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PubMed1993

Antithrombin III producing hepatocellular carcinoma.

A case of primary hepatocellular carcinoma with an abnormal increase in the antigenic quantity and activity of Antithrombin III (AT-III) is reported. The patient was a 53-year-old man. The liver was palpated for a five fingerbreadths, but no jaundice or ascites was noted. Computed tomogram (CT) revealed the presence of many nodules of various sizes in the right hepatic lobe. Both viral markers of HBV and HCV were negative. For tumor markers, PIVKA-II was high (27.7 AU/ml) but AFP was normal. Among coagulation and fibrinolytic factors, the activity and antigenic levels of AT-III were abnormally high (290% and 81.6 mg/dl). An US guided needle biopsy of the tumor revealed hepatocellular carcinoma, Edmondson I. The cellularity was high and the tumor cells were small, well differentiated. The tumor cells were positively stained in immunohistochemical staining using the anti-AT-III antibody. It was believed that AT-III produced by the tumor cells was responsible for this exaggerated level.

Antigens, Neoplasm↗
PubMed1993

alpha-Thrombin within fibrin clots: inactivation of thrombin by antithrombin-III.

To demonstrate that human alpha-thrombin is effectively inactivated by human antithrombin III (AT) during the production of a fibrin clot we measured the amount of alpha-thrombin activity which can be recovered from a clot generated from purified human proteins. We discovered that 0.05-0.07% of the original alpha-thrombin activity is recovered from a fibrin clot produced from a reaction mixture where the initial concentrations of AT and alpha-thrombin were chosen at a ratio (17.5) to allow complete conversion of fibrinogen to fibrin. These results indicated that alpha-thrombin is successfully inactivated by AT during the production of a fibrin clot. Further, when an amount of alpha-thrombin equal to that recovered from a fibrin clot is introduced into a solution of fibrinogen and AT identical to that utilized to produce the clot only 4% of the fibrinogen is converted to fibrin. These results suggest that i) when a fibrin clot is dissolved during fibrinolytic therapy little active alpha-thrombin should be released from the clot and ii) this amount of thrombin is insufficient to catalyze rethrombosis without proposing de novo production of thrombin. The action on factors XI, VIII, and V of the small amount of thrombin released upon thrombolysis, however, may provide the stimulus for de novo production of sufficient thrombin to catalyze rethrombosis.

Antithrombin III↗
PubMed1994

Factor VII, antithrombin III, leukocyte and platelet counts in a sample of black and white Zimbabwean blood donors.

Studies in Southern Africa have shown that whites have significantly greater morbidity and mortality from coronary heart disease than blacks. This study investigated the distribution of some haemostatic variables known or suspected to be correlated with greater risk for coronary heart disease in healthy black and white Zimbabwean men. Factor VII, antithrombin III, leukocyte and platelet counts were measured in 56 blacks and 29 whites aged between 20 and 50 years. We found significantly greater factor VII and leukocyte counts in the whites compared to the blacks. The other variables measured were similar in the two ethnic groups. These results suggest that the greater prevalence of coronary heart disease in whites is consistent with high levels of factor VII and white blood cell counts previously identified as risk factors for this condition.

Adult↗
PubMed1994

Influence of conditions of blood sampling on coagulation activation markers (prothrombin fragment 1 + 2, thrombin-antithrombin complexes and D-dimers) measurements.

In this study, we evaluated the effects of anticoagulants used in blood sampling on the measurements of coagulation activation markers F1 + 2, TAT, D-Dimers by Elisa methods. The study was carried out on normal subjects and patients with inherited deficiency of coagulation inhibitors, antithrombin III (ATIII) protein C (PC) and protein S (PS). Three different anticoagulant solutions were compared: 1) ACD/EDTA/adenosine/heparin, 2) EDTA/aprotinin/a synthetic thrombin inhibitor and 3) sodium citrate. The results showed that sodium citrate, commonly used in coagulation laboratories, is a suitable anticoagulant for the study of coagulation activation markers. In addition, the type of tubes (plastic tubes vs glass Vacutainer R tubes) used for blood sampling as well as the order of sampling (early or late after the phlebotomy procedure) did not influence the results. We concluded that assays of coagulation activation markers F1 + 2 and D-Dimers can be performed in samples collected routinely by haemostasis laboratory staff using Vacutainer R tubes with sodium citrate. Further investigations are needed to understand why TAT measurements gave a pattern of results quite different from F1 + 2 or D-Di measurements.

Anticoagulants↗
PubMed1994

Amino acid substitutions of the P2 residue of human antithrombin that either enhance or impair function.

Recombinant forms of human antithrombin (AT) were expressed in COS-1 cells, and their interaction with human thrombin characterized by comparing the reactivity of two engineered mutant forms of AT with the wild-type recombinant. Both mutant forms contained single amino acid substitutions of Asp (G392D) or Pro (G392P) for the wild-type Gly, at residue 392, termed the P2 position with reference to the adjacent reactive centre bond. All three forms of AT co-migrated on Western blots, with an apparent molecular weight of 58 kD, with endoglycosidase F treatment reducing their mobility to 47 kD. The two mutant forms of AT reacted with thrombin differently from the wild-type molecule, in that the G392D substitution abrogated the thrombin inhibitory capacity of the protein, while the G392P substitution enhanced the reactivity of the recombinant mutant AT with thrombin. Under pseudo-first order conditions, the second order rate constants for the reaction of the recombinant wild-type and G392P mutant AT were determined to be 1.4 x 10(4) L-mol-1 sec-1 and 3.0 x 10(4) L-mol-1 sec-1, respectively, a difference of 210%. In contrast, in the presence of heparin, the reaction rates of the G392P and wild-type AT forms with thrombin, differed by less than 25%. We conclude that the P2 position of AT is an important residue for AT to express its inhibitory activity, alterations to which can either enhance or impair the inhibition of thrombin by AT.

Amino Acid Sequence↗
PubMed1994

Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors: importance of heparin cofactor II.

Heparin (HEP) prevents thrombus formation (TF) and thrombus growth (TG), by accelerating thrombin (THR) inhibition by antithrombin III (ATIII). Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II (HCII), can inhibit TF and TG as effectively as HEP. This study compared the antithrombotic effects of HEP and another agent, Sulodexide (SLX) which catalyzes thrombin inhibition by ATIII and HCII simultaneously. TF was induced in rabbit jugular veins, using the stasis/hypercoagulation model. TG was measured as the accretion of 125I-fibrin onto existing thrombi in rabbit jugular veins. HEP and SLX inhibited TF when given in doses of 10 and 5 anti-thrombin U/kg, respectively. SLX (16 anti-thrombin U/kg or 260 micrograms/kg) was more effective than HEP (120 anti-thrombin U/kg or 800 micrograms/kg) in preventing TG when administered either as a bolus or by continuous infusion. These data suggest that agents which accelerate THR inhibition by both ATIII and HCII simultaneously, can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP.

Animals↗
PubMed1995

Fluorescence and circular dichroism studies during the interactions of sulfated polysaccharides with antithrombin III.

The changes in relative fluorescence of antithrombin III (AT-III) during its interaction with sulfated xylans were compared with that of sulfated glycosaminoglycans by measuring the ratio of the increase in fluorescence of AT-III in the presence of sulfated polysaccharide to the fluorescence of AT-III alone for various mass ratios. Interactions of corn cob xylan sulfate (CCXS) and sodium pentosan polysulfate (SP-54) with AT-III resulted in enhancements of relative fluorescence which were lower than commercial heparin. At mass ratios below 1, heparan sulfate and low molecular weight heparin (LMWH) gave increases in the relative fluorescence higher than that of commercial heparin, while highly sulfated semisynthetic chondroitin sulfates A and C gave much smaller increases. The relative fluorescence enhancements of AT-III by heparan sulfate, commercial heparin, LMWH and heparin derived pentasaccharide (HDP) increased with increasing mass ratios while the enhancements by CCXS, SP-54 and the highly sulfated chondroitin sulfates A and C were reversed at higher mass ratios. The estimated dissociation constants (kd) for the interaction of AT-III and the heparin-related compounds showed that heparin sulfate and LMWH gave the lowest kd values indicating a higher affinity for AT-III while commercial heparin and HDP gave higher kd values, indicating a lower affinity for AT-III. SP-54 gave a kd value lower than CCXS, indicating a greater affinity for AT-III. A comparison of the near ultraviolet (UV) circular dichroism (CD) spectrum of AT-III alone and during its interaction with oat spelts xylan sulfate (OSXS) showed enhancements of the two aromatic amino acid regions corresponding to phenylalanine and tryptophan.

Antithrombin III↗
PubMed1995

Antithrombin binding by human umbilical vein endothelial cells: effects of exogenous heparin.

Human umbilical vein endothelial cells cultured in growth media that did not contain exogenous heparin were found to grow less well while binding significantly more antithrombin (AT) than comparable cells cultured in growth media that did contain exogenous heparin (90 micrograms/ml). The binding of AT to plasma membranes of cultured endothelial cells was measured immunologically by flow cytometry. This binding was eliminated completely by reacting the cells with heparinase III before incubating them with AT, indicating that the most likely heparinase-sensitive process responsible for AT binding to plasma membranes was heparan sulfate proteoglycan. Increased AT binding also was promoted by addition of heparin-binding molecules (protamine, AT, or ECGF) to growth media, and the effects of other glycosaminoglycans and dextran on AT binding were found to be dependent on their sulfation. Thus, one response of endothelial cells to heparin deficiency is up-regulation of the ability to bind AT to plasma membranes.

Antithrombins↗
PubMed1995

Heparan-dependent endothelial antithrombin binding is increased by butyrate.

Heparin biosynthesis involves a critical early step of N-deacetylation which is inhibited by the short chain fatty acid n-butyrate. Such inhibition causes mast cells to produce heparins with high affinity for antithrombin (AT). We have cultured endothelial cells in media supplemented with short chain fatty acids and have found that isobutyric, propionic and valeric acids cause significant increases in endothelial binding of AT measured by flow cytometry, but n-butyric acid was the most effective fatty acid to increase AT binding. Such binding,was heparan sulfate-dependent, for it was decreased significantly by pre-treatment of the cells with heparinase. These findings suggest that inhibition of N-deacetylation in heparan biosynthesis affects sulfation and results in the distribution of negative charges and conformation changes within the heparan domain that binds AT to endothelial plasma membranes. These changes also were associated with up-regulation of the intercellular adhesion molecule-1, which is a marker of endothelial activation.

Anticoagulants↗
PubMed1995

Effects of antithrombin III (AT III) and Trp49-modified AT III on plasma level of 6-keto-PGF1 alpha in rats.

We evaluated the effect of antithrombin III (AT III) on the plasma level of 6-keto-PGF1 alpha in rats to determine whether AT III may promote the release of prostacyclin (PGl2) from endothelial cells in vivo. The intravenous administration of AT III (250 U/kg) significantly increased the plasma levels of 6-keto-PGF1 alpha, with a peak seen 90 min post-administration. Neither Trp49-modified AT III, which lacks affinity for heparin but retains an inhibitory capacity for thrombin, nor heparin plus AT III, increased the plasma level of 6-keto-PGF1 alpha 90 min after administration. Indomethacin pretreatment inhibited the increase in plasma levels of 6-keto-PGF1 alpha produced by AT III. Observations suggest that AT III may promote the release of PGl2 from endothelial cells by interacting with heparin-like glycosaminoglycans in vivo, consistent with previous observations in cultured endothelial cells.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Effects of low molecular weight heparin on a severely antithrombin III-decreased disseminated intravascular coagulation model in rabbits.

The effect of dalteparin, a low molecular weight heparin, on severely antithrombin III (ATIII)-decreased disseminated intravascular coagulation (DIC) model was compared with that of unfractionated heparin (heparin). The DIC model in rabbits was produced by continuous infusion of thrombin in combination with bolus injection of latex. After a 3 hr infusion of thrombin, plasma ATIII activity was lowered to 30% of normal plasma. Platelet number, fibrinogen content and alpha 2 plasmin inhibitor (alpha 2PI) activity were also decreased. Dalteparin (25-100 IU/kg/hr) and heparin (25-100 U/kg/hr) inhibited the decrease in ATIII activity, platelet number and fibrinogen content, and had no effect on alpha 2PI activity. Activated partial thromboplastin time (APTT) was prolonged by heparin (50 and 100 U/kg/hr), but not by dalteparin (25-100 IU/kg/hr). The ratio of anti-factor Xa (F.Xa) activity to anti-thrombin activity for dalteparin (50 IU/kg/hr) was higher than that for heparin (50 U/kg/hr). With the addition of exogenous ATIII, the ratio of anti-F.Xa to anti-thrombin for heparin increased, but that for dalteparin did not change. However, the increased ratio for heparin was still lower than the unchanged ratio for dalteparin. These results suggest that both dalteparin and heparin have the ability to rectify the abnormal parameters of severely ATIII-decreased DIC, and that the effects of dalteparin are mainly involved with anti-F.Xa activity whereas the effects of heparin are via anti-thrombin activity.

Animals↗
PubMed1996

Experimental haemorrhage and blood component transfusion in humans: no change in plasma concentration of thrombin-antithrombin complex and plasmin-antiplasmin complex.

The influence of haemorrhage and blood transfusion on primary haemostasis, coagulation and fibrinolysis was investigated in ten healthy male volunteers. Acute loss of 10% of the blood volume did not give any significant alteration in thrombin- antithrombin III (TAT) complex and plasmin-alpha 2-antiplasmin (PAP) complex levels compared with a control series. The skin bleeding time with the Simplate II device was not altered after the 10% blood loss. Acute loss of 10% of blood volume followed by transfusion of packed red cells or stored plasma did not resulted in any significant change in bleeding time, TAT and PAP complex levels. It could be concluded that a controlled haemorrhage does not give any detectable changes of the platelet dependent primary haemostasis, blood coagulation and fibrinolysis. Transfusion of one unit of packed red cells or stored plasma does not seem to adversely affect the haemostasis.

Adult↗
PubMed1983

Affinity of purified thrombin or antithrombin III for two insoluble anticoagulant polystyrene derivatives: I. In vitro adsorption studies.

In previous papers, we described insoluble polystyrene derivatives which exhibit a heparin-like antithrombic activity in plasma. In order to ascertain the heparin-like mechanism of this activity we have studied the interactions of thrombin and antithrombin III with two polymers of this series: sulphonated polystyrene and sulphonate-glutamic acid sulphonamide polystyrene. The adsorption was measured using purified enzyme and enzyme inhibitor and polymer beads whose average diameter was about 25 micron. The maxima of adsorption approximately correspond to a monolayer of protein. The results are discussed with respect to the most common isotherms used in chemisorption and the affinities of the enzyme and its inhibitor for both materials are evaluated: kT congruent to 10(7) (M/I)-1, kAT congruent to 3.10(5) (M/I)-1.

Adsorption↗
PubMed1984

Interaction of antithrombin III with preadsorbed albumin-heparin conjugates.

The adsorption of antithrombin III (AT III) onto polystyrene surfaces preadsorbed with albumin or albumin-heparin conjugates was studied using a two step enzyme immuno assay. When AT III-buffer solutions were used, the highest adsorption values were measured on high affinity albumin-heparin conjugate pretreated surfaces. Less AT III adsorption was found on nonfractionated albumin-heparin conjugate preadsorbed surfaces. AT III adsorption could also be detected on low affinity conjugate and albumin coated surfaces. When AT III was adsorbed from plasma or plasma dilutions with buffer, only AT III on surfaces preadsorbed with high affinity or nonfractionated albumin-heparin conjugate was found. These results demonstrate that the heparin moiety of the conjugate is directed to the solution phase whereas the albumin moiety contacts the polystyrene surface.

Adsorption↗
PubMed1988

Control and isotopic quantification of affinity of antithrombin III for heparin-like surfaces.

Heparin-like materials, characterized by a defined superficial density of functional groups which activate antithrombin III (AT III), when in contact with blood specifically inhibit thrombin as soon as it appears. This paper describes an isotopic method to estimate this density and to visualize the distribution of the affinity sites concerned, both directly with AT III labelled with 125Iodine and indirectly with an anti AT III monoclonal antibody labelled with 111Indium.

Adsorption↗
PubMed1988

Heparin-like tubings. II. Mechanism of the thrombin-antithrombin III reaction at the surface.

In a previous paper we described the surface treatment of tubings made of polystyrene grafted by irradiation onto polyethylene tubular materials. As a result, polystyrene moieties of their inner face were substituted by sulphonate and aspartic acid sulphamide groups. In order to study the mechanism of the thrombin-antithrombin III reaction occurring at the modified surface and to determine the kinetics of the reaction, step by step experiments were set up involving either the protease adsorbed at the surface reacting with the antiprotease circulating in the solution or the opposite. These procedures allowed us to demonstrate the heparin-like catalytic activity of the tubings.

Adsorption↗
PubMed1992

Sequence characterization of a sheep cDNA for antithrombin III.

We determined the cDNA sequence of the mRNA for antithrombin III (AT III) from sheep liver. It encodes a protein of 465 amino acids, including a signal peptide of 32 amino acids. The amino acid sequence of the mature protein shows a sequence identity of 89.1%, 95.6% and 85.0% to the human, bovine and rabbit equivalents, respectively. Cysteine residues involved in disulfide bonds as well as potential glycosylation sites are conserved between the four species. In contrast, the amino acid sequence of the signal peptide shows a smaller identity, i.e., 68.7% and 56.3% compared to the human and rabbit preprotein, respectively.

Amino Acid Sequence↗
PubMed1988

Design, synthesis and antithrombin activity for conformationally restricted analogs of peptide anticoagulants based on the C-terminal region of the leech peptide, hirudin.

Synthetic peptides cyclized via disulfide linkages have been synthesized as conformationally restricted analogs of a novel class of antithrombotic peptides that inhibit fibrinogen cleavage by binding to a non-enzymatic site on thrombin. Several conformational models for these inhibitors have been considered and cyclic analogs were synthesized to test their validity. Compounds designed on an alpha-helical model yielded several cyclic analogs that retained antithrombin activity. [D-Cys58, Cys61]-hirudin54-65, 5, and [D-Cys60, Cys63]-hirudin54-65, 6, had IC50 values of 26 and 30 microM, respectively, in an in vitro clot assay compared with a value of 3.7 microM for the linear hirudin54-65.

Amino Acid Sequence↗