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PubMed2000

Pharmacokinetics of recombinant transgenic antithrombin in volunteers.

UNLABELLED: Adequate levels of antithrombin (AT) III are essential for anticoagulation during cardiopulmonary bypass. Levels of AT are often decreased in patients receiving heparin before surgery. In these patients supplementation with exogenous AT can suppress the coagulation pathway and possibly decrease the risk of postoperative coagulopathy. However, the pharmacokinetics of AT have not been extensively analyzed. In this study we investigated the pharmacokinetics of transgenic recombinant AT in healthy volunteers. The concentrations of AT, after initial doses given over 30 min, were best described by a weight-normalized two-compartment model. The fast compartment volume was 41.1 mL/kg and the volume of distribution was 115.4 mL/kg. Intercompartmental clearance was 0. 0763 mL. kg(-1). min(-1) and elimination clearance was 0.0383 mL. kg(-1). min(-1). These variables are equivalent to a distribution half-life of 196 min and an elimination half-life of 2568 min. Approximately 75% of the supplemental dose is removed from plasma by the initial distribution process. A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass. IMPLICATIONS: A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass.

Adult↗

PubMed1993

General features of the heparin-binding serpins antithrombin, heparin cofactor II and protein C inhibitor.

The blood plasma serine proteinase inhibitors (serpins) are glycoproteins whose activities are involved in many important homeostatic reactions. The heparin-dependent plasma serpins, antithrombin, heparin cofactor II and protein C inhibitor, regulate the proteinases of blood coagulation. Heparin and some other glycosaminoglycans increase the rate of proteinase inhibition by these three plasma serpins. Proteinases recognize a specific peptide, termed the reactive site, near the carboxyl-terminus of serpins (for antithrombin and protein C inhibitor this is Arg-Ser and for heparin cofactor II this is Leu-Ser). Additionally, these three serpins contain unique structural elements that confer glycosaminoglycan binding activities. The therapeutic anticoagulant action of the glycosaminoglycan heparin is believed to depend partially on heparin-accelerated inhibition of proteinases by antithrombin. The physiological importance of specific proteoglycans has been attributed to their recognition of these serpins and their biological 'activation' of these proteinase inhibitors.

Amino Acid Sequence↗

PubMed2000

Antithrombin III deficiency in a patient with multifocal osteonecrosis.

The authors examined a 35-year-old man who had multifocal osteonecrosis on the right and left femoral heads, left humeral head, and right scaphoid. The patient previously had a diagnosis of Type I congenital antithrombin III deficiency but had no other risk factors for osteonecrosis. This patient was thought to have systemic thromboembolism because of the increased blood coagulability resulting from antithrombin III deficiency. Thrombophilia (increased likelihood of thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi) have been implicated as causative factors for osteonecrosis. This case shows a possible relationship between thrombophilic antithrombin III deficiency and multifocal osteonecrosis.

Adult↗

PubMed2003

Influence of modest endotoxemia on postoperative antithrombin deficiency and circulating secretory immunoglobulin a levels.

OBJECTIVE: To evaluate the influence of modest endotoxemia on postoperative antithrombin deficiency and cholestasis. SUMMARY BACKGROUND DATA: It has not been determined whether endotoxin translocation in small amounts is a physiological phenomenon or whether it is a potential health hazard. METHODS: Blood endotoxin, antithrombin III (ATIII), secretory immunoglobulin A (sIgA), which was selected as a marker of cholestasis, C-reactive protein (CRP), and alpha-1-antitrypsin (AAT) concentrations were measured from the 20 patients undergoing curative gastrectomy for gastric cancer preoperatively and postoperatively. Portal and systemic blood samples were taken for the analysis of endotoxin and interleukin-6 (IL-6) concentrations during surgery in these patients. RESULTS: Although plasma endotoxin levels showed a significant increase during surgery, we did not find a correlation with ATIII, sIgA, CRP, and IL-6 levels. Systemic blood endotoxin levels during surgery correlated with a postoperative rise of serum AAT levels. Plasma ATIII levels transiently decreased on the first and third postoperative day, and sIgA levels were shown to increase on the seventh postoperative day. There was a weak relationship between the extent of postoperative endotoxemia and a reduction in ATIII concentrations. CONCLUSIONS: The influence of modest endotoxemia on postoperative antithrombin deficiency and cholestasis was limited, and increased translocational endotoxemia during abdominal surgery may be a physiological phenomenon to trigger off an acute-phase protein response.

Adult↗

PubMed1975

A simple two-step isolation procedure for human and bovine antithrombin II/III (heparin cofactor): a comparison of two methods.

Human and bovine antithrombin II/III have been isolated by a simple procedure essentially using only affinity chromatography on heparin-agarose and polyethylene glycol precipitation. An additional ammonium sulphate step removes polyethylene glycol and trace contaminants. The final preparation is homogeneous by SDS-, disc- and agar slide electrophoresis. End group analysis of human antithrombin II/III shows histidine as the N-terminal amino acid. The pure preparation showed both progressive antithrombin activity and heparin cofactor activity.

Alpha-Globulins↗

PubMed1978

Some immunological investigations on antithrombin III 'Budapest'.

Immunoelectrophoretic studies were carried out on plasma from a patient with an abnormal antithrombin III molecule (antithrombin III 'Budapest'). One-dimensional immunoelectrophoresis using a commercial antibody to antithrombin III (antibody to alpha2-AtIII) showed two precipitin peaks of alpha2-AtIII antigen. Two-dimensional immunoelectrophoresis showed two precipitin peaks, one with normal electrophoretic mobility, the other with increased electrophoretic mobility. It was shown that alpha2-AtIII antigen with normal mobility was identical to normal alpha2-AtIII, and that the alpha2-AtIII antigen with increased electrophoretic mobility was antigenically deficient, and appeared to be present in higher concentration than the normal alpha2-AtIII antigen. Although one-dimensional immunoelectrophoresis on plasma from the patient's son showed only one peak, two-dimensional immunoelectrophoresis revealed that the son also had two populations of alpha2-AtIII, one with normal mobility, the other with increased mobility. However, the alpha2-AtIII antigen with normal mobility appeared to be present in higher concentration than the alpha2-AtIII antigen with increased mobility. One- and two-dimensional immunoelectrophoresis using a different commercial antibody to alpha2-AtIII showed only one precipitin peak using the patient's plasma. The precipitin peak observed following two-deminsional immunoelectrophoresis was asymmetric and showed increased mobility.

Adult↗

PubMed1978

Microheterogeneity of human antithrombin III.

Antithrombin purified from normal human plasma has been separated into two fractions by isoelectric focusing in a pH 4-6 gradient. These fractions were homogeneous by polyacrylamide gel electrophoresis, had similar amino acid composition and the same specific activity. Both of them cross reacted with antiserum against antithrombin. They were found to contain different amounts of sialic acid and aminosugars. After neuraminidase treatment only a single, homogeneous peak was found by isoelectric focusing--with unchanged antithrombin activity--suggesting that the microheterogeneity is due to a difference in glycosylation.

Antithrombins↗

PubMed1981

Coagulation abnormalities following intensive plasma exchange on the cell separator. II. Effects on factors I, II, V, VII, VIII, IX, X and antithrombin III.

The effects of intensive plasma exchange on the circulating levels of coagulation factors I, II, V, VII, VIII, IX, X and antithrombin III were determined. During courses of daily exchange marked cumulative reductions of coagulation factors may occur, particularly in the case of factors I, II and X, although usually remaining above the levels considered adequate for haemostasis. The extent of cumulative reduction and subsequent recovery differed for patients with different diseases. While antithrombin III levels were reduced during plasma exchange the results suggest that this may be partly due to consumption as well as physical removal. The very low incidence of haemorrhagic sequelae and absence of thrombotic events following plasma exchange at this Centre is explained by the maintenance of adequate levels of coagulation factors and of antithrombin III even during courses of daily plasma exchange.

Antithrombin III↗

PubMed1990

Antithrombin III and procoagulant activity: sex differences and effects of the menopause.

Among participants in the Northwick Park Heart Study, antithrombin III activity was lower in pre-menopausal women than in men of the same age. In the women, however, the menopause was associated with a significant increase in antithrombin III, mean levels in these older women then exceeding levels in men of the same age. The occurrence of the menopause was also accompanied by large increases in factor VII coagulant activity, VIIc, and in plasma fibrinogen, these increases being greater in those experiencing a natural menopause than in those whose menopause was artificial. Sex differences in antithrombin III may form part of the explanation for the observed differences between men and women in their experience of ischaemic heart disease (IHD) and also for the contrasting effects of oral contraceptives and of hormone replacement therapy on the risk of thromboembolic disease.

Adult↗

PubMed1990

Thrombin-antithrombin III complex in fulminant hepatic failure: evidence for disseminated intravascular coagulation and relationship to outcome.

Indirect evidence has suggested that intravascular coagulation may occur in patients with fulminant hepatic failure (FHF), the most severe form of acute liver disease. Thrombin is inhibited in circulation by antithrombin III, and measurement of the thrombin-antithrombin III complex (TAT) is a direct measure of thrombin formation. Using a new rapid enzyme-linked immunosorbent assay we have measured TAT in 54 patients on admission, with fulminant hepatic failure. TAT was significantly increased in patients with FHF compared with control subjects (25.8 +/- 2.7 micrograms l-1) compared with 2.6 +/- 0.2 micrograms l-1; n = 10: P less than 0.001). Patients who survived had significantly lower TAT levels than those who did not (17.2 +/- 2.7 micrograms l-1; n = 27 compared with 34.0 +/- 4.2 micrograms l-1; n = 27: P less than 0.005) and patients with FHF caused by viral hepatitis had significantly lower TAT levels than those with FHF due to paracetamol overdose (14.6 +/- 4.7 micrograms l-1; n = 9 compared with 28.0 +/- 3.1 micrograms l-1; n = 45: P less than 0.05). Levels of TAT correlated significantly with prothrombin time (r = 0.36, P less than 0.01) and inversely with fibrinogen (r = -0.51, P less than 0.001). There was no significant correlation with antithrombin III concentration. Thus, using a simple and rapid technique, we have been able to demonstrate increased levels of TAT complex in patients with FHF. This provides more direct evidence of intravascular coagulation and thrombin generation in these patients. These results confirm that the coagulation system is activated in FHF.

Acetaminophen↗

PubMed1985

Pst I polymorphism of the antithrombin III gene in a French population.

Pst I endonuclease fragment length polymorphism of the antithrombin III probe was studied in a French population. Among 25 subjects tested, 15 were found heterozygous at the Pst I site, so that this polymorphism might serve as a useful markers of antithrombin III gene in families with antithrombin III deficiency.

Antithrombin III↗

PubMed1976

Acceleration of the reaction between thrombin and antithrombin III by non-stoichiometric amounts of heparin.

The accelerating effect of heparin on the reaction between purified human antithrombin and thrombin has been investigated by measuring the amount of thrombin inactivated during a short incubation of the enzyme with the inhibitor in the presence and absence of non-stoichiometric amounts of heparin. It was demonstrated that one molecule of heparin was able to promote the binding of a large number of antithrombin molecules to thrombin. Thus heparin may affect the rate of the inactivation of thrombin by antithrombin in a catalytic manner.

Antithrombins↗

PubMed1994

Prothrombin fragment 1 + 2 and antithrombin III-thrombin complex in microalbuminuric type 2 diabetic patients.

In microalbuminuria there is an increased cardiovascular risk not fully explained by the excess of conventional risk factors. To investigate whether or not microalbuminuria is associated with haemostatic abnormalities in Type 2 diabetic patients, we measured the prothrombin fragment 1 + 2, a marker of thrombin generation, and the thrombin-antithrombin complex, a marker of thrombin neutralization. Plasma levels of prothrombin fragment 1 + 2 and thrombin-antithrombin complex were assayed in 17 microalbuminuric patients (albumin excretion rate, AER 20-200 micrograms min-1) and in 17 comparable normoalbuminuric (AER < 20 micrograms min-1) Type 2 diabetic patients. Plasma prothrombin fragment 1 + 2 was significantly higher in microalbuminuric than in normoalbuminuric patients (1.09 +/- 0.06 vs 0.86 +/- 0.04 nM, p = 0.003). Individual values of F1 + 2 were above the upper limit of the normal range in 8/17 microalbuminuric and in none of the normoalbuminuric Type 2 diabetic patients. Plasma thrombin-antithrombin complex values were not significantly different in the two groups and were not correlated with AER. These results suggest that microalbuminuria is associated with a prethrombotic state and a relatively defective thrombin neutralization. Coagulation abnormalities might be part of the cardiovascular risk in microalbuminuric patients.

Aged↗

PubMed1985

A Swedish family with abnormal antithrombin III.

An abnormal variant of antithrombin III is reported in a young male with deep vein thrombosis. The heparin cofactor, progressive thrombin inhibition, and factor Xa inactivation are decreased. The abnormality seems to be a mutation which is transmitted in an autosomaldominant way. The half-life and fractional catabolic rate of 125I antithrombin III concentrate is the same in this patient as in patients with the classic type of antithrombin III deficiency and in a control.

Adult↗

PubMed1992

Comparison of antithrombin III, protein C and protein S levels in capillary and venous blood of newborn infants.

The plasma concentrations of antithrombin III, protein C and protein S in capillary and venous blood samples obtained simultaneously from 30 neonates were compared in order to determine the suitability of using capillary blood for estimation of these proteins with anticoagulant action. Our findings showed that while capillary and venous blood did not differ significantly in antithrombin III functional activity and protein C antigen levels, the capillary samples had significantly lower protein C functional activity and higher antithrombin III antigen level. Protein S antigen level was also significantly higher in the capillary samples although the difference was relatively small. The capillary and venous concentrations of the binding protein of protein S, C4b binding protein, were almost identical.

Antigens↗

PubMed1987

Heparin promotes the inactivation of antithrombin by neutrophil elastase.

Heparin is an acceleratory cofactor for antithrombin, a circulating inhibitor of blood coagulation enzymes. The presence of heparin on blood vessel walls is believed to contribute to the nonthrombogenic properties of those surfaces. In apparent opposition to this function, heparin was found to greatly accelerate the in vitro inactivation of antithrombin by neutrophil elastase. Inactivation rates in solution were potentiated several hundredfold by specific heparin fractions with anticoagulant activity. Although the data suggest that a heparin-antithrombin complex is essential for the inactivation by elastase to occur, the enzyme itself interacts tightly with heparin. These results suggest a mechanism which, if operating in vivo, could lead to a localized neutralization of the anticoagulant function of heparin at the endothelial surface.

Antithrombin III↗

PubMed1977

Standardisation of a simple method for the determination of antithrombin activity.

A procedure is described for performing a functional assay of serum antithrombin activity. The method consists of adding serum to a thrombin solution and measuring, after a fixed incubation time, the residual thrombin activity on a substrate plasma. The mean serum antithrombin activity found in 96 healthy blood donors using this procedure was 109.5% (range 82%-160%). The method was linear over an activity range between 30.5% and 176%, was significantly correlated with antithrombin-III protein concentration determined by radial immunodiffusion (r = 0.86, P less than 0.01), and showed good reproducibility (coefficient of variation 2.7%). On account of its simplicity and precision this functional assay should be of considerable use in evaluating hypercoagulability.

Adult↗

PubMed1989

Enzyme linked immunosorbent assay for measuring antithrombin III.

A competitive ELISA for the measurement of antithrombin III antigen was developed using a pure preparation of antithrombin. This two step immunoassay requires only one antibody binding step and avoids the binding of anti-antithrombin antibody to the solid phase. Plasma samples measured by this ELISA correlated well with measurements taken with immune electrophoresis measurements (r = 0.933); the ELISA was also shown to be both sensitive and precise.

Antithrombin III↗