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 523 records · Page 29Linked to original sources

PubMed1992

The endothelial heparan sulfate-antithrombin III natural anticoagulant pathway in normal and transplanted human kidneys.

This is the first study of the antithrombin III-heparan sulfate natural anticoagulant pathway in human kidneys. Immunocytochemical experiments were done to demonstrate the pathway on normal renal endothelial cells. Enzymatic studies were done to show that the antithrombin III was anchored to endothelium by molecules of heparan sulfate. Displacement studies were done with glycosaminoglycans to show that the antithrombin III was bound to its glycosaminoglycan anchor via a heparinlike binding site, and replacement studies showed that antithrombin III could be returned to the same endothelial cells from which it was displaced. Immunocytochemical studies of biopsies showed that normally functioning renal allografts manifested the endothelial antithrombin III-heparan sulfate anticoagulant pathway. The pathway was compromised or absent from the microcirculation of biopsies from rejecting or rejected renal allografts, and the diminishment of endothelial ATIII was associated with the presence of fibrin deposition. It is concluded that compromise of the antithrombin III-heparan sulfate natural anticoagulant pathway results in compromised renal function in transplanted kidneys.

Adolescent↗

PubMed2006

A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.

The objective was to estimate the effect of antithrombin therapy on mortality in disseminated intravascular coagulation (DIC) of severe sepsis and septic shock. Randomized clinical trials (RCT) on patients with DIC and severe sepsis or septic shock assigned to intravenous antithrombin or placebo were searched. Eligible studies reported death as the outcome measure. Of 35 RCT, 32 trials were excluded because patients were not randomized to antithrombin versus placebo, or no separate data on patients with DIC were given. In three RCT, 364 patients with severe sepsis or septic shock and DIC were randomized. The disease severity, definition of DIC, dose and duration of treatment varied among the trials. In two of the three RCT, data were from subgroup analyses (patients not stratified by DIC). The combined odds ratio for short-term all-cause mortality in those who received antithrombin was 0.649 (95% confidence interval, 0.422-0.998). Data on bleeding complications in patients treated with antithrombin were reported only in one of the RCT and were not considered suitable for systematic safety estimation. In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival. Current available evidence, however, is not suited to sufficiently inform clinical practice.

Antithrombins↗

PubMed1979

Routes of thrombin action in the production of proteolytically modified, secondary forms of antithrombin-thrombin complex.

The reaction between thrombin and antithrombin results in the formation of an inactive, stable, equimolar complex between the two proteins. However, under most reaction conditions several secondary complex forms, which have lower apparent molecular weights in dodecyl sulfate/polyacrylamide gel electrophoresis, appear concomitantly with or immediately following the production of the primary form of the complex. Purification of nascent, intact complex and treatment of this complex form with thrombin demonstrated that these subsidiary forms of antithrombin-thrombin complex may arise by proteolysis of the nascent complex by excess thrombin. Dissociation of such proteolytically modified complex preparations by hydroxylamine, and examination of the dissociation products by dodecyl sulfate/polyacrylamide gel electrophoresis suggested that degradation occurs primarily in the thrombin part of the complex, and only after prolonged proteolysis in its antithrombin moiety also. Incubation of antithrombin with several autolytically modified thrombin preparations showed that formation of subsidiary complex forms can also occur by an alternative route, i.e. between premodified thrombin forms and the inhibitor. In contrast, complex formation between thrombin and active forms of antithrombin, which have been modified by thrombin before complex formation, is unlikely, since no such active forms of antithrombin could be demonstrated.

Animals↗

PubMed1989

The heparin and pentosan polysulfate binding sites of human antithrombin overlap but are not identical.

Four sulfated polysaccharides (unfractioned heparin, low-molecular-mass heparin, heparan sulfate and pentosan polysulfate) were investigated for their abilities (a) to bind antithrombin, (b) to induce conformational change of the inhibitor and (c) to potentiate antithrombin inhibition of thrombin. The binding capacity was reflected by the shielding of the heparin binding site. This was characterized by the extent to which a polysaccharide could protect chemical modification of Lys-125 and Lys-136, two lysyl residues of antithrombin which have been implicated in heparin binding. The conformational change was measured by fluorescence enhancement and the increased accessibility of Lys-236 to chemical modification. Our results reveal that the events of polysaccharide binding, conformational change and the enhancement of inhibitory activity are not quantitatively interlinked. Compared to the unfractionated heparin on an equal mass basis, the low-molecular-mass heparin (molecular mass 4-6 kDa) binds more strongly to antithrombin, induces a greater conformational change (about twofold), but is less potent in accelerating the inhibitory activity. Both heparin and heparan sulfate shield Lys-125 and Lys-136 and induce a conformational change that leads to exposure of Lys-236 and an increased fluorescence. On the other hand, pentosan polysulfate protects only Lys-125 and causes no appreciable conformational change, although it is also capable of enhancing the antithrombin-thrombin interaction. These data clearly demonstrate that the heparin and pentosan polysulfate binding sites of antithrombin overlap (at Lys-125) but are not identical.

Antithrombins↗

PubMed1976

Acquired thrombophilia: a hitherto unrecognized procoagulant-antithrombin imbalance.

Inherited, acquired and iatrogenic 'diseases of low antithrombin activity' share a common denominator: each is associated with an increased tendency toward, or incidence of, thrombosis. This suggested the possibility that these diseases constituted a distinct pathogenetic entity. Molecular models and clinical studies suggested 3 interrelated phenomena: increased serum procoagulants; decreased antithrombin; a tendency to thrombosis. The term 'Acquired Thrombophilia' is proposed to designate pre-thrombotic and thrombotic individuals presenting this non-inherited combination of laboratory and clinical findings. The antithrombin clotting time is shown to be inversely related to the level of circulating serine procoagulants, directly related to the level of antithrombin, and results from a procoagulant-antithrombin inter-molecular reaction. Patients with Acquired Thrombophilia have 'turned-on' or excessive procoagulants resulting in 'turned-off' or tightly bound antithrombin molecules.

Adult↗

PubMed2005

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency.

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.

Adult↗

PubMed1980

Comparison of three methods for the estimation of plasma antithrombin.

Plasma antithrombin levels were measured by clotting, immunological, and amidolytic methods on two groups of subjects: 20 normal individuals and nine patients studied serially post-operatively (hip replacement). The postoperative patients were observed for the emergence of deep-vein thrombosis using 125I-fibrinogen uptake measurements (FUT). The three methods gave similar ranges for the normal subjects, were reproducible (cv less than 5%), and detected early postoperative reduction of antithrombin levels. All three methods failed to show any significant differences in preoperative antithrombin levels between the positive and negative FUT groups. Correlation studies were performed on the pooled data from the normal and postoperative group (range 60-130% of normal; 100 samples). The best correlation (r = 0.75; P less than 0.01) was achieved with the chromogenic kit assay method versus the Mancini immunoassay technique. The thrombin agarose (total antithrombin) gel diffusion technique correlated less well with the chromogenic (r = 0.65; P less than 0.01) and Mancini immunoassay (r = 0.45; P less than 0.01) methods. It is concluded that the chromogenic kit method gives a rapid, reproducible, and specific measurement of antithrombin III. The thrombin agarose diffusion method, though not specific for antithrombin III, is a cheap and simple method to perform. The potential of the three methods for detecting the prethrombotic stage and early thrombosis is discussed.

Adolescent↗

PubMed1991

Screening for heparin binding variants of antithrombin.

A chromogenic assay for use as a screening test for the identification of antithrombin deficiency is described. The heparin concentration and the incubation time in the assay were optimised specifically to permit the detection of heparin binding defects of antithrombin. The sensitivity of antithrombin assays for the detection of this type of variant was significantly impaired when an incubation time of more than 30 seconds was used. Several commercially available assays recommend a longer incubation time than 30 seconds and therefore some patients with heparin binding defects of antithrombin may not be identified. The assay described here allows heparin binding variants of antithrombin to be identified and distinguished from other types of antithrombin deficiency in a simple two stage procedure.

Antithrombins↗

PubMedDate not supplied

Anticoagulant effect of unfractionated heparin in antithrombin-depleted plasma in vitro.

The aim of the study was to determine the effect of the antithrombin concentration on the anticoagulant response to heparin in vitro. Pooled plasma was depleted of antithrombin using heparin Sepharose. Unfractionated heparin (final concentration between 0 and 1 U/ml) was added to plasma with different antithrombin concentrations, and the activated partial thromboplastin time (APTT) was determined. Plasma with an antithrombin concentration over 0.27 U/ml shows a similar response to heparin as normal plasma; at lower levels the response is diminished. Even in plasma fully depleted of antithrombin, the APTT can be prolonged to a therapeutic level, although the amount of heparin needed is twice as high. At antithrombin concentrations over 0.27 U/ml, heparin is the major determinant of the anticoagulant effect.

Anticoagulants↗

PubMed1992

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to s1C proximity to highly conserved internal beta strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, s1C is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of s1C variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function.

Adolescent↗

PubMed2004

The effect of haemodilution on antithrombin concentration during cardiac surgery.

The effect of haemodilution on antithrombin concentration was investigated in 73 patients undergoing elective cardiac surgery with and without cardiopulmonary bypass. In patients who required cardiopulmonary bypass (n = 45), the antithrombin concentration fell to 52% of baseline during surgery (24.2 mg.dl(-1) to 12.6 mg.dl(-1)), and the haemoglobin level fell to 55% (136 g.l(-1) to 75 g.l(-1)). In patients who did not require cardiopulmonary bypass (n = 28), the antithrombin concentration fell to 82% of baseline (23.7 mg.dl(-1) to 19.5 mg.dl(-1)), and the haemoglobin concentration fell to 78% (141 g.l(-1) to 109 g.l(-1)). The overall correlation coefficient (r) for changes in antithrombin and haemoglobin concentrations was 0.76. The results indicate that most of the decrease in concentration of antithrombin during cardiac surgery is a consequence of cardiopulmonary bypass and is due to haemodilution. This data demonstrates that the percentage decrease in haemoglobin concentration can be used to estimate the percentage decrease in antithrombin concentration that occurs during cardiac surgery, if blood products that might effect the results are not administered between measurements.

Antithrombin III↗

PubMed2000

Rapid genetic diagnosis in neonatal pulmonary artery thrombosis caused by homozygous antithrombin Budapest 3.

We report a case of spontaneous left pulmonary artery thrombosis in a 3-day-old male neonate. The presentation of heparin resistance and thrombosis raised the possibility of a type II heparin binding site antithrombin deficiency. A continuous infusion of antithrombin concentrate was used successfully, following failure of plasma, to correct the heparin resistance. Rapid genetic analysis allowed sequencing of the antithrombin gene within 5 working days. This showed the infant to be homozygous for the substitution of C to T at nucleotide 2759. This base change causes mutation of the native leucine at codon 99 to a phenylalanine. This antithrombin variant has been previously reported (antithrombin Budapest 3) and results in reduced binding of heparin to antithrombin. Such a molecular diagnostic approach is feasible and warranted in such cases of neonatal thrombosis because of the diagnostic difficulties encountered.

Antithrombin III Deficiency↗

PubMed1985

Dysfunctional antithrombin III in sick premature infants.

Antithrombin III, a major inhibitor of activated coagulation factors has low immunologic levels in the human infant. The objective of this study was to determine if the antithrombin III molecule is fully functional in sick premature infants. The populations studied included: adult controls (n = 20), full term healthy infants (n = 18), sick premature infants on day 1 (n = 16) and at greater than 7 days of age (n = 10), and infants with disseminated intravascular coagulation (n = 11). This was diagnosed in the presence of prolonged screening tests, decreased levels of fibrinogen, and platelets along with elevated fibrin degradation products. Plasma antithrombin III levels were measured biologically (chromogenic substrate S2238) and immunologically (radialimmunodiffusion), and expressed as a percent of adult pooled plasma. Crossed immunoelectrophoresis were performed in the presence and absence of heparin. The antithrombin III biologic/immunologic ratios for adults, healthy full term infants, and sick premature infants on day 1 of life were all near unity. In contrast sick premature infants beyond the 1st wk of life and infants with disseminated intravascular coagulation had lower biologic activity compared to immunologic (B/I = 0.77 +/- 0.28, 0.78 +/- 0.17, p less than 0.01), respectively. In all groups, the antithrombin III molecule was normal on crossed immunoelectrophoresis except for one infant with disseminated intravascular coagulation. Sick premature infants may acquire a dysfunctional antithrombin III molecule in the postnatal period.

Adult↗

PubMed1975

Adverse effect of heparin in thrombin-antithrombin III interaction.

Thrombin, while reacting in the presence of hepatin, impairs the inhibitory capacity of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased or abolished. This adverse effect of hepatin has been observed directly with at least 1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating in the reaction. The inhibitory capacity was then totally destroyed and some residual thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation of thrombin in the presence of hepatin was fast and complete, however, a significant decrease of inhibitory capacity below that found in reaction without heparin, has been established by measuring the residual antithrombin III activity. In defibrinated human plasma at least 2 units of thrombin per each antithrombin III unit were required to demonstrate directly the adverse effect of heparin but a fast depletion of inhibitory capacity has been also observed after repeated additions of small thrombin portions into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared with great velocity; subsequent portions, however, accumulated building up a high thrombin level not seen in the absence of heparin. The accumulation of residual enzyme was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant at lower concentrations and was particularly noticeable in antithrombin III deficient plasma. These results may have some bearings on the approach to heparin therapy in the event when thrombin continuously generates or when a marked deficiency of antithrombin III exists.

Antithrombins↗

PubMed1992

The role of the COOH-terminal region of antithrombin III. Evidence that the COOH-terminal region of the inhibitor enhances the reactivity of thrombin and factor Xa with the inhibitor.

To elucidate the role of the COOH-terminal region of antithrombin III, we studied the effects of synthetic peptides corresponding to its sequence on the amidolytic and proteolytic activities of thrombin and Factor Xa in the presence or absence of the inhibitor, antithrombin III. The peptides ANRPFLVFI and IIFMGRVANP corresponding to residues Ala404 to Ile412 and Ile420 to Pro429, respectively, blocked the inhibition by antithrombin III. The effect of IIFMGRVANP was reduced in the presence of heparin. Both peptides at a concentration of 1 mM blocked complex formation between antithrombin III and thrombin or Factor Xa. The two peptides, particularly IIFMGRVANP, directly enhanced the amidolytic activity of thrombin and Factor Xa on the synthetic substrate Boc-Ala-Gly-Arg-MCA (where Boc is t-butoxycarbonyl and MCA is 4-methylcoumarin), which corresponds to residues P3-P1 of the reactive site of antithrombin III, and also on other substrates due to increased Vmax. IIFMGRVANP also shortened the thrombin-induced fibrinogen clotting time, whereas ANRPFLVFI inhibited the thrombin-catalyzed activation of protein C both in the presence and absence of thrombomodulin. The direct effect of ANRPFLVFI and IIFMGRVANP on thrombin was confirmed by enhancement of the incorporation of dansylarginine-N-(3-ethyl-1,5-pentanediyl)amide into thrombin. These findings suggest that the COOH-terminal region of antithrombin III interacts with thrombin and Factor Xa to increase the reactivity of the enzyme, which may enhance acyl-bond formation between the inhibitor and the enzyme.

Amino Acid Sequence↗

PubMed1990

Prevention of venous thrombosis after total knee arthroplasty. Comparison of antithrombin III and low-dose heparin with dextran.

In a prospective, randomized trial, we compared the efficacy of a combination of antithrombin III and heparin with that of dextran 40 as prophylaxis against venous thrombosis after total knee arthroplasty. Ascending venography identified thrombosis in about one-third of the patients who received the combination of antithrombin III and heparin, compared with about four-fifths of those who received dextran (p less than 0.001). In both groups, the patients who had venous thrombosis had a significantly lower concentration of antithrombin III postoperatively than those who did not have thrombosis. Venous thrombosis occurred in all patients in whom the concentration of antithrombin III was less than 65 per cent postoperatively. These findings demonstrated that, after total knee replacement, the combination of antithrombin III and heparin effectively reduces the incidence of postoperative venous thrombosis and is significantly better than dextran. Furthermore, the findings suggested a relationship between postoperative deficiency of antithrombin III and the occurrence of thrombotic complications.

Adult↗

PubMed1991

Thrombin-hirudin complex stability: a comparison with the thrombin-antithrombin III complex.

In the present in vitro study the stabilities of the thrombin-hirudin and the thrombin-antithrombin III complexes were investigated. After incubation of the complexes with free inhibitors the thrombin-antithrombin III levels were determined by ELISA. The thrombin-hirudin complex proved to be stable in the presence of antithrombin III or heparin. However, in the presence of heparin and plasma equivalent concentrations of antithrombin III, the thrombin-hirudin complex dissociated and hirudin was displaced. In contrast, both thrombin-antithrombin III and thrombin-antithrombin III/heparin complexes are very stable even in the presence of a large excess of hirudin.

Antithrombin III↗

PubMed1991

Antithrombin III in liver disorders.

Biological and immunological antithrombin III was studied in 26 patients of viral hepatitis including 6 with encephalopathy, and in 11 patients with cirrhosis of liver. There was a significant reduction in both biological and immunological activity of antithrombin III in all the groups of liver disorders studied. There was a good correlation between biological and immunological activity of antithrombin III (P less than 0.05). Further, there was a significant inverse correlation between immunological activity of antithrombin III and SGOT/SGPT (P less than 0.01) as well as serum bilirubin (P less than 0.001), signifying the prognostic value of antithrombin III in hepatitis. Biological activity on the other hand did not show any relation with the hepatic enzymes or bilirubin elevation. The antithrombin III levels appeared to decline in direct proportion to the degree of hepatic necrosis, probably due to reduced synthesis.

Alanine Transaminase↗