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PubMed1992

Interaction of heparin with myosin ATPase: possible involvement with the hemorrhagic activity and a correlation with antithrombin III high affinity-heparin molecules.

Up to 50% of [35S]-heparin molecules prepared from rat skin bind to rabbit muscle myosin ATPase, in a concentration dependent manner, producing a stable complex with a dissociation constant of 3 x 10(-7) M. The [35S]-heparin in the complex has a distinct electrophoretic behaviour and is precipitated by TCA together with myosin. Other [35S]-glycosaminoglycans, namely, heparan sulfate, dermatan sulfate and chondroitin sulfate also prepared from rat tissues are unable to form complexes with the enzyme. Among the sulfated glycosaminoglycans obtained from different sources only heparin is able to displace the bound [35S]-heparin from the ATPase. Heparin with high affinity for antithrombin III, prepared by antithrombin-affinity chromatography, dislodges up to 90% of the bound [35S]-heparin. Furthermore, antithrombin III-high affinity heparin shows a high affinity for myosin ATPase when compared to antithrombin III-low affinity heparin which shows a low affinity for the enzyme. It is also shown that myosin ATPase inhibits the "in vitro" plasma anticoagulant activity of heparin. These are suggestive that the special structure of the heparin molecules needed for the binding to antithrombin and myosin ATPase bears important similarities. The mechanism of the hemorrhagic effect of heparin is discussed in view of these interactions.

Adenosine Triphosphate↗

PubMed1994

A phenylalanine 402 to leucine mutation is responsible for a stable inactive conformation of antithrombin.

In a South African family with antithrombin deficiency and unexplained thrombosis, genomic DNA analysis revealed a substitution of Phe 402 by Leu. This mutation involves an amino acid located in the carboxyterminal side of the antithrombin reactive loop and has already been observed in a French family (antithrombin Maisons-Laffitte). In both cases, the expression of the mutation is pleiotropic, i.e. results in a reduction in the circulating concentration of antithrombin and impairs both its anti-thrombin activity and its ability to bind heparin. The effect of a denaturing agent (sodium dodecyl sulfate) on the recognition of the plasma antithrombin by a polyclonal antibody was studied in an immuno-enzymatic assay. The Phe to Leu mutation decreased the sensitivity to denaturation, suggesting that the mutation increases the stability of the protein. Whether this stable conformation is due to a partial insertion of the amino-terminal side of the reactive loop, which would explain how both protease binding and heparin binding are affected, remains to be determined.

Adolescent↗

PubMed1979

A study of rabbit plasma progressive antithrombinic activity during acute phase inflammatory reaction and in experimental nephrotic syndrome.

1. The development of the progressive antithrombinic activity in rabbit plasma as a function of the level of the two alpha-macroglobulins in two experimental pathologies: acute phase inflammatory reaction and nephrotic syndrome, were studied. 2. In the first case, the antithrombinic activity is a result of the increased biosynthesis of plasmatic antithrombins: antithrombin III, alpha 1 antitrypsin and alpha macroglobulins. 3. In the nephrotic syndrome, this activity follows the increase in the alpha M levels, the other antithrombins having been massively eliminated from the circulation in the urine.

Animals↗

PubMed1996

Hamster antithrombin III: purification, characterization and acute phase response.

Antithrombin III was purified to homogeneity from hamster plasma by affinity chromatography on heparin-agrose, ion-exchange chromatography on Mono Q and size-exclusion chromatography on TSK G3000SWG column with 50% yield. The molecular mass of hamster antithrombin III was estimated at 62.5 kDa and the absorption coefficient (A280 nm 1%, 1 cm) at 6.48 (in 0.1 M sodium phosphate pH 7.0). Several isoforms of the inhibitor were detected with the pI in range of 4.95-5.25. The protein contains all residues characteristic for complex-type carbohydrate chains. The N-terminal amino acid sequence shows 84% of identity to mouse and 76% to human analogue. The hamster antithrombin III gives low immunological cross-reactivity with antibodies to human antithrombin III. Initiation of the acute phase response only slightly affected the plasma concentration of inhibitor (+/- 10% within 72-h period). The kinetic data suggest high efficiency in bovine and human thrombin inhibition. In summary, the study shows only similarities between hamster and other mammal antithrombins.

Acute-Phase Reaction↗

PubMed2005

Antithrombin III attenuates pulmonary tissue injury caused by mesenteric ischemia-reperfusion.

BACKGROUND: Mesenteric ischemia-reperfusion (I/R) is a well-known event causing both local and remote organ injuries, including the lungs. Recently, several studies indicated that activated leukocyte-endothelial cell interactions play an important role in the mechanisms of these injuries. As a natural inhibitor of serine proteases, antithrombin was shown previously to attenuate the tissue damage after local I/R in several organ systems. Here, we examined the effects of antithrombin on pulmonary injury after mesenteric I/R. METHODS: Wistar albino rats underwent median laparotomy and were randomized into 3 groups: (1) sham-operated control (n = 12), (2) 60 minutes of mesenteric ischemia and 3 hours of reperfusion (n = 12), and (3) antithrombin-pretreated (250 U/kg) group before the I/R (n = 12). At the end of reperfusion, animals were killed and neutrophil sequestration, myeloperoxidase (MPO) activity, and Evans blue dye extravasation in the lung parenchyma were assessed and compared. RESULTS: There was a statistically significant increase in the quantity of Evans blue dye concentration, leukocyte sequestration, and MPO activity in the I/R group when compared with the control group. The pretreatment of animals with antithrombin significantly decreased the pulmonary injury characterized by increased Evans blue dye extravasation, leukocyte sequestration, and MPO activity. CONCLUSION: The data of the present study suggest that mesenteric ischemia and reperfusion induces pulmonary injury characterized by activated neutrophil sequestration and increased microvascular leakage in the lungs. A significant attenuation of intestinal I/R-related lung injury with the use of antithrombin concentrate warrants further studies to elucidate the potential role of this natural serine protease inhibitor in clinical settings.

Animals↗

PubMed2006

Antithrombin activity in children with chylothorax.

OBJECTIVE: To determine whether increased antithrombin loss is present in children with chylothorax after cardiac surgery. METHODS: Plasma and pleural effusion samples of children with chylous and non-chylous pleural effusion were assayed for antithrombin activity. RESULTS: Ten children with chylothorax and five children with non-chylous pleural effusion were investigated. There was statistically significant increase in mean antithrombin activity in chylous samples (32.2+/-11.4%) compared to non-chylous samples (14.4+/-13.9%), and significant decrease in plasma of children with chylothorax (44.6+/-15.4%) compared to children with non-chylous pleural effusion (69.9+/-22.4%). Seven of 10 children with chylous and none of the children without chylous developed thrombosis (p<0.007). CONCLUSIONS: Increased loss of antithrombin is present in children with chylothorax, potentially predisposing these children to an increased risk of thrombosis. Repeated antithrombin substitution should be considered in critically ill children with chylothorax.

Antithrombins↗

PubMed2006

Role of antithrombin and factor XIII in leukocyte-independent plasma extravasation during endotoxemia: an intravital-microscopic study in the rat.

BACKGROUND: Platelet-endothelial interactions have been shown to be main mediators of leukocyte-independent endothelial damage. Besides altering platelet-endothelial interactions, both antithrombin and factor XIII reduce microvascular permeability in leukocyte-dependent experimental models. Thus, it was our aim to investigate the effects of antithrombin and factor XIII on microvascular permeability during leukocyte-independent endotoxemia. MATERIAL AND METHODS: In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60, and 120 min after the start of the experiment. Fucoidin and a continuous infusion of lipopolysaccharides were used to generate leukocyte-independent endotoxemia. The experiment was divided into two parts 1) an antithrombin study and 2) a factor XIII study. RESULTS: No differences between groups in leukocyte rolling and venular wall shear rate could be observed in both parts of the experiment. Pretreatment with antithrombin reduced microvascular permeability significantly compared with control subjects (120 min: Fuco [untreated]: 0.14 +/- 0.03; Fuco/ETX [control]: 0.37 +/- 0.06; Fuco + ATIII/ETX: 0.15 +/- 0.02; P < 0.05). Factor XIII reduced microvascular permeability significantly after 60 min (Fuco [untreated]: 0.10 +/- 0.03; Fuco/ETX [control]: 0.36 +/- 0.07; Fuco + FXIII/ETX: 0.13 +/- 0.04; P < 0.05). This effect diminished after 120 min (Fuco [untreated]: 0.12 +/- 0.03; Fuco/ETX [control]: 0.5 +/- 0.08; Fuco + FXIII/ETX: 0.29 +/- 0.05; P < 0.05). CONCLUSIONS: Antithrombin and factor XIII reduce leukocyte-independent microvascular permeability. Yet, factor XIII also shows a nonprotective effect on a long-term basis. These data emphasize the central role of platelets in leukocyte-independent endotoxemia.

Animals↗

PubMed1996

Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy.

OBJECTIVE: Acute fatty liver of pregnancy has been associated with a syndrome of marked depression of antithrombin III and disseminated intravascular coagulation. We sought to identify the clinical importance of this accelerated coagulation. STUDY DESIGN: The medical records of patients with acute fatty liver of pregnancy identified during the period of 1982 to 1994 were retrospectively reviewed. RESULTS: Twenty-eight patients with acute fatty liver of pregnancy were identified for an incidence of 1:6692 births. Laboratory evidence of persistent disseminated intravascular coagulation was found in all patients tested. Six patients had clinical bleeding, all associated with genital tract injury. Twenty-three of twenty-three patients tested had markedly decreased antithrombin III levels (average 11%, normal range 80% to 100%). Seven patients received antithrombin III transfusions, which was associated with a significant transient rise in the plasma level. Compared with patients not transfused, however, there was a similar clinical outcome. CONCLUSION: Profoundly depressed antithrombin III levels and laboratory evidence of disseminated intravascular coagulation were present in all cases of acute fatty liver of pregnancy but rarely influenced clinical outcome unless there was concomitant genital tract injury. Antithrombin III transfusions increased plasma levels, but no definite clinical benefit was established in this series because of the small number of cases.

Acute Disease↗

PubMed2002

Antithrombin III prevents deleterious effects of remote ischemia-reperfusion injury on healing of colonic anastomoses.

BACKGROUND: Antithrombin III is known as the most important natural inhibitor of thrombin activity and has been shown to attenuate local harmful effects of ischemia-reperfusion injury in many organs. In recent animal studies, delaying effect of remote organ ischemia-reperfusion injury on healing of intestinal anastomoses has been demonstrated. In this study, we investigated whether antithrombin III reduces deleterious systemic effects of ischemia-reperfusion injury on healing of colonic anastomoses in rats. METHODS: Anastomosis of the left colon was performed in 24 rats that were divided into three groups: sham operated control (group I, n = 8), 30 minutes of intestinal ischemia-reperfusion by superior mesenteric artery occlusion (group II, n = 8), antithrombin III treated group (250 U/kg before and after the ischemia-reperfusion, group III, n = 8). On postoperative day 6, all animals were sacrificed, and bursting pressure and tissue hydroxyproline content of the anastomoses were assessed and compared. RESULTS: On postoperative day 6 the mean bursting pressures were 149.6 +/- 4.8, 69.8 +/- 13.5, and 121.8 +/- 8.7 mm Hg for groups I, II, and III, respectively (P = 0.000). Mean tissue hydroxyproline concentration values were 389.5 +/- 29.6, 263.1 +/- 10.0, and 376.0 +/- 33.8 microg/mg for groups I, II, III respectively (P = 0.005). CONCLUSIONS: This study showed that, antithrombin III treatment significantly prevented the delaying effect of remote organ ischemia-reperfusion injury on anastomotic healing in the colon. Further clinical studies are needed to clarify whether antithrombin may be a useful therapeutic agent to increase the safety of the anastomosis during particular operations where remote organ ischemia-reperfusion injury takes place.

Analysis of Variance↗

PubMed1998

Hydration structure of antithrombin conformers and water transfer during reactive loop insertion.

The serine protease inhibitor antithrombin undergoes extensive conformational changes during functional interaction with its target proteases. Changes include insertion of the reactive loop region into a beta-sheet structure in the protein core. We explore the possibility that these changes are linked to water transfer. Volumes of water transferred during inhibition of coagulation factor Xa are compared to water-permeable volumes in the x-ray structure of two different antithrombin conformers. In one conformer, the reactive loop is largely exposed to solvent, and in the other, the loop is inserted. Hydration fingerprints of antithrombin (that is, water-permeable pockets) are analyzed to determine their location, volume, and size of access pores, using alpha shape-based methods from computational geometry. Water transfer during reactions is calculated from changes in rate with osmotic pressure. Hydration fingerprints prove markedly different in the two conformers. There is an excess of 61-76 water molecules in loop-exposed as compared to loop-inserted conformers. Quantitatively, rate increases with osmotic pressure are consistent with the transfer of 73 +/- 7 water molecules. This study demonstrates that conformational changes of antithrombin, including loop insertion, are linked to water transfer from antithrombin to bulk solution. It also illustrates the combined use of osmotic stress and analytical geometry as a new and effective tool for structure/function studies.

Antithrombins↗

PubMed1982

Further characterization of the antithrombin-binding sequence in heparin.

An octasaccharide with high affinity for antithrombin, isolated after partial deaminative cleavage of heparin and previously found to have the following predominant structure (see formula in text) has been studied further. High-voltage, paper electrophoresis of the 3H-labelled disaccharides obtained by deamination with HNO2 (pH 1.5) followed by reduction with Na[3H]BH4 showed approximately 25% of mono-O-sulfated components, in addition to L-iduronic acid(2-O-SO3)-2,5-anhydro-D-[3H]mannitol (6-O-SO3). The monosulfated disaccharides were identified by high pressure, ion-exchange chromatography as L-iduronic acid(2-O-SO3)-2,5-anhydro-D-[3H]mannitol, L-Iduronic acid-2,5-anhydro-D-[3H]mannitol(6-O-SO3). and D-glucuronic acid-2,5-anhydro-D-[3H]-mannitol L, iduronic acid 2,5-anhydro-D-[3H]mannitol(6-O-SO3), and D-glucuronic acid-2,5-anhydro-D-[3H]-mannitol. These components originated from the reducing, terminal disaccharide residue (units 7 and 8), as indicated by selective labelling with Na[3H]-BH4. The structural variability within this region suggests that it is not part of the antithrombin-binding sequence. Neither enzymic removal of the non-sulfated L-iduronic acid unit 1 nor N-deacetylation (by hydrazinolysis) at unit 2 had any significant effect on the affinity of the octasaccharide for antithrombin. However, removal of the disaccharide corresponding to units 1 and 2, by selective deamination of the N-deacetylated octasaccharide, yielded a low-affinity hexasaccharide. In addition, a high-affinity deamination product was formed, presumably an octasaccharide containing a 6-sulfated 2-deoxy-2-C-formyl-D-pentofuranosyl unit due to ring contraction in unit 2. These results suggest that the 6-sulfate group in unit 2 may be involved in antithrombin binding. It is concluded that the antithrombin binding site in heparin is represented by the pentasaccharide sequence extending from unit 2 to unit 6 of the octasaccharide studied.

Animals↗

PubMed1999

Antithrombin increases pulmonary endothelins: inhibition by heparin and Ca2+ channel antagonism.

We investigated the mechanism of antithrombin III-induced vascular release of endothelins in rat isolated lung. The antithrombin III-stimulated release of big endothelin-1 and endothelin-1 (1.7-fold and 1.3-fold over baseline) was abolished by nicardipine (L-type Ca2+ channel blocker), heparin, and N-acetyl heparin (a derivative devoid of antithrombin affinity), whereas staurosporine and genistein (inhibitors of protein kinase C and tyrosine kinase, respectively) were ineffective. Thus, (i) the antithrombin III-induced release of endothelins requires extracellular Ca2+, but not protein kinase C or tyrosine kinase activation, and (ii) heparin binding to antithrombin III is not necessary for its inhibitory effect.

Analysis of Variance↗

PubMed1998

A kinetic analysis of the interaction of human recombinant tissue factor pathway inhibitor with factor Xa utilizing and immunoassay and the effect of antithrombin III/heparin on the complex formation.

We have recently shown that a complex formation of tissue factor pathway inhibitor (TFPI) and factor Xa (Xa) promotes a clearance of proteoglycans-associated TFPI. In the current studies, the interaction between human recombinant TFPI (h-rTFPI) and Xa were kinetically analyzed by utilizing both a protease inhibitor, p-(amidophenyl) methanesulfonyl fluoride hydrochloride, and a specific enzyme-linked immunosorbent assay for the complex of h-rTFPI with Xa. We further investigated the effect of antithrombin III on the complex formation between h-rTFPI and Xa. We found that the h-rTFPI/Xa complex formed in a time-dependent manner: the second-order rate constant (K1) for the complex formation was calculated to be 0.86x10(6) M(-1)s(-1). The addition of antithrombin III to the h-rTFPI solution modestly reduced the rate of the complex formation between h-rTFPI and Xa. Heparin strikingly enhanced antithrombin III's inhibition of Xa and resulted in complete abrogation of the complex formation between h-rTFPI and Xa in the absence or presence of acidic phospholipids. Furthermore, antithrombin III induced dissociation of the preformed h-rTFPI/Xa complex in the presence of heparin. These results suggest that in the presence of heparin, antithrombin III interferes with the catabolism of TFPI mediated via Xa.

Antithrombin III↗

PubMed1998

Differential effects of low molecular weight heparin and unfractionated heparin on circulating levels of antithrombin and tissue factor pathway inhibitor (TFPI): a possible mechanism for difference in therapeutic efficacy.

There is growing evidence on the superior efficacy and safety of low molecular weight heparins (LMWHs) over unfractionated heparin (UFH) for the treatment of both venous and arterial thromboembolism. Heparin exerts its function by potentiating antithrombin and by mobilizing tissue factor pathway inhibitor (TFPI) into the circulation. The present study was conducted to compare the effect of subcutaneous LMWH and infusion of UFH on these two anticoagulants in plasma. Eighteen healthy male volunteers were randomly allocated to therapy with continuous intravenous (iv) UFH (n=6) (initial infusion rate 450 IU/kg/day) or low molecular weight heparin (LMWH) (enoxaparin, 1.5 mg/kg/day) subcutaneously (sc) once daily for 72 hours. Free TFPI antigen, measured by a solid-phase two-site enzyme immunoassay, and antithrombin and protein C activities, measured by chromogenic assays, were assessed in plasma samples before, during, and after anticoagulant treatment. Infusion of UFH, but not subcutaneous LMWH, was found to attenuate the antithrombotic defense by a selective decrease of both circulating antithrombin (-21+/-7%, p<0.0001) and of free and endothelial-bound TFPI. The changes in antithrombin and TFPI by LMWH and UFH were statistically different between groups (p<0.001). The differential effect of UFH and LMWH on antithrombin and TFPI may explain the superior efficacy of subcutaneous LMWH compared with conventional intravenous UFH for treatment of both arterial and venous thrombosis.

Administration, Cutaneous↗

PubMed1997

Protein C, protein S and antithrombin III in children with portal vein obstruction.

BACKGROUND/AIMS: Portal vein obstruction is the most common single cause of portal hypertension in children and its cause is unknown in most instances. The aim of the present study was to evaluate the incidence of protein C, protein S and antithrombin III deficiencies and to screen for possible genetic deficiencies of these proteins. METHODS: A prospective study was undertaken in 20 consecutive children with portal vein obstruction, their parents and 20 matched healthy children. RESULTS: Children with portal vein obstruction displayed a reduction in protein C (p<0.05), protein S (p<0.0001), and antithrombin III (p<0.001) activities as compared with controls. Protein C and protein S activities were below 60% in nine and eleven of the children with portal vein obstruction, respectively, and antithrombin III activities were below or equal to 85% in ten of them. Repeated assay of protein C activity in seven children following a surgical portosystemic shunt showed a decrease as compared with preoperative values. Protein C, protein S and antithrombin III were normal in all parents, except two mothers in whom the levels of protein S activity and protein S antigen were found to be either below or at the lower limit of the normal range. CONCLUSIONS: These results indicate that protein C, protein S and/or antithrombin III deficiencies are frequently found in children with portal vein obstruction but are not likely to be of genetic origin in most cases.

Adolescent↗

PubMedDate not supplied

1976-1983, a critical period in the history of heparin: the discovery of the antithrombin binding site.

Heparin inhibits blood coagulation by binding to the protease inhibitor antithrombin, thus promoting inactivation of the protease "factors" of the coagulation cascade mechanism. The article provides an overview of the studies, by different research groups, that led to the structural elucidation of the antithrombin-binding region of heparin. These studies were triggered by the finding that only a fraction of heparin molecules were capable of binding with high affinity to antithrombin, and further that this fraction essentially accounted for the anticoagulant activity of the unfractionated material. Oligosaccharides obtained by selective, partial depolymerization of heparin were fractionated on immobilized antithrombin, and the smallest high-affinity molecules recovered were subjected to structural analysis, in conjunction with various modification steps. The results were interpreted in terms of a binding site for antithrombin constituted by a pentasaccharide sequence with an internal unique 3-O-sulfated glucosamine unit, in addition to sugar residues and sulfate groups present elsewhere also in the polysaccharide. The structure/function relations deduced were verified by chemical synthesis of several pentasaccharide variants with the predicted bioactivities.

Anticoagulants↗

PubMed1993

Complete nucleotide sequence of the antithrombin gene: evidence for homologous recombination causing thrombophilia.

Antithrombin is the principle regulator of thrombin and other blood coagulation proteinases. It is a member of the serpin family of proteinase inhibitors. The genomic sequence of the antithrombin locus has been completed, revealing a gene spanning 13,477 base pairs from the transcription start site to the poly(A) addition signal. Nine complete and one partial Alu repeat elements were identified within the introns of the gene, with all but one orientated in the reverse direction. Inherited deficiency of antithrombin is associated with a venous thrombotic tendency. Restriction fragment mapping of the antithrombin genes in an individual with type I antithrombin deficiency identified an intragenic deletion in one allele. Localization of the deletion breakpoints involved restriction analysis and direct sequencing of amplified DNA spanning the deletion site. The deletion removed 2761 base pairs, affecting exon 5 and flanking introns, with the deletion ends contained within the left components of two Alu elements. It is likely, therefore, that the deletion arose by homologous recombination between the two Alu elements.

Adolescent↗

PubMed1992

1H NMR spectroscopic studies on the interactions between human plasma antithrombin III and defined low molecular weight heparin fragments.

The effects of length and composition upon the antithrombin-binding properties of heparin have been investigated for two series of structurally related heparin oligosaccharides. Each series consists of a tetrasaccharide, hexasaccharide, and octasaccharide heparin fragment composed of alternating hexuronic acid (either iduronate 2-sulfate or glucuronate) and glucosamine 6,N-disulfate residues. These two series represent dominant structural motifs in intact heparin and differ from each other by the presence of a glucuronic acid in one series in place of an iduronate 2-sulfate residue penultimate to the reducing end of the fragment. Perturbations to the 1H resonances in the NMR spectrum of antithrombin upon binding of the two series of heparin fragments are compared to those generated by intact heparin binding, as well as to the effects of binding of a synthetic high-affinity pentasaccharide. All of the heparin fragments examined appear to bind to antithrombin at the same site. Three of the heparin fragments (hexasaccharide-2, octasaccharide-2, and octasaccharide-1) produce almost identical perturbations in the antithrombin 1H NMR spectrum compared to binding of intact heparin, including perturbations of resonances from tryptophan 49. This indicates that neither the glucuronic acid nor the trisulfated glucosamine residue (structural elements known to be part of the high-affinity heparin motif) are necessary for the majority of the conformational changes induced upon heparin fragment binding to antithrombin. However, the low anticoagulant activity of these fragments indicates that the changes in protein conformation upon fragment binding, as manifested by these 1H resonance perturbations, are not sufficient for catalytic activation of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗