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PubMed2003

Relation between peri-operative antithrombin activity and deep vein thrombosis after elective hip replacement surgery.

BACKGROUND: The purpose of the study was to evaluate whether the postoperative depletion or the preoperative antithrombin (AT) activity is related to the occurrence of deep vein thrombosis (DVT) in patients receiving low-molecular-weight heparin for DVT prevention after elective hip replacement surgery. PATIENTS AND METHODS: In 93 patients AT-activity and standard laboratory parameter were determined on the preoperative day and daily for one week after operation. Furthermore, a color-coded compression sonography was performed before and 8-10 days after surgery. The amount of blood loss and blood transfusions was evaluated. Patients were divided into two groups in respect to the occurrence of a postoperative DVT. RESULTS: The overall incidence of DVT was 8.6% (n = 8). Patients with DVT had a significantly lower preoperative AT-activity (80.6 +/- 3.31%) compared to those without DVT (98.1 +/- 1.12%, p < 0.001), however, without being predictive for DVT (positive predictive value 0.71). There was no association between postoperative fall of AT, the lowest postoperative AT activity, blood loss or blood substitution and DVT. CONCLUSIONS: It has to be expected that a small fraction of patients for elective hip surgery present with AT-activity levels possibly being insufficient for a therapeutic effect of low-molecular-weight heparin even preoperatively. Those patients are subject to a significant higher risk of DVT postoperatively.

Adult↗
PubMed2002

Natural anticoagulants (antithrombin III, protein C, and protein S) in patients with mild to moderate ischemic stroke.

BACKGROUND AND PURPOSE: The role of the natural anticoagulants, antithrombin III (AT III), protein C (PC), and protein S (PS), in patients with mild to moderate ischemic stroke remains uncertain. We aimed to find out whether their levels in peripheral blood correlated with the severity of neurological deficit or can predict clinical outcome and recurrence. METHODS: We studied AT III, PC, and free PS levels in 55 consecutive patients likely to survive the study period on admission, 1 week, 1 month and 3 months after a first-ever ischemic stroke. Sex- and age-matched controls were studied once. All patients underwent a full neurological examination and blood sampling at each study time point; comprehensive stroke risk factors were recorded, and the etiology of the ischemic stroke was determined. All patients were contacted 3 years later for possible recurrent ischemic events. RESULTS: AT III level was found to be significantly lower at all time points after stroke; PC level was significantly increased on admission and normal at subsequent measurements, and PS level was normal on admission but significantly decreased later. The levels of the natural anticoagulants did not correlate with the etiology of stroke, any stroke risk factor, or neurological scores, except that the AT III level on admission showed significant correlation with stroke severity and disability at 3 months. Natural anticoagulant levels did not predict recurrence of ischemic stroke. CONCLUSIONS: The measurements of the level of AT III, PC, or PS did not deliver useful information for management of patients with mild or moderate ischemic stroke, expect that AT III level on admission might predict outcome.

Adult↗
PubMedDate not supplied

Relationship between an enhancer element in the human antithrombin III gene and an immunoglobulin light-chain gene enhancer.

Enhancers, cis-acting transcriptional control elements have been described in both viral and cellular genes. They influence transcription in a quantitative fashion, act over relatively large distances (several kilobases, kb) and behave independently of their position and orientation. Enhancers have been described in immunoglobulin, chymotrypsin and insulin genes. They bear little homology with each other except for an 8-base pair (bp) 'consensus' core element, GTGGAAATTTG (refs 10, 11), but even this element is sometimes non-homologous. I have searched for such elements in the human antithrombin III (AT-III) gene. AT-III is an important coagulation protein which inactivates thrombin. It is produced by the liver and, to a lesser extent, by the kidney. Here, I report that the 5' flanking region of the AT-III gene encodes a segment homologous with the enhancer containing the joining-constant kappa (J kappa-C kappa) intron of immunoglobulin kappa-chain genes. This extensive homology suggests the existence of regulatory factors that recognize common DNA sequences in lymphoid tissues and in those which express AT-III.

Acetyltransferases↗
PubMed1979

Affinity chromatography in the separation of human alpha 1-antitrypsin (alpha 1-AT) and antithrombin-III (AT-III).

The two antiproteases alpha 1-antitrypsin (alpha 1-AT) and antithrombin-III (AT-III) have been purified simultaneously from human plasma. Purification procedure consisted of gel filtration on Sephadex G-200 after initial processing of plasma, followed by ion exchange chromatography on DEAE-Sephadex A50 and DEAE-Cellulose, at a pH of 9.0 and pH 8.3 respectively. The two proteins could not be separated by any of these procedures including a lower pH (7.4) in ion exchange chromatography. Affinity chromatography on heparin-Sepharose separated the proteins since alpha 1-AT did not bind to the matrix. Alpha 1-AT unbound to the heparin-Sepharose was subsequently purified through con A-Sepharose affinity column. The final yield of both the proteins was about 20%. The molecular weight estimated on SDS electrophoresis for AT-III and alpha 1-AT was 63,000 and 50,000, respectively.

Antithrombin III↗
PubMed1987

Comparison of the inhibitory effects of antithrombin III, alpha 2-macroglobulin, and thrombin in human basilar arteries: relevance to cerebral vasospasm.

Isolated human basilar arteries were used in this study to evaluate the inhibitory effect of antithrombin III (AT III), thrombin, and alpha 2-macroglobulin (alpha 2-M) on contractions elicited by K+, serotonin (5-HT), prostaglandin (PG) D2, PGF2 alpha, and plasmin. alpha 2-M (0.5-1.0 mg/ml) failed to affect the contractions produced by contractile agonists significantly but did notably reduce the basal tone of the arteries. Thrombin (1 and 10 U/ml) reduced basal tone and significantly inhibited the contractions elicited by K+, PGF2 alpha, and plasmin. The relaxant effect of thrombin was abolished by procedures that destroy endothelium and by exposing the artery to thrombin for prolonged periods (tachyphylaxis). AT III (1-6 U/ml) reduced basal tone and significantly inhibited, in a concentration-dependent manner, the contractile responses to K+, 5-HT, PGD2, PGF2 alpha, and plasmin. In sharp contrast to thrombin, AT III did not induce tachyphylaxis nor was its vasorelaxant effect significantly reduced by destruction of the endothelium. The results show AT III to be a potent and nonspecific inhibitor of human cerebral arteries and support the hypothesis that AT III may contribute to the delay of cerebral vasospasm seen in patients who experience aneurysmal hemorrhage.

Adolescent↗
PubMed2003

Enzymatic synthesis of antithrombin III-binding heparan sulfate pentasaccharide.

Heparan sulfate (HS) proteoglycans are crucial to numerous biological processes and pathological conditions, but to date only a few HS structures have been synthesized and characterized with regard to structure-function relationships. Because HS proteoglycans are highly diverse in structure, there are substantial limitations on their synthesis by classical chemical means, and thus new methods to rapidly assemble bioactive HS structures are needed. Here we report the biosynthesis of bioactive HS oligosaccharides using an engineered set of cloned enzymes that mimics the Golgi apparatus in vitro. We rapidly and efficiently assembled the antithrombin III-binding pentasaccharide in just 6 steps, in contrast to the approximately 60 steps needed for its chemical synthesis, with an overall yield at least twofold greater and a completion time at least 100 times faster than for the chemical process.

Antithrombin III↗
PubMed1997

Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation.

A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.

Adolescent↗
PubMed1998

Relevance of proteins C and S, antithrombin III, von Willebrand factor, and factor VIII for the development of hepatic veno-occlusive disease in patients undergoing allogeneic bone marrow transplantation: a prospective study.

Factors that enhance hypercoagulability following BMT may have a pathogenetic role in VOD. To investigate the relevance of hemostatic parameters for the development of VOD, we prospectively measured protein C, protein S, antithrombin III (AT III), von Willebrand factor, and factor VIII in 50 consecutive patients undergoing allogeneic BMT. Each parameter was determined before conditioning, on day 0 of BMT and weekly for 3 weeks, and patients were monitored prospectively for the occurrence of VOD. VOD occurred in 26 patients at median post-BMT day 8.5 (range, day -2 to 17). Thirteen patients had mild, 10 had moderate and three had severe VOD. No coagulation parameters were significantly different at the baseline or on day 0 of BMT between patients with no/mild VOD and moderate to severe VOD. On day 7 and thereafter, levels of protein C and AT III were significantly lower in patients with moderate to severe VOD when compared to patients with no/mild VOD. Levels of protein C and AT III decreased before the clinical onset of VOD in patients with moderate to severe VOD. Early post-BMT reduction of these parameters may indicate the development of moderate to severe VOD.

Adolescent↗
PubMed1981

The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Chemical and 13C nuclear-magnetic-resonance studies.

The chemical composition and the 13C n.m.r. spectra of heparin oligosaccharides (essentially octasaccharides), having high affinity for antithrombin III and high anti-(Factor Xa) activity, prepared by three independent approaches (extraction, partial deaminative cleavage with HNO2 and partial depolymerization with bacterial heparinase), leading to different terminal residues, have been studied and compared with those of the corresponding inactive species. Combined wit chemical data, the spectra of the active oligosaccharides and of their fragmentation products afforded information on composition and sequence. The three types of active oligosaccharides were shown to have the common hexasaccharide core I-Aa-G-As*-Is-As, where I and alpha-L-idopyranosyl-uronic acid, Aa = 2-acetamido-2-deoxy-alpha-D-glucopyranose, G = beta-D-glucopyranosyl-uronic acid, Is = alpha-L-idopyranosyluronic acid 2-O-sulphate, As = 2-deoxy-2-sulphamino-alpha-D-glucopyranose 6-O-sulphate. The fourth residue (As*) is an unusually substituted amino sugar resistant to mild deamination. The 13C spectra of the active species are characterized by signals from the above atypical amino sugar, the most evident of which is at 57.7 p.p.m. These signals, compared with those of appropriate synthetic model compounds, are compatible with the recently proposed 3-O-sulphation of the residue As* [Lindahl, Bäckström, Thunberg & Leder (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 6551-6555].

Animals↗
PubMed2006

Conformational transitions induced in heparin octasaccharides by binding with antithrombin III.

The present study deals with the conformation in solution of two heparin octasaccharides containing the pentasaccharide sequence GlcN(NAc,6S)-GlcA-GlcN(NS,3,6S)-IdoA(2S)-GlcN(NS,6S) [AGA*IA; where GlcN(NAc,6S) is N-acetylated, 6-O-sulfated alpha-D-glucosamine, GlcN(NS,3,6S) is N,3,6-O-trisulfated alpha-D-glucosamine and IdoA(2S) is 2-O-sulfated IdoA (alpha-L-iduronic acid)] located at different positions in the heparin chain and focuses on establishing geometries of IdoA residues (IdoA(2S) and IdoA) both inside and outside the AGA*IA sequence. AGA*IA constitutes the active site for AT (antithrombin) and is essential for the expression of high anticoagulant and antithrombotic activities. Analysis of NMR parameters [NOEs (nuclear Overhauser effects), transferred NOEs and coupling constants] for the two octasaccharides indicated that between the 1C4 and 2S0 conformations present in dynamic equilibrium in the free state for the IdoA(2S) residue within AGA*IA, AT selects the 2S0 form, as previously shown [Hricovini, Guerrini, Bisio, Torri, Petitou and Casu (2001) Biochem. J. 359, 265-272]. Notably, the 2S0 conformation is also adopted by the non-sulfated IdoA residue preceding AGA*IA that, in the absence of AT, adopts predominantly the 1C4 form. These results further support the concept that heparin-binding proteins influence the conformational equilibrium of iduronic acid residues that are directly or indirectly involved in binding and select one of their equi-energetic conformations for best fitting in the complex. The complete reversal of an iduronic acid conformation preferred in the free state is also demonstrated for the first time. Preliminary docking studies provided information on the octasaccharide binding location agreeing most closely with the experimental data. These results suggest a possible biological role for the non-sulfated IdoA residue preceding AGA*IA, previously thought not to influence the AT-binding properties of the pentasaccharide. Thus, for each AT binding sequence longer than AGA*IA, the interactions with the protein could differ and give to each heparin fragment a specific biological response.

Antithrombin III↗
PubMed1990

Re-formation of disulphide bonds in reduced antithrombin III.

Human antithrombin III (AT-III) contains three disulphide linkages (Cys-8-Cys-128, Cys-21-Cys-95 and Cys-247-Cys-430), and two of them (Cys-8-Cys-128 and Cys-21-Cys-95) are situated near the heparin-binding domain of the inhibitor. We demonstrate in this paper that: (i) partially reduced AT-III (with Cys-8-Cys-128 and Cys-21-Cys-95 quantitatively reduced) could be re-oxidized in air to regain 70-80% of its heparin cofactor activity and thrombin-inhibitory activity; (ii) completely reduced AT-III was re-oxidized under similar conditions and recovered 30-35% of it biological activities. Structural analysis of refolded AT-IIIs indicates that restorations of their disulphide contents and conformations (evaluated by chemical modification) are congruent with recoveries of their biological activities.

Antithrombin III↗
PubMed1990

Functional role of the polysaccharide component of rabbit thrombomodulin proteoglycan. Effects on inactivation of thrombin by antithrombin, cleavage of fibrinogen by thrombin and thrombin-catalysed activation of factor V.

Thrombomodulin (TM), a major anticoagulant protein at the vessel wall, serves as a potent cofactor for the activation of Protein C by thrombin. Previous work has indicated that (rabbit) TM is a proteoglycan that contains a single polysaccharide chain, tentatively identified as a sulphated galactosaminoglycan, and furthermore suggested that this component may be functionally related to additional anticoagulant activities expressed by the TM molecule [Bourin, Ohlin, Lane, Stenflo & Lindahl (1988) J. Biol. Chem. 263, 8044-8052]. Results of the present study establish that (enzymic) removal of the polysaccharide chain abolishes the inhibitory effect of TM on thrombin-induced fibrinogen clotting as well as the promoting effect of TM on the inactivation of thrombin by antithrombin, but does not affect the ability of TM to serve as a cofactor in the activation of Protein C. Studies of yet another biological activity of rabbit TM, namely the ability to prevent the activation of Factor V by thrombin [Esmon, Esmon & Harris (1982) J. Biol. Chem. 257, 7944-7947], confirmed that TM markedly delays the conversion of the native 330 kDa Factor V precursor into polypeptide intermediates, and further into the 96 kDa heavy chain and 71-74 kDa light-chain components of activated Factor Va. In contrast, the activation kinetics of a similar sample of Factor V incubated with thrombin in the presence of chondroitinase ABC-digested TM did not differ from that observed in the absence of TM. It is concluded that the inhibitory effect of TM on Factor V activation also depends on the presence of the polysaccharide component on the TM molecule.

Animals↗
PubMed1992

The N-terminal domain of antithrombin-III is essential for heparin binding and complex-formation with, but not cleavage by, alpha-thrombin.

Normal and mutant forms of human antithrombin-III (AT-III) were synthesized in a cell-free system in order to identify putative functional domains required for heparin binding and complex-formation with alpha-thrombin. Heparin-Sepharose chromatography resulted in the elution of approx. 70% of cell-free-derived normal AT-III-(1-432)-polypeptide as a peak between 0.2 M- and 0.7 M-NaCl. The cell-free-derived normal AT-III also reacted with alpha-thrombin. Approx. 15% of this AT-III formed covalent complexes with alpha-thrombin in 2 min. Unfractionated heparin accelerated the rate of formation of such complexes. Two truncated forms of AT-III (amino acid residues 219-432 and 251-432), containing only the putative thrombin-binding domain, were synthesized independently in this cell-free system. These truncated AT-III polypeptides did not bind heparin and were unable to form stable covalent complexes with alpha-thrombin. However, both of these AT-III polypeptides were cleaved by alpha-thrombin, presumably at the reactive centre Arg-393-Ser-394. The formation of the disulphide bond between Cys-247 and Cys-430 in AT-III-(219-432)-polypeptide had no effect on the results obtained. Mutations in full-length AT-III at Cys-430 had no effect on the ability of AT-III to bind heparin. There was, however, a slight decrease in the formation of stable inhibitory complexes with alpha-thrombin. A cell-free-derived AT-III mutant, devoid of amino acid residues 41-49, which comprise heparin-binding region 1 of AT-III, had slightly decreased heparin binding compared with cell-free-derived normal AT-III-(1-432)-polypeptide. This mutant AT-III polypeptide was unable, however, to form a stable complex with alpha-thrombin. We conclude therefore that the N-terminal domain of AT-III is essential for both heparin binding and complex-formation with alpha-thrombin, but not for the cleavage of AT-III at its reactive centre by alpha-thrombin.

Antithrombin III↗
PubMed1981

Metabolism of antithrombin III in cirrhosis and carcinoma of the liver.

1. The metabolism of human antithrombin III (ATIII) was studied by using 125I-labelled tracer. 2. The plasma half-life (t0.5) was 2.71 +/- 0.26 days in normal subjects and was similar in patients with cirrhosis or primary carcinoma of liver. 3. Patients with cirrhosis had low ATIII levels, decreased intravascular mass, total body mass and decreased absolute catabolic rate, suggesting decreased synthesis. The positive correlation of ATIII level with fractional catabolic rate (K10) indicated that the decreased catabolic might exert a positive inhibition on ATIII production. 4. These abnormalities were more exaggerated in patients with macronodular cirrhosis associated with hepatitis surface antigen or in those with ascites. 5. In cirrhotic patients with ascites an additional extravascular pool of ATIII was present which did not turn over at the same rate as the intravascular pool. 6. Patients with primary carcinoma of liver had moderately low ATIII, but normal intravascular mass and total body mass because of the increased plasma volume and normal absolute catabolic rate. 7. The negative correlation of ATIII levels with K10 suggested that the low levels could be due to increased catabolism or consumption. 8. One patient with disseminated malignancy and active superficial thrombophlebitis had normal ATIII metabolism.

Antithrombin III↗
PubMed2001

Natural coagulation inhibitors (protein C, protein S, antithrombin) in patients with sickle cell anemia in a steady state.

BACKGROUND: Patients with sickle cell anemia (SCA) run the risk of having decreased levels of natural coagulation inhibitors. This may be due to either hemostatic abnormalities or hepatic dysfunction. This study is designed to evaluate coagulation profiles of patients with SCA in a steady state and to determine whether hypercoagulable state is present or not. METHODS: Seventeen children with SCA in a steady state were included in this study. The routine hematological evaluation was done with a coulter-counter. Reticulocyte percentage and blood coagulation tests were also determined. The coagulation inhibitors such as protein C (as activated partial thromboplastine time prolongation time), protein S (as Factor V inhibition) and antithrombin (colorimetric assay) were measured in all cases. RESULTS: In the coagulation profile, mean euglobuline lysis time and mean fibrin degradation product levels were both significantly higher in the patient group than in the control group (P<0.05), although other parameters were within normal limits. The values for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and indirect reacting bilirubin were significantly higher in the patient group than in the control group (P<0.001, P<0.005, P<0.0001, respectively). The serum protein levels were normal. Mean factor V level was significantly lower and mean factor VIII level was found significantly higher in the patient group than in the control group (P<0.05 and P<0.005, respectively). Protein C and AT levels were lower in patients with SCA than in control subjects (P<0.001). Protein S levels were also lower in the patient group than in the control group, but the difference between the two groups was not significant (P>0.05). CONCLUSION: It is indicated that antithrombotic functions of patients with SCA are handicapped even in a steady state; and both hemostatic abnormalities and hepatic dysfunction contribute to low levels of natural coagulation inhibitors.

Adolescent↗
PubMedDate not supplied

Antithrombin III in fresh frozen plasma, cryoprecipitate, and cryoprecipitate-depleted plasma.

Antithrombin III (AT III) is a plasma protein that inhibits several activated procoagulants. Hereditary disease or acquired conditions such as severe hepatic dysfunction, nephrotic syndrome and intravascular coagulation may be associated with reduced levels of AT III. Its replacement may be essential in controlling thrombosis. In order to determine the most effective form of replacement, we compared AT III biological activity and antigen levels in conventionally prepared fresh frozen plasma, cryoprecipitate and cryoprecipitate depleted plasma (CDP). Both the activity and antigen levels were comparable in all three products (approximately 100%) and AT III was not concentrated in cryoprecipitate. These results indicate that conventionally prepared CDP, fresh frozen plasma and cryoprecipitate contain equal quantities volume for volume of AT III. On this basis, all products are equally effective as therapy for AT III deficiency, but CDP and fresh frozen plasma are recommended as convenient sources of this factor.

Antithrombin III↗
PubMedDate not supplied

Preservation of antithrombin III activity in stored whole blood.

Antithrombin III (AT-III) is the major inhibitor of thrombin, Factor Xa, and other coagulation enzymes. Congenital and acquired deficiencies of AT-III are thought to contribute to thrombosis and disseminated intravascular coagulation. Because a recent report suggested reduced AT III in stored blood, we evaluated blood bank storage effects. Serial samples were taken from 6 units of whole blood drawn into citrate-phosphate-dextrose-adenine over 42 days, and assays for AT-III functional activity were performed on the same day. The values (mean +/- SD) were as follows: day 0,91.8 +/- 10.7 percent; day 2, 101.9 +/- 10.7 percent; day 8, 107.3 +/- 7.4 percent; day 15, 118.9 +/- 11.1 percent; day 22, 105.4 +/- 9.8 percent; day 35, 93.4 +/- 8.8 percent; and day 42, 97.4 +/- 7.5 percent. The rise from day 0 to day 15 was significant but presumably secondary to interassay variation because analysis of frozen aliquots showed no significant change when all samples from each unit were assayed in one batch. Immunoassay of AT-III also showed no change with storage. The results indicate AT-III retains functional activity in whole blood stored at 2 to 6 degrees C for 42 days, and AT-III replacement does not require fresh blood or fresh-frozen plasma. Low values may reflect individual donor differences or dilution of plasma by anticoagulant.

Antithrombin III↗
PubMed1989

Heat inactivation of human immunodeficiency virus in solutions of antithrombin III.

Human immunodeficiency virus (HIV), isolated from cultures of infected peripheral blood lymphocytes, was added to solutions of highly purified antithrombin III (AT-III), which was stabilized with 1 M citrate and 17 percent sucrose. The efficiency of heat inactivation of HIV in AT-III at 60 degrees C was compared with that of HIV in culture medium and followed for periods from 0 to at least 10 hours. The virus added, titer 10(5) by ID50, was inactivated as rapidly (less than 30 minutes) and efficiently (completely) in the stabilized AT-III as in the culture medium. Virus was determined both by direct measurement of the HIV-related reverse transcriptase activity and by quantitation of virus infectivity by ID50 assay.

Antithrombin III↗

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