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At least 91 records · Page 5Linked to original sources

PubMed1985

Antithrombin III "Northwick Park": a variant antithrombin with normal affinity for heparin but reduced heparin cofactor activity.

Further studies have been carried out in a previously reported family with congenital antithrombin III (AT III) deficiency due to an abnormal variant of AT III (AT III Northwick Park). The variant has been identified in five members of the family, three of whom had a history of venous thrombosis. Inheritance followed an autosomal dominant pattern. The affected family members have reduced levels of antithrombin heparin cofactor (41-67%) and progressive antithrombin activity (44-62%) but normal levels of immunoreactive AT III (91-162%). Two dimensional immunoelectrophoresis (2 DIE) of AT III in the absence of heparin revealed an abnormal fast-moving peak in addition to the normal peak but 2 DIE in the presence of heparin appeared normal. Further studies confirmed that the abnormal AT III binds completely to heparin but has no heparin cofactor or progressive antithrombin activity. These results would be consistent with a mutation affecting the binding site for thrombin.

Adolescent↗

PubMed1982

Differences between normal antithrombin III and antithrombin III Padua as determined by laser nephelometry.

Laser nephelometry was used to characterize an abnormal antithrombin III (AT III Padua) in comparison with normal antithrombin. Heparinized (0.2 IU/ml) or non-heparinized AT III Padua plasma reacts with Laser nephelometry antithrombin III antiserum in a different way compared with pooled normal plasma. There is in fact a slower antigen-antibody reaction during the first 40-45 min both in AT III Padua heparinized and non-heparinized plasmas, compared with pooled normal plasma; then the kinetics overlap. On the contrary the concentrations of antithrombin III Padua in percent correlate well with those obtained by Mancini's and Laurell's methods. These data indicate that Laser nephelometry is suitable for AT III antigen determinations and may also supply useful information for the characterization of abnormal clotting factors.

Antithrombin III↗

PubMed1978

Study of the activity of antithrombin-III in latent cholestasis. (A clinico-pharmacological study of the relationship between antithrombin-III activity and steroid cholestasis).

The relationship between steroid cholestasis and antithrombin-III activity were examined in users of oral contraceptives (Infecundin or Bisecurin) and in patients receiving anabolic hormone therapy (Nerobol). The control group for the oral contraceptive users consisted of patients with spontaneous anovulation. The untreated control group consisted of healthy women in the reproductive age. The increase in antithrombin-III activity was found to be directly related to the decline of anion excretion. Latent cholestasis in itself is not associated with an increased antithrombin-III activity, nor is the activity of antithrombin-III affected by long-continued use of those anabolic steroids which produce no decrease in anion excretion.

Adult↗

PubMed1983

Antithrombin III Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis.

A familial abnormal antithrombin III (AT-III) is reported. The characteristic of the abnormality in this family is low heparin cofactor activity with normal progressive antithrombin activity and normal or rather increased level of AT-III antigen. The patient is a 23-year-old female who had suffered from recurrent thrombophlebitis involving her lower extremities. Her plasma AT-III antigen concentration was 54 mg/dl and progressive antithrombin and factor Xa inhibitory activities were of normal level. However, the heparin cofactor activity of her plasma was as low as 26% of normal control. On crossed immunoelectrophoresis (CIE) containing heparin in the first dimension agarose, patient's AT-III showed no increase in electrophoretic mobility compared to that in the absence of heparin, suggesting that the patient's AT-III has no affinity for heparin. From CIE pattern in the presence of heparin, the patient was found to be a homozygote, and parents and one of her younger sisters were heterozygotes. Thus, the mode of inheritance is proposed to be autosomal dominant.

Adult↗

PubMed2006

Recombinant human antithrombin expressed in Chinese hamster ovary cells shows in vivo efficacy on rat DIC model similarly to plasma-derived antithrombin regardless of different N-glycosylation.

Plasma-derived human antithrombin (pAT) is used for the treatments of disseminated intravascular coagulation (DIC) and hereditary antithrombin deficiencies. We expressed recombinant human antithrombin (rAT) in Chinese hamster ovary (CHO) cells. The purified rAT is composed of 55% alpha-isoform and 45% beta-isoform. The structure of the N-linked oligosaccharides of rAT is the same biantennary complex type as previously found in pAT with less sialylated on the non-reducing ends. Most of the oligosaccharides of rAT are fucosylated at the reducing ends of N-acetylglucosamine, while those of pAT are not fucosylated. Despite of the difference in sialylation and fucosylation of the oligosaccharide units, rAT and pAT showed indistinguishable heparin cofactor and progressive activities, and they bound to thrombin in a one-to-one stoichiometric manner. In lipopolysaccharide (LPS)-induced and thromboplastin-induced DIC rat models, rAT reduced fibrinogen and platelet consumption to a similar extent with pAT. In LPS-induced DIC model, both ATs similarly restrained the increase of alanine aminotransferase and aspartate aminotransferase activities. Finally, pharmacokinetic analysis showed that both ATs had similar half-lives in the circulation of normal rats. Together, the present study demonstrated that rAT prepared in CHO cells has potential for a substitute of pAT in therapeutic use.

Alanine Transaminase↗

PubMed1975

Further investigations on antithrombin III in the plasmas of patients with the abnormality of antithrombin III Budapest.

Antithrombin III (AT-III) was studied in a thrombophilic family with an abnormal AT-III molecule (antithrombin III Budapest) using a modified crossed immunoelectrophoresis technique, gel filtration, 'rocket' immunoelectrophoresis and a heparin cofactor assay. When agarose was applied in the first phase of the crossed immunoelectrophoresis, the normal and the pathological AT-III revealed identical electrophoretic mobility. However, when heparin was mixed with agarose in the first phase of electrophoresis, the propositus' plasma displayed a different AT-III pattern from normal plasma. His plasma contained the first component of the normal plasma (Immune Antithrombin III1, IAT-III) in a concentration of only 5% of normal, and a protein in high concentration which although immunoreactive to AT-III antisera, had an electrophoretic mobility similar (but not identical to that of IAT-III2. This abnormal protein had no heparin cofactor activity and a molecular size greater than normal plasma AT-III. Unlike AT-III, the addition of heparin did not change the molecular size of the pathogic AT-III molecule significantly. The abnormal protein was present in lower concentrations in the patient's children and at the time of study they had no clinical or laboratory evidence of intravascular coagulation.

Adult↗

PubMed1982

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III.

Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.

Adult↗

PubMed1983

Isolation and characterization of a hereditary abnormal antithrombin III 'Antithrombin III Toyama'.

A hereditary abnormal antithrombin III (AT-III) 'Antithrombin III Toyama' was purified from the plasma of a patient with recurrent thrombophlebitis by a procedure involving barium chloride and ammonium sulfate fractionations, affinity chromatography on anti-AT-III-Sepharose gel, and DEAE-Sephadex chromatography. Purified abnormal AT-III was shown to be the same as normal one in the molecular size, having the same molecular weight, amino-terminal sequence and carboxy-terminal amino acid. Abnormal AT-III gave the same UV spectrum as normal AT-III and both proteins were immunologically identical. Abnormal AT-III, however, showed the different electrophoretic mobility on agarose gel electrophoresis and immunoelectrophoresis. Abnormal AT-III was more electronegative than normal one, before and after a neuraminidase digestion of both proteins. These results suggest that in antithrombin III Toyama an amino acid residue at the heparin-binding site has been replaced by less basic or more acidic one which has no ability to interact with heparin, resulting in a loss of heparin cofactor activity of this protein.

Adult↗

PubMed1992

Safety of virus inactivated antithrombin III concentrate antithrombin III immuno (AT III).

In a prospective clinical trial the risk of infection after application of virus inactivated antithrombin III concentrate ANTITHROMBIN III IMMUNO (AT III) was investigated in patients undergoing cardiovascular surgery. The study was conducted according to the recommendations of the International Committee on Thrombosis and Hemostasis (ICTH), with the exception that most patients required additional blood products as well as AT III. Twenty-seven patients were eligible to test for the risk of acquiring hepatitis B. Twenty-six patients could be evaluated in terms of hepatitis NANB transmission considering ALT-levels whereas 20 patients could be tested for anti-HCV one year after surgery. Samples from 78 patients could be monitored for anti-HIV-1. None of these patients showed any signs of infection. AT III IMMUNO seems to be an antithrombin III concentrate with low or absent infectivity.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Insight into residues critical for antithrombin function from analysis of an expanded database of sequences that includes frog, turtle, and ostrich antithrombins.

Complete sequences were determined for frog, turtle, and ostrich antithrombins. Protein sequence comparisons with the other 10 known antithrombin sequences and with sequences of other serpins have provided striking evidence for the conservation of the heparin activation mechanism and new insight into those residues important for heparin binding, for heparin activation, and for reactive center loop function, as well as an indication of which glycosylation sites might be needed for function. Importantly, an understanding of, as yet, poorly understood antithrombin-protein interactions will be greatly aided by this expanded database and comparative analysis.

Amino Acid Sequence↗

PubMed2001

Evaluation of a new immunoturbidimetric test (Liatest antithrombin III) for determination of antithrombin antigen.

Antithrombin (AT) is a glycoprotein mainly synthesised in the liver, and is one of the most important inhibitors of coagulation. Although AT activity determination is more important in clinical practice and anti-IIa and anti-Xa chromogenic tests are widely available, sometimes AT antigen measurement is preferred. Immunoradiometric and enzyme linked immunoabsorbent assay (ELISA) tests have been the only methods available so far for AT antigen determination, but both of them are relatively complicated, time consuming, and the ELISA test cannot be used for single sample assessment. A new immunoturbidimetric test (Liatest antithrombin III) is now available. We have adapted it for the Cobas Mira biomedical analyser. The intra- and inter-assay and total coefficients of variation for normal and low control plasma, as well as for normal pool plasma were low (< 3%). Blood samples from 32 patients with different clinical conditions were assessed both by the standard ELISA method and by the immunoturbidimetric method. The correlation coefficient was 0.95. According to our findings it seems that the immunoturbidimetric test (Liatest antithrombin III) for determination of AT antigen automated for the Cobas Mira biochemical analyser is easy to perform, time sparing and precise, with good comparability to other assays. It is suitable for measuring of AT antigen in routine laboratory work.

Antigens↗

PubMed2002

[Type I antithrombin deficiency due to 13389G deletion in antithrombin gene].

OBJECTIVE: To identify the gene mutation of a kindred with type I antithrombin deficiency. METHODS: All of the seven exons and intron-exon boundaries of antithrombin gene were analysed by PCR and direct sequencing of amplified PCR products from the propositus. RESULTS: A 13389G deletion in exon 6 was characterized in propositus, and this mutation led to frameshift. CONCLUSION: This is a novel mutation, which can cause antithrombin deficiency and thrombosis.

Adolescent↗

PubMed1983

Antithrombin III Padua: a "new" congenital antithrombin III abnormality with normal or near normal activity, normal antigen, abnormal migration and no thrombotic disease.

A "new" antithrombin III abnormality is described in four members of a family. The proposita is a 38 years old female who showed no thrombotic disease and the following laboratory pattern: normal routine clotting tests, normal or near normal AT III activity (chromogenic substrates S-2238 and Chromozym Th) both in plasma and in serum and in the presence or absence of heparin, slightly decreased antifactor Xa activity (chromogenic substrate S-2222), normal progressive antithrombin, normal AT III antigen but abnormal migration in the agarose-heparin bidimensional system. In the latter test, one major abnormal peak, less anodal than the normal counterpart, and a smaller, apparently normal peak, were seen. In agarose without heparin the pattern was similar to normal both in plasma and in serum. Heparin tolerance to heparin in vivo and in vitro was slightly increased but still within normal limits. The two sons and a paternal aunt showed the same pattern. The hereditary pattern seems therefore autosomal dominant. The abnormality described appears different from AT III Budapest. The toponym of antithrombin III Padua is proposed to define this peculiar abnormality.

Adult↗

PubMed1996

Antithrombin-mediated inhibition of factor VIIa-tissue factor complex by the synthetic pentasaccharide representing the heparin binding site to antithrombin.

We examined the effect of the synthetic pentasaccharide representing the minimal binding site of heparin to antithrombin on the antithrombin-mediated inactivation of factor VIIa bound to tissue factor. This effect was compared to the effect of unfractionated heparin. Using purified recombinant human coagulation factors and either a clotting or an amidolytic assay for the determination of the residual activity of factor VIIa, we showed that the pentasaccharide was an efficient antithrombin-dependent inhibitor of the coagulant activity of tissue factor-factor VIIa complex. In our experimental conditions, assuming a mean MW of 14,000 for heparin, the molar pseudo-first order rate constants for ATIII-mediated FVIIa inhibition by ATIII-binding heparin and by the synthetic pentasaccharide were found to be similar with respective values of 104,000 +/- 10,500 min-1 and 112,000 +/- 12,000 min-1 (mean +/- s.e.m., n = 3).

Antithrombin III↗

PubMed1999

Treatment of consumption coagulopathy with antithrombin concentrate in children with acquired antithrombin deficiency--a feasibility pilot study.

UNLABELLED: Consumption coagulopathy is a serious problem in childhood. In addition to treatment of the underlying disease, consumption coagulopathy was previously treated with heparin. Nowadays it is treated by substitution of coagulation factors, especially antithrombin (AT) concentrate, alone or in combination with heparin. In this pilot study we administered AT concentrate (dosage 80 U/kgbw/d), without additional heparin treatment, to 29 children beyond infancy with acquired AT deficiency. Antithrombin, platelet count, fibrinogen, PT, and APTT were assayed before and during the course of AT substitution. These coagulation parameters returned to normal 48 hours after normalisation of the plasma AT level. AT levels normalised within 24 h of initial substitution in all children. Lethal outcome due to the underlying disease was observed in only two children. CONCLUSION: Data of this pilot study suggest that, concomitantly with the treatment of the underlying disease, consumption coagulopathy in childhood can be managed successfully with early substitution of AT concentrate.

Adolescent↗

PubMed2000

Pulmonary arterial thrombosis in a neonate with homozygous deficiency of antithrombin III: successful outcome following pulmonary thrombectomy and infusions of antithrombin III concentrate.

We report a newborn male who presented with severe central cyanosis on the third day of life. Partial thrombotic obstruction of the pulmonary trunk secondary to Antithrombin III (homozygous defect of heparin binding site) deficiency was subsequently diagnosed. Surgical thrombectomy, and infusions of Antithrombin III concentrate, led to a successful outcome. We postulate that intrauterine thrombosis occurred to give this unusual presentation.

Anticoagulants↗

PubMed2005

Characterization of molecular defect of 13387-9delG mutated antithrombin in inherited type I antithrombin deficiency.

As a major physiological inhibitor of thrombin and other coagulation proteases, antithrombin (AT) plays an important role in the maintenance of normal hemostasis and its deficiency is associated with a predisposition for familial venous thromboembolic disease. Recently, we found a novel mutation (13387-9delG) in the antithrombin gene that is associated with type I AT deficiency. To examine the molecular pathologic mechanism of this mutation causing type I AT deficiency, the wild-type and the mutant AT constructs were expressed in COS-7 cells or Chinese Hamster Ovary cells. No AT antigen could be detected by enzyme-linked immunosorbent assay in the conditioned media of cells expressing the mutant protein, and the AT antigen level was reduced in cell lysates. The mutant AT-expressing cells did not have less intracellular mRNA levels than the wild-type transfectants as estimated by quantitative reverse transcriptase-polymerase chain reaction. Metabolic and pulse-chase experiments showed the newly synthesized wild-type AT protein was gradually secreted into the media, whereas no labeled mutant AT protein was detected in the media and the total amount of radioactivity was significantly reduced in the cells during the chase periods. By immunofluorescence analysis, the staining of the mutant AT was weaker than that of the wild type, and was predominantly diffuse without perinuclear enhancement. These results indicate that the 13387-9delG mutation, which disrupts the disulfide bridge Cys247-Cys430, impairs the secretion and stability of the truncated AT protein associated with intracellular degradation.

Adolescent↗

PubMed1982

A new familial variant of antithrombin III: 'antithrombin III Paris'.

A 59-year-old woman presented a recurrent history of thromboembolism. A qualitative defect of antithrombin III (AT III) was suggested by the discrepancy between a normal amount of AT III antigen and a decreased heparin cofactor activity. Six members of the same family showed a similar defect although clinically asymptomatic. The qualitative abnormality of AT III was confirmed by two-dimensional immunoelectrophoresis. In the absence of heparin, a single peak was obtained with both control and patients' plasmas. In the presence of heparin, two peaks of AT III were observed in the patients' plasmas: the mobility of one peak was similar to that of the control, whereas the other showed a decreased mobility, suggesting a lack of binding to heparin. The two populations of AT III were separated by affinity chromatography on heparin-agarose. 50% of the patients' AT III bound to the agarose beads. The remainder, recovered in the supernatant, migrated in two-dimensional immunoelectrophoresis as a single peak with the same mobility in the presence or absence of heparin, and was devoid of heparin cofactor activity. This familial AT III variant characterized a reduced affinity for heparin is tentatively named 'Antithrombin III Paris'.

Antigens↗