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PubMed2002

Secretion of antithrombin is converted from nonpolarized to apical by exchanging its amino terminus for that of apically secreted family members.

The three members of the serpin family, corticosteroid binding globulin, alpha1-antitrypsin, and C1 inhibitor are secreted apically from Madin-Darby canine kidney (MDCK) cells, whereas two homologous family members, antithrombin and plasminogen activator inhibitor-1, are secreted in a nonpolarized fashion. cDNAs coding for chimeras composed of complementary portions of an apically targeted serpin and a nonsorted serpin were generated, expressed in MDCK cells, and the ratio between apical and basolateral secretion was analyzed. These experiments identified an amino-terminal sequence of corticosteroid binding globulin (residues 1-19) that is sufficient to direct a chimera with antithrombin mainly to the apical side. A deletion/mutagenesis analysis showed that no individual amino acid is absolutely required for the apical targeting ability of amino acids 1-30 of corticosteroid binding globulin. The corresponding amino-terminal sequences of alpha1-antitrypsin and C1 inhibitor were also sufficient to confer apical sorting. Based on our results we suggest that the apical targeting ability is encoded in the conformation of the protein.

Amino Acid Sequence↗

PubMed2002

Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1.

Heparan sulfate 3-O-sulfotransferase transfers sulfate to the 3-OH position of a glucosamine residue of heparan sulfate (HS) to form 3-O-sulfated HS. The 3-O-sulfated glucosamine residue contributes to two important biological functions of HS: binding to antithrombin and thereby carrying anticoagulant activity, and binding to herpes simplex viral envelope glycoprotein D to serve as an entry receptor for herpes simplex virus 1. A total of five HS 3-O-sulfotransferase isoforms were reported previously. Here we report the isolation and characterization of a novel HS 3-O-sulfotransferase isoform, designated as HS 3-O-sulfotransferase isoform 5 (3-OST-5). 3-OST-5 cDNA was isolated from a human placenta cDNA library and expressed in COS-7 cells. The disaccharide analysis of 3-OST-5-modified HS revealed that 3-OST-5 generated at least three 3-O-sulfated disaccharides as follows: IdoUA2S-AnMan3S, GlcUA-AnMan3S6S, and IdoUA2S-AnMan3S6S. Transfection of the plasmid expressing 3-OST-5 rendered wild type Chinese hamster ovary cells susceptible to the infection by herpes simplex virus 1, suggesting that 3-OST-5-modified HS serves as an entry receptor for herpes simplex virus 1. In addition, 3-OST-5-modified HS bound to herpes simplex viral envelope protein glycoprotein D. Furthermore, we found that 3-OST-5-modified HS also bound to antithrombin, suggesting that 3-OST-5 also produces anticoagulant HS. In summary, our results indicate that a new member of 3-OST family generates both anticoagulant HS and an entry receptor for herpes simplex virus 1. These results provide a new insight regarding the mechanism for the biosynthesis of biologically active HS.

Animals↗

PubMed2002

Purification of a modified form of bovine antithrombin III as an HIV-1 CD8+ T-cell antiviral factor.

CD8(+) T-cells secrete soluble factor(s) capable of inhibiting both R5- and X4-tropic strains of human immunodeficiency virus type 1 (HIV-1). CCR5 chemokine ligands, released from activated CD8(+) T-cells, contribute to the antiviral activity of these cells. These CC-chemokines, however, do not account for all CD8(+) T-cell antiviral factor(s) (CAF) released from these cells, particularly because the elusive CAF can inhibit the replication of X4 HIV-1 strains that use CXCR4 and not CCR5 as a coreceptor. Here we demonstrate that activated CD8(+) T-cells of HIV-1-seropositive individuals modify serum bovine antithrombin III into an HIV-1 inhibitory factor capable of suppressing the replication of X4 HIV-1. These data indicate that antithrombin III may play a role in the progression of HIV-1 disease.

Animals↗

PubMed2003

Antithrombin III phenylalanines 122 and 121 contribute to its high affinity for heparin and its conformational activation.

The dissociation equilibrium constant for heparin binding to antithrombin III (ATIII) is a measure of the cofactor's binding to and activation of the proteinase inhibitor, and its salt dependence indicates that ionic and non-ionic interactions contribute approximately 40 and approximately 60% of the binding free energy, respectively. We now report that phenylalanines 121 and 122 (Phe-121 and Phe-122) together contribute 43% of the total binding free energy and 77% of the energy of non-ionic binding interactions. The large contribution of these hydrophobic residues to the binding energy is mediated not by direct interactions with heparin, but indirectly, through contacts between their phenyl rings and the non-polar stems of positively charged heparin binding residues, whose terminal amino and guanidinium groups are thereby organized to form extensive and specific ionic and non-ionic contacts with the pentasaccharide. Investigation of the kinetics of heparin binding demonstrated that Phe-122 is critical for promoting a normal rate of conformational change and stabilizing AT*H, the high affinity-activated binary complex. Kinetic and structural considerations suggest that Phe-122 and Lys-114 act cooperatively through non-ionic interactions to promote P-helix formation and ATIII binding to the pentasaccharide. In summary, although hydrophobic residues Phe-122 and Phe-121 make minimal contact with the pentasaccharide, they play a critical role in heparin binding and activation of antithrombin by coordinating the P-helix-mediated conformational change and organizing an extensive network of ionic and non-ionic interactions between positively charged heparin binding site residues and the cofactor.

Antithrombin III↗

PubMed1976

A simple amidolytic method for the determination of functional active antithrombin III.

A simple amidolytic method for the determination of the concentration of functionally active antithrombin III is described. Plasma is diluted with buffer containing EDTA and Polybrene. In stage I, diluted plasma is incubated with thrombin. EDTA retards fibrin polymerization, and plasma fibrinogen does not influence the assay. Polybrene makes the assay result independent of heparin. In stage II, remaining thrombin is determined with the chromogenic substrate benzoyl-Phe-Arg-p-NA. The method is simpler and has a higher accuracy than clotting methods. There is a close correlation between the results obtained with this assay and with immunoassay of antithrombin III.

Antithrombins↗

PubMed1989

Effects of high dose medroxyprogesterone acetate treatment on antithrombin III and other plasma proteins in males with renal cell or prostatic carcinoma.

In 18 patients, 12 with renal cell and 6 with prostatic carcinoma treatment with high dose medroxyprogesterone acetate (MPA) significantly increased serum antithrombin III and haptoglobin concentrations. During treatment the proteins correlated with each others suggesting a response to similar regulatory mechanisms. Levels of orosomucoid, a1-antitrypsin, C1-inhibitor and von Willebrand factor did not change during treatment showing that the increase of haptoglobin was not due to an acute-phase response. The increased antithrombin III levels may have a favourable impact on the frequency of thromboembolic complications during treatment with MPA.

Adenocarcinoma↗

PubMed2004

Low-dose oral combination of 17beta-estradiol and norethisterone acetate in postmenopausal women decreases factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1.

OBJECTIVE: Controversies still persist concerning hormone replacement therapy (HRT) and its effects upon blood coagulation and fibrinolysis. This study was carried out to evaluate possible effects of continuously administered low-dose 17beta-estradiol (E2) and norethisterone acetate (NETA) on coagulation and fibrinolytic factors. METHODS: We conducted a randomized double-blind, placebo-controlled, 1-year study in 120 healthy postmenopausal women. The three groups consisted of a placebo group (n = 40), a group receiving oral continuous combined E2 1 mg and NETA 0.25 mg (n = 40) and a group receiving oral continuous combined E2 1 mg and NETA 0.5 mg (n = 40). RESULTS: The two low doses of E2-NETA induced significantly lower plasma levels of factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1 (PAI-1), compared with placebo treatmen CONCLUSIONS: Low-dose E2 (1 mg) in combination with NETA resulted in favorable changes of factor VII activity and fibrinogen, compared with placebo. The lower plasma levels of PAI-1 may lead to increased fibrinolytic activity. These findings suggest a decreased risk of developing coronary heart disease. Antithrombin activity was also reduced, which may increase the risk of developing venous thromboembolism. The clinical significance of the lower levels of these factors remains to be clarified.

Administration, Oral↗

PubMed1991

Monoclonal antibodies against human antithrombin III.

Three monoclonal antibodies identified as D8, B11 and C5 of different specificities have been produced against human antithrombin III (AT). The apparent dissociation constants (Kd app) of the AT-antibody interaction were determined by ELISA method: Kd app (D8) = 2.4 nmole, Kd app (B11) = 13 nmole, Kd app (C5) = 24 nmole. All three antibodies reacted with isolated AT on immunoblots obtained with "native" PAGE. The D8 antibody also reacted with plasma and serum AT while B11 antibody reacted with serum thrombin-antithrombin (TAT) complexes as well.

Animals↗

PubMed1977

Antithrombin III and Factor VIII in patients with neoplasms.

Possible increased activation of the coagulation pathway was measured in a group of patients with neoplastic diseases. In addition to standard tests, the thromboplastin generation test, thrombin generation test and immunologic and coagulant activities of both Factor VIII and antithrombin III were utilized in the evaluation. The correlation between immuno-Factor VIII (VIII-Ag) and its clotting activity (VIII-C1) was good (r = 0.83). In contrast, this was not the situation for antithrombin III-Ag and its clotting activity. Thromboplastin generation was accelerated in 60% and thrombin generation was accelerated in 40% of the patients. Fibrinogen was elevated in half the cases: in most of these patients, thrombin times were slightly prolonged. These results indicate that some patients who have cancer have abnormal clotting patterns and are often in a potentially hypercoagulable state that is reflected by the thromboplastin generation test, thrombin generation test, and high levels of Factor VIII (both VIII-Ag and VIII-C1).

Adolescent↗

PubMed1980

An evaluation of antithrombin III laboratory tests.

Three laboratory tests for the measurement of antithrombin III (AT III) were evaluated. The tests measured functional AT III in serum and plasma, and the third measured AT III antigen in plasma. Normal values for each method were obtained by testing samples from 20 normal subjects. Each test was then performed on specimens from 15 patients clinically suspected of having hypercoagulable states. Each determination was run in duplicate. The hypercoagulable states included disseminated intravascular coagulation, pulmonary embolism, and pregnancy. Two-thirds of these patients were found to have antithrombin III levels below the normal range by all three of the methods studied. Patients who had decreased AT III activity in the functional assays also had decreased AT III antigen.

Adult↗

PubMed1980

Measurement of antithrombin III in normal and pathologic states using chromogenic substrate S-2238. Comparison with immunoelectrophoretic and factor Xa inhibition assays.

Synthetic substrates have recently been developed for the assay of several of the proteolytic enzymes required for blood coagulation, One of these substrates, S-2238, is specific for thrombin and hence can also be used to measure antithrombin-heparin co-factor (AT-III). The thrombin remaining after neutralization by AT-III cleaves a chromophore, p-nitroaniline, from the substrate, which can then te quantified in a spectrophotometer. This new assay for AT-III inhibitory activity was evaluated for normal subjects and for patients who had certain pathologic conditions associated with reduced levels of AT-III. Results from this assay were compared with those from AT-III assays by Laurell immunoelectrophoresis (an immunologic method) and antithrombin inhibition of factor Xa (a biologic clotting method). The chromogenic assay using S-2238 was found to be sensitive, accurate, and easy to perform; its results for both normal subjects and patients correlated extremely well with those of the immunologic and factor Xa inhibition assays (r = 0.94-0.98). Measurement of AT-III using this synthetic substrate should be a valuable addition to routine assays in a clinical coagulation laboratory. These and future substrates may prove extremely useful for assays of factors involved in blood coagulation and fibrinolysis.

Antithrombin III↗

PubMed1980

Clinical laboratory determination of antithrombin III. A new semi-automated method.

A new, semi-automated method for determination of antithrombin III activity in the clinical laboratory is presented. The assay is performed utilizing the chromogenic substrate S-2238 and the ABA-100. Results are expressed in arbitrary units of activity; thus, construction of standard curves with interpolation of values is not necessary. The assay has a low day-to-day coefficient of variation (6%), is insensitive to heparin, and gives reliable results in a variety of clinical situations known to affect antithrombin III activity.

Antithrombin III↗

PubMed1982

Budd-Chiari Syndrome and antithrombin III deficiency.

Presented herein is a case report of a 20-year-old woman with a past history of oral contraceptive use who developed Budd-Chiari syndrome. Onset of her illness was abrupt and stormy, simulating fulminant viral hepatitis or toxic hepatic injury. She died within six months of her initial presentation. Although the patient discontinued the use of oral contraceptives two years prior to the initial presentation of the disease, the morphologic features of the venous thrombosis and hepatic damage were indicative of a chronic, ongoing process of longer than six months' duration, thus raising the possibility of a cause-effect relationship between the "pills" and thrombotic process. Of interest was the finding of persistently depressed antithrombin III levels. While a relationship between oral contraceptive usage, antithrombin III deficiency and the Budd-Chiari syndrome is strongly suggested in this case, prospective studies are needed to substantiate this view.

Adult↗

PubMed1995

Clinical management of unstable angina: the place of antithrombins and platelet GP IIb/IIIa receptor blockers.

Unstable angina is a clinical and anatomic mosaic in which platelet aggregation, thrombus formation and fixed and dynamic coronary artery restrictions play variable and changing roles. Emerging medical and mechanical options to deal with each of these components show promise. GP IIb/IIIa receptor blockade is a significant advance over aspirin as all pathways to platelet aggregation are blocked by the new agents. Whether the new antithrombins represent a major advance over heparin is less clear as prothrombin activation is not blocked and rebound is seen as a result. For these new antiplatelet and antithrombin medications, encouragement is based upon small trials. The initial impressions need to be confirmed in larger trials before the role of these expensive new agents can be defined.

Angina, Unstable↗

PubMed1981

Preparation of biologically active fluorescent heparin composed of fluorescein-labeled species and its behavior to antithrombin III.

A hog-mucosal heparin purified gel-chromatographically (total sulfate, 2.20; N-sulfate, 0.82; N-acetyl, 0.15 (mol/mol HexN); activity, 184 USP units/mg) was partially N-desulfated to give a product (total sulfate, 2.12; N-sulfate, 0.71 (mol/mol HexN); activity, 159 USP units/mg). The free amino groups in the product was extensively labeled with fluoresceinylthiocarbamoyl (FTC) groups, and the labeled product was chromatographed on Octyl-Sepharose CL-4B to give a heparin preparation of fluorescein-labeled species (total sulfate, 2.04; N-sulfate, 0.72; degree of substitution, 0.059 (mol/mol HexN); activity, 155 USP units/mg). The fluorescent heparin thus obtained was indicated from its analytical data to have one FTC group pr heparin molecule irrespective of the molecular weight. The fluorescent heparin was separated into the low-affinity (56.6%) and high-affinity (43.4%) fractions for antithrombin III, and the anticoagulant activities of the two types of fluorescent heparin were compared with those of the starting heparin and the partially N-desulfated heparin, suggesting that FTC-substitution in heparin molecules had no effect on the known biological interaction with mobilized or immobilized antithrombin III.

Animals↗

PubMed1997

Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation.

UNLABELLED: This study was designed to determine if, and to what extent, antithrombin III (AT) levels affect the response of the activated clotting time (ACT) to heparin in concentrations used during cardiac surgery, and to characterize the relationship between AT levels and markers of activation of coagulation during cardiopulmonary bypass (CPB). After informed consent, blood specimens obtained from eight normal volunteers (Phase I) were used to measure the response of the kaolin and celite ACT to heparin after in vitro addition of AT (200 U/dL) and after dilution with AT-deficient plasma to yield AT concentrations of 20, 40, 60, 80, and 100 U/dL. In Phase II, blood specimens collected before the administration of heparin and prior to discontinuation of CPB, were used to measure the response of the kaolin ACT to heparin (preheparin only), AT concentration, and a battery of coagulation assays in 31 patients undergoing repeat or combined cardiac surgical procedures. In Phase I, strong linear relationships were observed between kaolin (slope = 1.04 AT - 2, r2 = 0.78) and celite (slope = 1.36 AT + 6, r2 = 0.77) ACT slopes and AT concentrations below 100 U/dL. In the pre-CPB period of Phase II, only factors V (partial r = -0.49) and VIII (partial r = -0.63) were independently associated with heparin-derived slope using multivariate analysis; an inverse relationship was observed between AT and fibrinopeptide A levels (r = -0.41) at the end of CPB. Our findings indicate that the responsiveness of whole blood (ACT) to heparin at the high concentrations used with CPB is progressively reduced when the AT concentration decreases below 80 U/dL. Because AT is variably, and sometimes extensively, reduced in many patients before and during CPB, AT supplementation in these patients might be useful in reducing excessive thrombin-mediated consumption of labile hemostatic blood components, excessive microvascular bleeding, and transfusion of blood products. IMPLICATIONS: Heparin, a drug with anticoagulant properties, is routinely given to patients undergoing cardiac surgery to prevent clot formation within the cardiopulmonary bypass circuit. However, when levels are reduced, heparin is not as effective. Findings within this study indicate that administration of antithrombin III may help to preserve the hemostatic system during cardiopulmonary bypass.

Anticoagulants↗

PubMed2000

The in vitro effects of antithrombin III on the activated coagulation time in patients on heparin therapy.

UNLABELLED: Heparin requires antithrombin III (AT) to achieve anticoagulation, and patients on continuous small-dose heparin preoperatively experience decreased levels of AT-causing heparin resistance. When this occurs, 2-4 units of fresh frozen plasma ( approximately 1000 units of AT) are often administered to increase AT levels and restore heparin responsiveness. We evaluated purified human AT concentrate (Thrombate III; Bayer, Inc., Elkhart, IN) to restore in vitro anticoagulation responses in patients receiving heparin. Blood samples were obtained from cardiac surgery patients including 22 patients receiving heparin and 21 patients not receiving heparin preoperatively. Heparin was added to blood in final concentrations of 4.1, 5.4, and 6.8 U/mL (equivalent to 300, 400, and 500 U/kg), and kaolin-activated clotting times (ACTs) were determined with and without AT at a final concentration of 0.2 units/mL to mimic fresh frozen plasma administration. The mean duration of preoperative heparin therapy was 4.0 days (range 2-10 days). AT activity was 69% +/- 9% in patients receiving heparin and 92% +/- 8% in patients not receiving heparin (P < 0.01). Heparin >4.1 U/mL failed to further increase ACT values in all patients. Attempts to increase ACT in patients receiving heparin may require supplemental AT administration. Purified AT even in small doses significantly prolongs the ACT response to heparin. IMPLICATIONS: In vitro addition of antithrombin III (0.2 U/mL) to heparinized blood samples (4.1-6.8 units of heparin/mL) from patients on previous heparin therapy increases sensitivity to supplemental heparin as reflected by significantly prolonged activated clotting time.

Aged↗

PubMed2001

Low preoperative antithrombin activity causes reduced response to heparin in adult but not in infant cardiac-surgical patients.

UNLABELLED: We evaluated the interaction of preoperative antithrombin (AT) activity and intraoperative response to heparin in cardiac surgery. Heparin anticoagulation is essential during cardiopulmonary bypass (CPB). Heparin itself has no anticoagulant properties, however it causes a conformational change of the physiologic plasma inhibitor AT that converts this slow-acting serine protease inhibitor into a fast acting one. Thus, adequate AT activity is a prerequisite for sufficient heparin anticoagulation. AT activity is reduced by long-term heparin therapy. This prospective, observational study investigated 1516 consecutive cardiac-surgical patients (1304 patients >1 yr (Group A) and 212 patients < or = 1 yr (Group I)). AT activity was measured the day before surgery by a chromogenic substrate assay. The celite-activated activated clotting time (ACT) was used to guide intraoperative heparin administration. Heparin sensitivity was calculated and the postoperative blood loss and perioperative blood requirement was recorded. Infant patients had significantly less preoperative AT activity compared with older patients: 84 (33)% vs 97 (17)%, median (interquartile range) (P < 0. 05). The subgroup of patients aged <1 mo (n = 64) demonstrated a preoperative AT activity of 56 (27)% as compared with 90 (23)% in infant patients between one month and one year (n = 148). In adult patients, preoperative AT activity depended predominantly on preoperative heparin treatment: 62% of the patients with an AT activity <80% were pretreated with heparin. Five minutes after heparin but before CPB the ACT was 587 (334) s in Group A patients with AT activity > or = 80%, and 516 (232) in patients with AT activity < or = 80% (P < 0.05). The target ACT of 480 s was achieved in 70% of patients with normal AT activity in Group A compared with only 54% of patients with AT activity <80% (P < 0.05). In Group A patients with decreased AT activity, 18% demonstrated an inadequate ACT response-defined as ACT <400 s-to the first bolus injection of heparin. In Group I, preoperative AT activity did not influence the ACT response (ACT 5 min after heparin: 846 [447] s in patients with AT activity > or = 80% vs 1000 [364] s in patients with decreased AT activity). The heparin sensitivity was 2.4 (1.1) s/unit heparin/kg compared with 1.5 (0.8) s/unit heparin/KG in group A (P < 0.05). These results suggest that preoperative diminished AT activity causes reduced response to heparin in adult but not in infant patients. Infant patients demonstrate a higher heparin sensitivity despite lower preoperative AT activity. Measurement of preoperative AT activity identifies adult patients at risk of reduced sensitivity to heparin. IMPLICATIONS: In patients less than one year of age, low antithrombin (AT) activity is caused by the immature coagulation system. Despite low AT activity, these young patients demonstrate a normal or increased response to heparin anticoagulation before cardiopulmonary bypass (CPB). In contrast, in patients older than one year of age and adult patients decreased preoperative AT activity is mainly caused by preoperative heparin therapy and causes insufficient response to heparin anticoagulation with a standard heparin dosage. Measurement of preoperative AT activity identifies patients at risk of inadequate anticoagulation during CPB.

Adolescent↗