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 559 records · Page 31Linked to original sources

PubMed1998

A novel antithrombin-heparin covalent complex: antithrombotic and bleeding studies in rabbits.

Heparin has been used extensively for prophylaxis and treatment of deep vein thrombosis. However, heparin has several limitations including a short intravenous half-life, inability to inhibit clot-bound thrombin, and bleeding. We have developed a covalent antithrombin-heparin complex (ATH) that has a longer intravenous half-life and greater anticoagulant activity than heparin. The antithrombotic activity of ATH was tested in a rabbit jugular vein thrombosis treatment model. Administration of ATH caused a 17% reduction in clot weight compared with an increase of 24, 60, 172 and 135% for administration of antithrombin plus heparin, heparin, antithrombin and saline, respectively. Clot weight and fibrin accretion were both significantly lower in the ATH group than in the antithrombin plus heparin group (P < 0.05). The peak anti-factor-Xa activity was fourfold higher in the ATH group than in the antithrombin plus heparin group. Using a rabbit bleeding ear model, there was no significant difference in cumulative blood loss between ATH and antithrombin plus heparin groups, at similar plasma anti-factor-Xa levels. In conclusion, ATH has superior antithrombotic activity and similar bleeding effect compared with heparin on a mass basis. The enhanced antithrombotic activity of ATH may be a result of its increased anticoagulant activity or its longer half life, or both.

Animals↗

PubMed2006

Retinal vein occlusion associated with antithrombin deficiency secondary to a novel G9840C missense mutation.

OBJECTIVE: To describe a novel missense mutation in the antithrombin gene associated with antithrombin deficiency type I in a 40-year-old man with retinal vein occlusion. DESIGN: Investigational case report. RESULTS: Ophthalmoscopy of the right eye showed hemicentral retinal vein occlusion. The patient's medical history was negative for glaucoma or cardiovascular risk factors. Screening for thrombophilic disorders revealed antithrombin deficiency type I. Based on a genetic analysis, a novel missense mutation of a transition of guanosine to cytosine at nucleotide position 9840 was detected, predicting the replacement of aspartic acid by histidine encoded by codon 366 (D366H) in exon 5. CONCLUSIONS: Selective screening may be helpful in identifying patients with retinal vein occlusion with thrombophilic defects. When ordering laboratory tests in patients with retinal vein occlusion, antithrombin deficiency type I should be considered in the differential diagnosis. CLINICAL RELEVANCE: Our results contribute to a better understanding of the molecular bases of antithrombin deficiency, adding a novel entry for the molecular defects causing antithrombin deficiency type I. Moreover, the identification of this thrombophilic disorder in retinal vein occlusion may be relevant to the issue of the initiation and duration of oral anticoagulant therapy.

Adult↗

PubMed2005

Pharmacokinetics of UH and LMWH are similar with respect to antithrombin activity.

BACKGROUND: The ability to administer low molecular weight heparins (LMWH) subcutaneously without laboratory monitoring contributes to their popularity for the treatment of thrombotic disorders. Subcutaneous unfractionated heparin, although less expensive, is deemed to require routine laboratory monitoring on the basis of more variability in drug effect compared to LMWH. However, the more predictable pharmacokinetic profiles of low molecular weight heparins are largely based on anti-Xa activity, while antithrombin activity may be at least as important to their mechanisms of action. METHODS: We performed a clinical pharmacokinetic trial to compare the variability in peak antithrombin effect between subcutaneous unfractionated heparin and various LMWHs, all given in recommended weight-adjusted treatment doses. Sixty-one patients enrolled in a warfarin clinic were randomized to receive one of four different weight-adjusted subcutaneous heparin doses: unfractionated heparin, 250 units/kg (n=15); tinzaparin, 175 units/kg (n=15); dalteparin, 200 units/kg (n=15); or enoxaparin, 1 mg/kg (n=16). The areas under the curves of antithrombin levels during the first 3 h after administration were determined for each patient, and the coefficients of variation (CV) and 95% confidence intervals of the AUCs were compared among the treatment groups. RESULTS: There was no statistically significant difference in the coefficients of variation of antithrombin effect between unfractionated heparin (52.8, 95% CI: 32.6-72.9) and enoxaparin (56.5, 95% CI: 35.7-77.4) or dalteparin (43.5, 95% CI 25.4-61.6). Tinzaparin had statistically significant decrease in coefficients of variation (21.6, 95% CI: 12.2-30.9) relative to unfractionated heparin, dalteparin and enoxaparin. CONCLUSIONS: LMWHs, as a class of drugs, are no more predictable in antithrombin effect after subcutaneous injection than unfractionated heparin. There were considerable differences among LMWHs in the observed variability of antithrombin effects, with tinzaparin being somewhat more predictable than the other drugs tested.

Aged↗

PubMed2000

[Molecular basis of hereditary antithrombin defects in 10 Czech families].

BACKGROUND: Molecular basis of antithrombin deficiency has not yet been studied in Czech Republic. We looked for the causal mutations throughout the antithrombin gene in 26 patients from 10 unrelated families with antithrombin defect. METHODS AND RESULTS: We screened the gene by conformation sensitive gel electrophoresis and sequenced the mismatched regions using fluorescence technology to characterise mutations and polymorphisms. Mutations were detected in all ten families. Four novel mutations were identified in four families with type I antithrombin defect: Trp-6Arg, 5386-5387delCT, Glu163Stop, and 13246-13248del TGA causing deletion of Glu377 with change of Asn376 to Lys. In other three type I families we found following mutations: splicing site mutation G2777C, Arg197Stop and entire gene deletion. In the family carrying Trp-6Arg mutation antithrombin Vienna (Gln118Pro) was also detected. Leu99Phe recurrent in south-eastern Europe was identified in three families with type II defect. Only the homozygous carries of the mutation were symptomatic, although the heterozygous carries had decreased functional levels. CONCLUSIONS: Four novel mutations in families with type I antithrombin deficiency were characterised. In one family two different genetic defects were identified to be responsible for type I and II phenotypes. Altogether our data agree with the expected heterogeneity of the AT genetic defect.

Adolescent↗

PubMed2004

Biochemical activity and gene analysis of inherited protein C and antithrombin deficiency in two Chinese pedigrees.

BACKGROUND: We identified the gene mutations in two Chinese pedigree of type I hereditary protein C deficiency and type I hereditary antithrombin deficiency. METHODS: The plasma level of protein C activity (PC:A), protein C antigen (PC:Ag), protein S activity, antithrombin activity (AT:A) and antithrombin antigen (AT:Ag) of propositi and two family members were detected using ELISA and chromogenic assay, respectively. All exons and intron-exon boundaries of protein C gene and antithrombin gene were analyzed by direct sequencing of the corresponding amplified PCR products in DNA from the propositus. RESULTS: The plasma PC:A and PC:Ag of propositus 1 was 26% and 1.43 mg/dl, respectively. The PC:Ag and PC:A of his father were normal. The decreased PC:A level was seen in his mother and 4 of his maternal pedigree. PS:A and AT:A were all normal in pedigree 1 members. A C5498T heterozygous mutation in exon 3 of protein C gene, resulting in the substitution of Arg for Trp at the 15th amino acid, was identified in propositus 1 and 8 of his relatives. The plasma AT:A and AT:Ag of propositus 2 was 48.6% and 10.4 mg/dl, respectively. The reduced AT:A and AT:Ag levels were found in his father and 5 of paternal pedigree. PC:A, PC:Ag and PS:A were all in normal range. A heterozygous 13387-9G deletion in exon 6 of antithrombin gene was identified in propositus 2. This mutation introduced a frameshift and a premature stop at codon 426 and existed in 6 members of pedigree 2. CONCLUSION: The C5498T heterozygous mutation in exon 3 of protein C gene, first reported in China, leads to type I hereditary protein C deficiency. The 13387-9G deletion, a novel mutation, can cause antithrombin deficiency and thrombosis.

Adolescent↗

PubMed1986

Hereditary antithrombin III deficiency: case report and review of recent therapeutic advances.

We report on a newly diagnosed family with hereditary antithrombin III deficiency, with thromboembolic complications in the propositus. Both the propositus and his asymptomatic sister had decreased plasma levels of antithrombin III antigen and activity (28-52% of normal with good agreement between functional and immunologic assays). The propositus developed deep venous thrombosis, followed by massive pulmonary emboli despite heparin therapy and was treated with streptokinase and heparin with excellent results. Shortly thereafter, small bowel obstruction required surgical intervention, and antithrombin III concentrate, recently available in the United States as an investigational new drug (I.N.D.), was administered with no postoperative thrombotic complications. He was subsequently asymptomatic while on warfarin prophylaxis but twice developed venous thrombosis when he failed to take warfarin. The addition of danazol therapy led to a sustained rise in the antithrombin III level. Each of these therapeutic approaches is discussed and the literature reviewed with emphasis on the newer agents--streptokinase, antithrombin III concentrate, and danazol.

Adult↗

PubMed1995

Modulation of hemostatic balance with antithrombin III replacement therapy in a case of liver cirrhosis associated with recurrent venous thrombosis.

Patients with liver failure can present both thrombotic and hemorrhagic complications because of the deficiency in coagulation factors and inhibitors (protein C and S, antithrombin III) and impairment of fibrinolytic balance. Here we report the case of a 63-year-old man with liver cirrhosis, recurrent thrombosis, and features of low-grade consumption coagulopathy, showing severe antithrombin III deficiency (about 30% of normal values). Treatment with antithrombin III (2000 U/day) and low doses of heparin (5000 U b.i.d.) was successful in modulating the coagulation system toward an antithrombotic effect. After discharge from hospital the ambulatory treatment with antithrombin III concentrates (2000 U twice a week) allowed the attainment of antithrombin III activity of about 60% and prevented the patient from recurrence of venous thrombosis.

Antithrombin III↗

PubMed1978

Platelet antithrombin deficiency: a new clinical entity.

A kindred with a history of multiple thromboses was studied for coagulant abnormalities. A deficiency of serum antithrombin III was found in approximately half of the 13 family members by either coagulant or immunologic assay. No clear relationship between antithrombin III deficiency and a history of thrombosis was present. Platelet antithrombin assays were also studied in the same subjects. Ten of the 13 members were deficient. None of the remaining three had a history of thrombosis. On the basis of these findings, the hypothesis is proposed that in some cases familial hypercoagulability may be due to a platelet antithrombin deficiency and that the serum antithrombin III deficiency in some cases is a secondary rather than a primary effect.

Adolescent↗

PubMed1996

Molecular genetics of antithrombin deficiency.

Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism. Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence. The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identified that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or 'pleiotropic effects' (Type II deficiency, altering both functional domains and the level of protein).

Antithrombin III↗

PubMed2002

The anti-inflammatory actions of antithrombin--a review.

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.

Anti-Inflammatory Agents↗

PubMed2000

Pharmacologic modulation of thrombin generation associated with human clots by human purified antithrombin alone or in the presence of low molecular weight heparin or unfractionated heparin.

Procoagulant activities associated with human clots may contribute to thrombus extension. We investigate the inhibition of clot-associated factor Xa and thrombin activities by purified human antithrombin either alone or as combination with a low molecular weight heparin (enoxaparin) as compared with unfractionated heparin (UFH). The standard clots were prepared by recalcification of frozen platelet-poor human plasma. Clot-associated thrombin was measured on the clot after clot incubation in recalcified buffer or recalcified prothrombin solution. The enzymatic reaction was measured using a specific substrate for thrombin (CBS 3447). The thrombin concentration was determined both on the clots and in the reaction mixtures. In parallel, prothrombin fragment 1.2 and thrombin-antithrombin complexes (TAT) were measured using enzyme-linked immunosorbent assay methods. We demonstrated that in the presence of purified human prothrombin and antithrombin (AT), a partial inhibition of clot associated thrombin activity correlated with an increase of TAT complexes. However, antithrombin was unable to inhibit thrombin generation induced by the clot-associated factor Xa. Enoxaparin (low molecular weight heparin) and UFH did not enhance clot-bound thrombin inhibition induced by AT. We conclude that clot-bound thrombin is accessible to human antithrombin alone. AT is also able to inhibit thrombin generated by factor Xa-associated clot. However, neither a low molecular weight heparin or UFH enhanced the effect of AT alone.

Antithrombin III↗

PubMed1990

The confirmation of preclinical familial antithrombin deficiency using polymorphism and specific oligonucleotide probes .

Familial deficiency of antithrombin causes venous thromboembolism which may not become clinically apparent until the third or fourth decade of life. In affected families conventional tests of antithrombin activity and antithrombin antigen levels may not be sufficiently accurate to discriminate with certainty between those young people who have inherited the abnormal gene and those who have not. Molecular probes for polymorphisms linked to the gene of interest may be informative but in some families are not. We have used the knowledge of the precise molecular defect in antithrombin Glasgow to design and manufacture DNA probes and have used these probes to detect the presence of the abnormal gene in DNA from clinically unaffected family members and thus confirm their inheritance of antithrombin deficiency and their predisposition to venous thromboembolic disease.

Antithrombin III↗

PubMed1987

[Replacement therapy of acquired antithrombin III deficiency in experimental nephrotic syndrome].

The influence of antithrombin III on hemostasis and renal function was studied in experiments on rats with nephrotic syndrome. The development of nephrotic syndrome was accompanied by the activation of blood coagulation and appearance of acquired antithrombin III deficiency due to its loss with the urine. The replacement therapy by bovine antithrombin III at a dose of 25 U/kg a day for 10 days decreased the signs of excessive thrombinogenesis in experimental animals and increased the amount of thrombin-antithrombin III complexes in the blood flow. The activation of coagulation in rats with nephrotic syndrome predominantly induced the disturbances of the excretory renal function which could be efficiently corrected by antithrombin III.

Animals↗

PubMed1983

[The physiological inhibitors of blood coagulation. 1. Antithrombin III (AT III)].

In a brief survey, recent data on the molecular structure and functions of antithrombin III as well as on the similarity of identity with antithrombin III of newborns and mammals are referred to. Moreover, the survival time in circulation and its broad inhibiting spectrum comprising not only all activating factors of coagulation, but also other proteases, is discussed. The accelerating effect of heparin on response and possible mechanisms of this acceleration are discussed. The various procedures of determination are briefly dealt with. Furthermore, the distinct tendency towards thromboembolic complications occurring in patients with only a slight reduction of antithrombin III level is dealt with, as it was described in inherited and acquired deficiency of antithrombin III. Finally, the possibilities of therapy for this deficiency are discussed and is underlined on the key position of antithrombin III for maintaining the balance of coagulation.

Antithrombin III↗

PubMed1981

[Progressively acting antithrombins and plasma heparin resistance in ischemic heart disease].

A comparative study of activity of the progressively acting antithrombin and their heparin-cofactor activity was undertaken in 27 patients with angina pectoris and 46 with macrofocal myocardial infarction. It was established that the count of thrombin inactivation during 5 minutes (Abiligaard method) shows no disorders in the majority of patients. Only in 3 patients with the primary antithrombin III and 3 (40% of patients with acute myocardial infarction showed a marked decrease of this parameter. Inactivation count of the endogenous thrombin according to the "self-coagulogram" during one hour enabled one to show decrease of activity of antithrombin in of 80% of patients. The heparin-cofactor activity in the serial heparin-thrombin test is markedly disrupted, which was used to compute the indices of activity of antithrombin and of the antithrombin plasma reserve. This disorder did not depend much on the increase of the antiheparin factor of thrombocytes in plasma.

Adult↗

PubMed1997

Inhibition of the plasma contact activation system of immobilized heparin: relation to surface density of functional antithrombin binding sites.

End-point immobilization of heparin to artificial materials gives rise to a surface that prevents triggering of the plasma contact activation system and, presumably as a result thereof, generally has thrombo-resistant properties. The present investigation was undertaken to determine what density of immobilized heparin molecules expressing functionally intact antithrombin binding sites is required to achieve these blood compatible properties. Six different heparin surfaces were prepared on polyethylene tubing and studied in contact with human plasma. The content of bound heparin was the same on all surfaces while the densities of antithrombin binding sites ranged from 1 to 28 pmol/cm2. The surfaces expressing 4 pmol/cm2 or more of specific antithrombin binding sites generated no measurable enzymatic activity in contact with plasma, either on the exposed surfaces or in the plasma phases. Below this level, the degree of activation gradually increased with decreasing densities, and in parallel the thrombo-resistant properties deteriorated. Addition of heparin to the plasma phase reduced the capacity of the heparin surfaces to bind antithrombin, leading to a diminished ability of the surfaces to prevent contact activation. This finding supports the hypothesis that antithrombin is the critical coagulation inhibitor for the suppression of contact activation on end-point immobilized heparin.

Anticoagulants↗

PubMed1982

Depression of functional and antigenic plasma antithrombin III (AT-III) due to therapy with L-asparaginase.

Eleven patients with leukemia and lymphoma were treated with 14 courses of E. coli L-asparaginase. Abnormalities of the coagulation screening tests and decreased fibrinogen levels were observed in all patients during treatment. Significant depressions of functional (mean 32%) and antigenic (mean 48%) antithrombin III were observed by day 14 of therapy. There was no laboratory evidence of intravascular coagulation during 11/14 courses of L-asparaginase. Crossed immunoelectrophoresis of plasma obtained at the antithrombin nadir did not demonstrate an abnormal pattern which can be associated with an abnormal antithrombin III or an increase in antithrombin III-coagulation factor complexes. The major underlying mechanism of this depression is believed to be decreased hepatic synthesis, and the low levels of antithrombin III may be associated with an increased risk of thrombosis.

Adult↗

PubMed2001

Three novel high performance affinity chromatographic media for the separation of antithrombin III from human plasma.

Novel monodisperse, non-porous, cross-linked poly (glycidyl methacrylate) beads (PGMA) were employed as the support for high performance affinity chromatography. Heparin was covalently attached to PGMA beads by three different coupling methods. Heparin-PGMA-I was prepared by directly coupling amino-groups of heparin with PGMA. Heparin-PGMA-II and III were prepared by the coupling of heparin to amino-PGMA, which was obtained by amination of PGMA. Heparin-PGMA-II was prepared by coupling the carboxyl groups of heparin to amino-PGMA by using water-soluble carbodiimide as coupling reagent, and heparin-PGMA-III was prepared by the reductive amination of heparin and amino-PGMA with sodium cyanoborohydride. The heparin contents of heparin-PGMA-I, II and III were 1.6, 10.2 and 1.0 mg/g beads, respectively. Their affinity capacities for antithrombin III were investigated. Their binding activity to antithrombin III was not proportional to the content of heparin immobilized, and heparin-PGMA-I was the most efficient affinity medium for antithrombin III. The resultant affinity media presented minimal non-specific interaction with other proteins and can be used in a wide pH range. All the three heparin-PGMA beads were exploited for the separation of antithrombin III from human plasma. The purity of antithrombin III obtained was higher than 90%, which was confirmed by high performance size exclusion chromatography.

Antithrombin III↗