval filter carriers and controls revealed no significant difference which leads to the conclusion that inferior vena caval filters do not induce detectable systemic activation of prothrombin under adequate oral anticoagulation therapy.

Administration, Oral↗

PubMed1977

[Antithrombin III deficiency and tendency to thrombosis (author's transl)].

Antithrombin III (AT III) was determined in 290 patients with deep venous thrombosis and/or pulmonary embolism by immunological methods (radial immunodiffusion, Laurell technique) and by biological activity (heparin cofactor activity and anti-Xa activity). Patients with venous thrombosis had a significantly lower AT III concentration, as determined by the immunological methods or biological method (heparin cofactor activity), than normal persons without any history of venous thrombosis. A decreased level of AT III was found in 27 patients. In these patients the immunoreactive antithrombin III was decreased to the same degree as biological activity (heparin cofactor activity or anti-Xa activity). Thirteen out of these 27 patients belonged to 9 families and, hence, congenital AT III deficiency can be assumed in these cases. The aetiology was unknown in the other half. Patients with AT III deficiency are prone to spontaneous and/or recurrent venous thrombosis. A high incidence of pulmonary embolism and particularly, of fatal pulmonary embolism is remarkable. In more than half of the patients the first thrombotic event occurred before the age of 35. The treatment of choice in such patients is with oral anticoagulants of the coumarin group.

Adult↗

PubMed1997

Antithrombin: molecular basis of deficiency.

Antithrombin is a plasma protein regulator of coagulation proteinase activity, particularly that of thrombin. Its deficiency is a risk factor for venous thromboembolism. Considerable progress has been made in understanding the organisation and function of the antithrombin gene and protein, and the molecular basis of deficiency, all of which are reviewed, but briefly, here.

Antithrombin III↗

PubMed1998

Antithrombin cambridge II (Ala384Ser): clinical, functional and haplotype analysis of 18 families.

Thirty-one individuals from 18 unrelated families with antithrombin deficiency have been identified as having a single point mutation within codon 384 (13268 GCA-->TCA) resulting in an alanine to serine substitution. Six families (11 individuals) were identified by the screening of individuals with thromboembolic disease or with a family history of thromboembolic disease, whilst the remaining 12 families (20 individuals) were identified by screening of asymptomatic blood donors. Four individuals had a history of venous thrombotic disease, a further 2 gave a history of superficial thrombophlebitis but the remaining 25 individuals were asymptomatic. Affected individuals demonstrated normal immunological levels of antithrombin but a decrease in anti-IIa activity in the presence of heparin. Haplotype analysis was used to examine the possibility of a founder effect to explain the high frequency of this non-CpG mutation. 29/31 individuals showed a single common "core" haplotype, the only variation existing in the number of copies of an (ATT)n repeat polymorphism--13, 14, 15 or 17. The results suggest that at most there are four independent origins for this mutation.

Alanine↗

PubMed1991

Plasma thrombin-antithrombin III complexes in the diagnosis of primary hepatocellular carcinoma complicating liver cirrhosis.

Detection of hypercoagulable state might be helpful in the diagnosis of primary hepatocellular carcinoma (HCC) complicating liver cirrhosis (LC). Plasma levels of thrombin-antithrombin III complex (TAT) were determined in 50 patients of LC with or without HCC. The levels were above 2 ng/ml in 80% of 25 HCC patients, but only in 12% of 25 non-HCC patients (P less than 0.01). The levels over 2 ng/ml occurred even in five of six HCC patients whose serum alpha-fetoprotein levels were below 20 ng/ml as well as in two of three patients with HCC less than 2 cm in diameter. Those levels in HCC patients were significantly decreased within 8 days after treatment with transcatheter arterial embolization or infusion of antitumor agents, without affecting plasma antithrombin III levels. These results suggest that plasma TAT levels may be useful in the diagnosis of HCC complicating LC.

Aged↗

PubMed1983

Antithrombin III progressive function: a biochemical analysis.

Antithrombin III (AT III) was isolated by two procedures using polyethylene glycol-400 (PEG) precipitation as the first stage. The PEG supernatant (PEG-sup) was applied to a heparin-affinity chromatographic system and AT III-heparin cofactor (AT III-HCF) was isolated. The PEG precipitate (PEG-ppt) was separated by a Sephacryl S-200 column. Fractions were collected and those demonstrating maximum AT III antigen and progressive thrombin inhibition were pooled and reapplied to the washed Sephacryl S-200 column. Fractions were again collected and assayed via specific antisera for AT III, alpha 1-antitrypsin (alpha 1 AG), alpha 2-macroglobulin (alpha 2 M), and alpha 1-acid glycoprotein (alpha 1 AT). AT III antigen (AT III AGN) and progressive function were confined primarily to one peak containing virtually no alpha 2 M, a low level of alpha 1 AT, and moderate quantities of alpha 1 AG. The PEG-sup, PEG-ppt, AT III-HCF, and the fraction obtained after two passes across Sephacryl S-200 (S#2) were similar in that they showed reactivity with specific AT III antisera and demonstrated heparin cofactor activity. They differed, however, in that the PEG-sup and AT III-HCF demonstrated considerably reduced progressive antithrombin function assessed over 30 min. This function was present in the PEG-ppt and S#2 fractions and this progressive activity was potentiated by EDTA. AT III two-dimensional immunoelectrophoresis (2-DIE) in the presence of heparin of both the Sephacryl and heparin-affinity purified components were very different, with the Sephacryl-purified AT III AGN showing both a fast peak and a very prominent slow-moving hump. The AT III heparin affinity fraction showed primarily a fast component. Dilution of the S#2 and PEG-ppt fractions resulted in considerable loss of the progressive activity and also the slow-moving component on 2-DIE. On the basis of these observations, it is postulated that AT III purified by PEG precipitation is in an aggregated form and that aggregate formation and dissolution is associated with AT III progressive activity.

Antithrombin III↗

PubMed1995

Two antithrombin mutations in a compound heterozygote: Met20Thr and Tyr166Cys.

The molecular basis for a family with Type I antithrombin deficiency has been established. Amplification and sequencing of the antithrombin gene identified two mutations: Met20Thr (2523T-->C) within exon 2 and Tyr166Cys (5493A-->G) within exon 3a. Further analysis indicated that the propositus was a compound heterozygote but in addition provided evidence for phase disruption during the amplification and/or cloning procedure. The Met20Thr mutation appears to be a neutral mutation with no functional consequences. In contrast, the Tyr166Cys mutation is associated with a Type I phenotype.

Antithrombin III↗

PubMed2004

A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next?

Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been used clinically as an antithrombotic agent since the 1940s. In the early 1980s it was discovered that a unique pentasaccharide domain in some heparin chains activates antithrombin III (AT-III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. Sanofi-Synthélabo and Organon developed a synthetic analogue of this pentasaccharide. The resulting antithrombotic drug arixtra, which went on the market in the USA and Europe in 2002, shows superior antithrombotic activity and brings about AT-III-mediated activity against factor Xa exclusively. Structure-based design has subsequently led to analogues with longer-lasting activity, such as idraparinux, as well as novel conjugates and long oligosaccharides with specific anti-Xa and antithrombin activities. The new drug candidates are more selective in their mode of action than heparin and less likely to induce thrombocytopenia.

Anticoagulants↗

PubMed2007

Protein adsorption on polyurethane catheters modified with a novel antithrombin-heparin covalent complex.

Highly anticoagulant covalent antithrombin-heparin complex (ATH) was covalently grafted onto polyurethane catheters to suppress adsorption/activation of procoagulant proteins and enhance adsorption/activation of anticoagulant proteins for blood compatibility. Consistency of catheter coating was demonstrated using immunohistochemical visualization of ATH. The ability of the resulting immobilized ATH heparin chains to bind antithrombin (AT) from plasma, as measured by binding of (125)I-radiolabeled AT, was greater than that for commercially-available heparin-coated catheters, and much greater than for uncoated catheters. Complementary measurements of antifactor Xa (FXa) activity and plasma protein binding were also performed. Both ATH-coated and heparin-coated catheters demonstrated functional binding of exogenous AT. However, the ATH-coated catheters gave a trend towards elevated anti- FXa activities/AT binding ratios, consistent with the higher active pentasaccharide content in starting ATH. Western blot analysis of proteins adsorbed to catheters after incubation with rabbit plasma established protein binding profiles that showed AT and albumin as major plasma proteins adsorbed to ATH-coated catheters, while AT and altered forms of fibrinogen were major plasma protein species adsorbed to heparinized catheters.

Adsorption↗

PubMed2004

Exact molecular mass determination of various forms of native and de-N-glycosylated human plasma-derived antithrombin by means of electrospray ionization ion trap mass spectrometry.

Human plasma-derived antithrombin was characterized in both the native and de-N-glycosylated forms (without separation of isoforms) by means of electrospray ionization ion trap mass spectrometry (ESI-ITMS). In order to determine the limits of the instrument set-up, the molecular mass precision and accuracy of the ESI-ITMS analysis was evaluated with the standard protein enolase and some instrumental data acquisition parameters were optimized. Mass precision was determined as a function of the number of averaged mass spectra (= scans) and data acquisition time. For this study, 20 and 50 scans were averaged and the data acquisition time was chosen to be between 0.5 and 5 min. It turned out that data acquisition times longer than approximately 2 min show no significant differences of the standard deviation of the determined molecular mass. Furthermore, the ion trap scan rate was varied at constant acquisition time of 2 min and the number of averaged scans was set to 20. At the scan rate of 13,000 u s(-1) a mass precision of +/-1.8 Da and a mass accuracy of +0.026% were determined. On reducing the scan rate to 5500 u s(-1), better agreement with the theoretical molecular mass was obtained, showing a mass accuracy of +0.012% but with a decrease in the mass precision to +/-3.0 Da. Using the optimized scan rate of 13,000 u s(-1) and a data acquisition time of 2 min, the exact molecular mass was determined of the three forms of antithrombin, namely the alpha-form, the beta-form and the natural mixture (present in human plasma) containing both forms. The protonated molecular masses were found to be 57,854 and 55,664 Da for the affinity chromatography-isolated alpha-and beta-form, respectively. The mass difference of 2190 Da is attributed to the known difference in carbohydrate content at one specific site. The protonated molecular mass of the dominating species of the natural mixture in human plasma was shown to be 57,850 Da, corresponding to the alpha-form, the major component in native plasma. In this mixture the beta-form was also detected, exhibiting a protonated molecular mass of 55,655 Da, but showing a much lower abundance, as expected. To obtain a complete release of the N-glycan residues by means of PNGase F, a denaturation, reduction and alkylation step of the glycoproteins was performed before the enzymatic reaction. After enzymatic removal of all N-glycans, the protonated molecular masses obtained were 49,399, 49,380 and 49,391 Da for the alpha-form, the beta-form and the unseparated natural mixture, respectively. These values are in good agreement (+0.026% for the alpha-form, -0.012% for the beta-form and +0.010% for the unseparated mixture) with the calculated molecular mass based on the SwissProt data. The determined molecular masses after reduction/alkylation and de-N-glycosylation of the alpha-and beta-forms are almost equal, indicating that no major differences exist between the three preparations on the amino acid level.

Antithrombins↗

PubMed1980

Reduced antithrombin III levels during L-asparaginase therapy.

Antithrombin III levels were measured in serum before, during, and after therapy with three different dosage regimens of L-asparaginase in 11 children with acute lymphoblastic leukemia. Levels determined by both functional and immunologic methods were transiently reduced during alternate-day or daily L-asparaginase treatment but not affected when the drug was administered only every 10 days. The probable mechanism of this effect is impaired hepatic synthesis of antithrombin III, resembling the acute and transient deficiency of other asparagine-rich proteins during L-asparaginase administration.

Adolescent↗

PubMed2002

Characterization of N-linked oligosaccharides attached to recombinant human antithrombin expressed in the yeast Pichia pastoris.

We studied the structures of four N-linked oligosaccharide chains of the recombinant human antithrombin (rAT) expressed in the yeast Pichia pastoris. rAT was fully glycosylated at Asn 96 and Asn 155, whereas the glycosylation on Asn 135 and Asn 192 was partial. The glycosylation level on Asn 135 was only 12% and this reduction is assumed to be one of the reasons for a higher heparin-binding affinity of rAT than plasma-derived human antithrombin (pAT). In order to determine the sizes and electrostatic charges of the N-linked oligosaccharides, rAT was treated with PNGase F, and the reduced ends were labelled by pyridylamination followed by analysis using anion exchange and amide adsorption columns. The N-linked oligosaccharides were 78% neutral and 22% phosphomannosylated. The neutral oligosaccharides were thought to be Man(9-12)GlcNAc(2) as their major components. The phosphomannosylated oligosaccharides were then subjected to mild acid hydrolysis and/or digestion with alkaline phosphatase, and their charge shifts were analysed by the affinity to an anion exchange column. Among phosphomannosylated oligosaccharides, monophosphate diester type was predominant, whereas negatively charged diphosphate diester and monophosphate monoester types were minor components. The mannose residues at the non-reducing end(s) of Man(9-12)GlcNAc(2) were phosphomannosylated or phosphorylated and these are the major components. Because rAT is less negatively charged than pAT, which has disialyl biantennary N-glycans, it might be less repulsive to pentasaccharide-bearing anticoagulantly active heparan sulphate proteoglycan molecules exposed on the surface of the damaged vascular vessels.

Alkaline Phosphatase↗

PubMed2000

Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin.

Antithrombin, uniquely among plasma serpins acting as proteinase inhibitors in the control of the blood coagulation cascade, circulates in a relatively inactive form. Its activation by heparin, and specifically by a pentasaccharide core of heparin, has been shown to involve release of the peptide loop containing the reactive centre from partial insertion in the A sheet of the molecule. Here we compare the structures of the circulating inactive form of antithrombin with the activated structure in complex with heparin pentasaccharide. We show that the rearrangement of the reactive centre loop that occurs upon activation is part of a widespread conformational change involving a realignment of the two major domains of the molecule. We also examine natural mutants that possess high affinity for heparin pentasaccharide, and relate the kinetics of their interaction with heparin pentasaccharide to the structural transitions occuring in the activation process.

Amino Acid Sequence↗

PubMed1998

Glucocorticoid attenuates a decrease of antithrombin III following major surgery.

BACKGROUND: Major surgery, such as esophagectomy, activates inflammatory responses and the coagulation system, and this activation is characterized by release of inflammatory cytokines and a decrease in antithrombin-III (AT-III), respectively. Preoperative glucocorticoid administration has been reported to suppress circulatory cytokine levels after major surgery. PATIENTS AND METHODS: A total of 28 patients underwent esophagectomy for esophageal carcinoma; 14 of them were given 10 mg/kg of methylprednisolone intravenously upon induction of anesthesia and 14 served as controls. Circulating levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), polymorphonuclear (PMN) elastase, thrombin-antithrombin III complex (TAT), AT-III, and albumin were measured before and immediately after the operation and on postoperative days (PODs) 1, 3, 5, and 7. RESULTS: TNF-alpha, IL-6, and TAT levels significantly increased after esophagectomy in both groups. AT-III and albumin decreased to their minimum levels on POD 1 and POD 3, respectively. Methylprednisolone treatment effectively inhibited the increases in TNF-alpha and IL-6 and the decreases in AT-III and albumin, but did not inhibit the increases in PMN-elastase and TAT levels. There were significant correlations between AT-III, IL-6, and albumin levels. CONCLUSIONS: These results suggest that methylprednisolone pretreatment attenuates the decrease in AT-III by reducing IL-6 production postoperatively.

Aged↗