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PubMed1995

[Changes in antithrombin III, prothrombin fragment 1 + 2 and thrombin-antithrombin III complex following implantation of a coronary Palmaz-Schatz stent].

To detect changes in the clotting parameters antithrombin III (AT III), prothrombin-fragment 1 + 2 (F 1 + 2) and thrombin-antithrombin-III-complex (TAT) after implantation of Palmaz Schatz stents, coagulation was monitored at standardized time points in 35 patients for 10 days. All patients were anticoagulated using a combination of heparin, phenprocoumon, and acetyl salicylic acid. Heparin therapy was guided by APTT levels (normal range 25-35 s), which were still within the therapeutic range (median 49.6 s (25%/75% percentiles 41.6/54.4) on day 10. Simultaneous oral anticoagulation was found to be effective on day 8 on average (INR median 2.24 (1.93/2.50)). The AT III activity dropped significantly (p < 0.0001) after a heparin loading dose of 15,000 IU during stenting. As the heparin dose was reduced on the following days, AT III levels increased significantly (p < 0.0001) during the observation time. There was a highly significant (p < 0.001) negative correlation between AT III and heparin levels. On days 4 and 5 F 1 + 2 values were significantly (p < 0.001 and p < 0.05) higher than on the day of stenting (median 1.07 (0.90/1.31) 1.13 nmol/l and 1.06 (0.85/1.23) nmol/l vs. 0.97 (0.69/1.15) nmol/l) and dropped during anticoagulation. F 1 + 2 levels showed a significant negative correlation (p < 0.0005) with APTT values. TAT values showed no significant changes during the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1989

Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate.

Antithrombin III (ATIII) is the predominant naturally occurring inhibitor of serine proteases generated during blood coagulation [Rosenberg RD: Annu Rev Med 1978; 29: 367-378]. Since 1965, several assays have been developed that allow rapid and precise determination of ATIII in plasma. As a consequence, the existence of acquired ATIII deficiency in many pathologic conditions has been described. Acquired ATIII deficiency is based on decreased synthesis, increased loss or increased consumption, or induced by drugs. An inherited ATIII deficiency is associated with a lifelong tendency to venous thromboembolism. In contrast, the clinical significance of acquired ATIII deficiency has been less well defined. A precise estimate of the risk of thromboembolism in the acquired ATIII deficiency state cannot easily be provided, owing to the lack of studies in consecutive patients. In 1978, a purified human ATIII concentrate became available for clinical investigation. Despite numerous small studies, the value of ATIII replacement therapy in patients with acquired deficiency remains to be demonstrated.

Antithrombin III↗

PubMed1985

Comparison between the effect of pentosan polysulphate heparin and antithrombin III injections in antithrombin III deficient patients.

Pentosan polysulphate is an heparin analogue which acts via an antithrombin III (AT III) independent pathway. We compared the effect of this drug to that of heparin and AT III infusions in AT III deficient patients. Four patients with AT III congenital deficiency received on three different occasions: (i) an infusion of human AT III concentrate (20 U/kg or 40 U/kg), (ii) an intramuscular injection of pentosan polysulphate (2 mg/kg), (iii) a subcutaneous calcium heparin injection (100 U/kg). AT III infusion inhibits the excessive thrombin generation (46% of inhibition) observed in the plasma of AT III deficient patients during at least 12 hours, but does not modify the factor Xa formation. On the contrary, pentosan polysulphate has a marked effect on both thrombin (62% of inhibition) and factor Xa generation (57% of inhibition) still present 8 hours after injection. Heparin injection has the same effect, more prolonged, as pentosan polysulphate on thrombin generation but is not so effective on impairing factor Xa generation (27% of inhibition). The marked effect of pentosan polysulphate on thrombin and factor Xa generation in these patients is due to its AT III independent mechanism of action.

Antithrombin III↗

PubMed1990

Elimination of antithrombin III concentrate in healthy pregnant and preeclamptic women with an acquired antithrombin III deficiency.

The activity elimination half-life of heat-treated antithrombin III (AT III) concentrate was studied in 5 healthy pregnant and 5 preeclamptic women with a documented AT III deficiency. Healthy pregnant women received 1500 units over 20 minutes. Serial blood specimens were obtained over the next 12 hours. The mean (+/- SEM) activity elimination half-life of AT III was 29.4h +/- 3.4h. Preeclamptic subjects had a mean baseline AT III activity of 70.5 +/- 2% (range 61 to 75%). Their activity eliminator half-life after 3000 units of AT III concentrate was 8.5 +/- 1.2h. There was a direct relationship between the pre-concentrate AT III activity level and the AT III activity elimination half-life (r = 0.79, p = 0.01) for all subjects. Based upon parameters calculated from the first infusion, the AT III activity of preeclamptic subjects was maintained by a constant infusion at approximately 100% for 96h. At the conclusion of the infusion, the activity elimination half-life was again measured. A dramatic increase in the activity elimination half-life was demonstrated (433.6h). We conclude that the activity elimination half-life of AT III concentrate is increased during normal pregnancy and further increased in preeclamptic women with an acquired deficiency.

Antithrombin III↗

PubMed1992

The antithrombin III gene polymorphism in Japan: examination for haplotypes relevant to disordered antithrombin III biosynthesis.

In the human antithrombin III (AT III) gene of Caucasian, two restriction fragment length polymorphism (RFLPs) have been identified and used for the linkage analysis of many congenital AT III abnormality and deficiency. In the present study, we attempted to examine the existence and distribution of these RFLPs in Japanese and utilize them for the molecular survey of the members in the AT III Toyama kindred and 4 type Ia deficient families. An AT III cDNA clone was isolated by ourselves and served as a hybridization probe. In Japanese, the intragenic polymorphism, which is referred to + and - alleles, was evenly distributed (.49: .51), and the 5'-length polymorphism, designated as S and F alleles, was also conserved at a ratio of .4 to .6. However, the combined genotypes of both polymorphisms revealed disproportionate, and + and S, and - and F alleles seemed mainly to coexist. AT III genes of the AT III Toyama kindred showed the homozygous genotype of -/F, and all affected members of the deficient families demonstrated no distinguishable alterations on Southern blots, suggesting that a subtle defect in the AT III gene or the "trans-acting" disordered mechanism is responsible for the decreased AT III levels. According to some reports that a defective AT III gene is the cause of inherited AT III deficiency, it was implied that the abnormal AT III gene was located on the haplotype of -/F in 3 families and +/F in one. In two deficient families with heterozygous genotypes, the RFLPs were considered to bring a clue to determine the structural changes.

Alleles↗

PubMed1995

Use of antithrombin III concentrates to correct antithrombin III deficiency during vascular surgery.

Congenital deficiency of antithrombin III (AT III) is the only inherited hypercoagulable disorder for which a concentrate of purified protein is available for replacement therapy during periods of increased thrombotic risk. This report describes how such concentrates have been used in a patient with congenital AT-III deficiency undergoing venous surgery. A 40-year-old woman with AT III deficiency was evaluated for bilateral grade 3 chronic venous insufficiency. Noninvasive venous assessment and ascending venography revealed incompetence of the lower leg perforators, a patent deep venous system, and competent greater and lesser saphenous veins. Staged subfascial ligations were performed. Pasteurized AT III was administered 1 hour before surgery and at 30 hours at a dose calculated to increase AT-III activity to at least 120%. Perioperative AT III activity levels were measured. Subcutaneous heparin and oral warfarin were initiated the evening of surgery. An infusion of AT III increased plasma AT III from the baseline activity of 51% to 180%; it was 87% 13 hours later. Two measurements of the initial half-life of AT III were 7 and 14 hours. No perioperative thrombotic complications occurred. The ulcers healed, and the patient remains symptom free. Pasteurized AT III concentrates are now commercially available, easily administered, and provide a useful adjunct to the anticoagulation regimen of patients with AT III deficiency undergoing vascular surgery.

Adult↗

PubMed1993

Heparin binding affinity of normal and genetically modified antithrombin III measured using a monoclonal antibody to the heparin binding site of antithrombin III.

The inhibitory activity of the plasma serine proteinase inhibitor antithrombin III (AT III) is enhanced about 1000-fold upon binding to heparin. We have determined the dissociation constants, Kd, of 48.8 nM for the heparin-AT III interaction, of 175 nM for the specific pentasaccharide-AT III interaction, and of 13 microM for the low-affinity heparin-AT III interaction, using a binding assay based on a monoclonal antibody (MAb) that recognizes an epitope at or close to the heparin binding site of AT III. The heparin binding affinities and proportions of normal and variant AT III in plasma from patients with mutations of AT III have been quantitated for the first time using the binding assay. Substitution mutations in three regions of AT III have been investigated: (i) mutations in the reactive site loop affecting Ala382, Arg393, and Ser394 have no discernible effect on heparin binding; (ii) mutations in the previously identified N-terminal heparin binding region, affecting Arg47, Leu99, and Arg129, produce variant AT III molecules with heparin affinities reduced 11-924-fold, the largest reduction being observed for the substitution mutation Arg47-Cys in Padua 2, which has an affinity of 65.6 microM; (iii) mutations in the hydrophobic regions around strand 1C of the C terminus, affecting Phe402, Ala404, Asn405, Pro407, and Pro429, have pleiotropic effects that include the production of reduced amounts of low-affinity AT III with dissociation constants from 6 to 43 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

PubMed2002

Intracellular accumulation of antithrombin Morioka (C95R), a novel mutation causing type I antithrombin deficiency.

Antithrombin (AT) is a major plasma protease inhibitor with three intramolecular disulfide bonds, and its deficiency is associated with increased venous thrombosis. Recently, we found a novel missense mutation named AT Morioka (C95R), which causes the loss of one of the three disulfide bonds. In this study, we prepared Chinese hamster ovary cells stably overexpressing wild type or mutant AT and examined the intracellular fate of the ATs. In pulse-chase experiments, newly synthesized wild type AT was secreted into the medium with a half-life of approximately 1.5 h. In contrast, most of the mutant type AT was not secreted during the chase period of 9 h and, surprisingly, was not degraded in the cells. The kinetics of the secretion suggests that the mutant was secreted about 50 times more slowly into the medium. Most of the mutant AT in the cells had high mannose type oligosaccharides, suggesting that it was retained in the endoplasmic reticulum (ER). In addition, half of the mutant AT existed in a dimeric form with an intermolecular disulfide bond. On immunoelectron microscopy, the mutant AT was found to have accumulated in variously sized structures surrounded by a single membrane in the cytoplasm. Immunogold particles exhibiting calnexin immunoreactivity were detected on the membranes. Ribosomes were attached to some of the small structures that had accumulated the mutant AT. Further, we prepared Chinese hamster ovary cells stably overexpressing another mutant AT in which two cysteine residues at 21 and 95, responsible for disulfide bond formation, were substituted for arginines. In pulse-chase experiments, the mutant AT (C21C,C95R) was secreted faster than that of AT Morioka (C95R) into the medium. These results suggest that AT Morioka remained for a long time in ER without being degraded and accumulated in newly formed membrane structures derived from the ER. The dimerization of AT Morioka (C95R) through Cys-21 seems to be critical for its intracellular accumulation.

Amino Acid Substitution↗

PubMed1994

Antithrombin III replacement in animal models of acquired antithrombin III deficiency.

Plasma antithrombin III (AT III) levels decrease early during Gram-negative septicaemia, and even a moderate decrease in this major inhibitor of the coagulation system is associated with serious disseminated intravascular coagulation (DIC). This study reports the efficacy of high dose (at least 250 units/kg) AT III replacement in three animal models of Escherichia coli endotoxaemia or bacteraemia. Highlights of our findings are: 1. Endotoxaemic rat model: DIC occurs early, before the appearance of deleterious cardiovascular abnormalities; AT III prophylaxis attenuates DIC; and AT III prophylaxis increases permanent survival. 2. Endotoxaemic sheep pulmonary dysfunction model: AT III prophylaxis prevents the typical decrease in arterial oxygen partial pressure and AT III prophylaxis combined with alpha 1-proteinase inhibitor significantly attenuates indices of pulmonary dysfunction. 3. E. coli bacteraemic baboon model: AT III prophylaxis and treatment significantly attenuates indices of DIC and organ damage, and prevents death in an otherwise 100% lethal bacterial challenge. In conclusion, prophylactic treatment with high doses of AT III may be efficacious in disease states of impending DIC such as Gram-negative septicaemia. Data presented herein demonstrate that plasma levels of AT III must be maintained at levels markedly higher than normal to be efficacious in animal models of Gram-negative endotoxaemia or bacteraemia.

Animals↗

PubMed1982

Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin.

The incidence of thromboembolic complications (TE) during pregnancy in women with congenital antithrombin III (AT) deficiency has retrospectively been estimated to be about 70%. 8 women with congenital AT deficiency were studied during 9 pregnancies. Subcutaneous or intravenous heparin in doses to prolong the activated partial thromboplastin time (APTT) was given during pregnancy as prophylaxis or therapeutic treatment. During delivery and abortion the AT level was brought to normal by infusion of AT concentrate and the heparin was reduced or withdrawn. Four pregnancies were uncomplicated with regard to TE and resulted in 4 healthy children. Five pregnancies were terminated by induced or spontaneous abortion. 1 woman had TE during heparin prophylaxis and 2 women had TE before the prophylaxis was started. 1 of the latter suffered from a new TE during continued heparing treatment. Insufficient prolongation of APTT was registered at the time of TE in both women with TE during heparin treatment.

Adult↗

PubMed1981

Antithrombin III concentrate: its catabolism in health and in antithrombin III deficiency.

The catabolism of purified radiolabelled antithrombin III (AT III) concentrate was studied in two normals and two patients with congenital AT III deficiency both alone and combined with warfarin. The radiolabelling with iodine monochloride did not change the quality of the concentrate. The half-life varied between 3.4 and 4.8 days. No difference between normals and patients with congenital deficiency in non-acute stage could be observed in the catabolic parameters; nor was there any influence with warfarin.

Adult↗

PubMed2005

[Study on the molecular mechanism of antithrombin gene C2759T (Leu99Phe) mutation causing antithrombin deficiency].

OBJECTIVE: To study the molecular mechanism of antithrombin (AT) gene C2759T (Leu99Phe) mutation causing AT deficiency. METHODS: A mutated AT cDNA expression plasmid ATM2759 was constructed by mega-primer method. ATM2759 and wild type AT cDNA expression plasmid ATN were transfected into COS7 cells or CHO cells by using Superfect reagent respectively for in vitro expression study and immunofluorescence assay. RESULTS: The antigen levels of AT (AT:Ag) in the cell lysate of ATM2759 transfected COS7 cells and the cell culture supernatant were 174.97% and 35.63% of that of ATN transfected COS7 cells respectively, whereas the AT activity in the cell culture supernatant was 47.73% of the control's. Immunofluorescence analysis showed that the fluorescence intensity was significantly higher in ATM2759 transfected CHO cells than in those transfected with ATN. CONCLUSIONS: Leu99Phe substitution may not affect the binding capacity of AT with heparin. Secretion defect and intracellular accumulation of the mutated AT protein might be the mechanisms of this mutation causing AT deficiency.

Animals↗

PubMed1991

[Clinical and genetic aspects of antithrombin III deficiency and abnormal antithrombin III].

Antithrombin III (AT III) has been confirmed to play an important role as a serine protease inhibitor in the mechanism of blood coagulation, and its deficiency or abnormality is found to cause thromboembolic disorders by reducing the anticoagulant activity. In this paper AT III gene of patient with congenital AT III deficiency, which was suggested to have qualitative abnormality by isoelectric focusing, was investigated. Analysis of the genomic structure by Southern blot hybridization with a cDNA probe (pAT6) revealed no detectable changes indicating any deletions, rearrangements and translocations. Therefore, we focused to analyze the sequence of exon 6 of AT III gene by polymerase chain reaction (PCR) methods followed by direct sequencing analysis. Nucleotide sequencing of exon 6 of AT III gene showed a G to T transitional mutation resulting in the conversion of arginine-406 to methionine coexisted with normal allele which encodes arginine. The mutation is located near the reactive center of AT III molecule, which region has been proved to be highly conserved during the evolution of serine protease inhibitor (serpin) family. From these results, it is concluded that the new type of mutation at amino acid site 407, which is similar to AT III Utah, is important for maintaining the structural and biological function of this inhibitor.

Antithrombin III↗

PubMed1990

[Management with antithrombin III concentrate in a pregnant woman with hereditary antithrombin III deficiency].

Pregnant women with hereditary antithrombin III (AT-III) deficiency are frequently associated with thromboembolic disorders. We have treated a pregnant woman with hereditary AT-III deficiency, who had suffered from thromboembolic disorders at her past three gestations, with AT-III concentrate. Dosage of AT-III concentrate to maintain plasma AT-III activity over 80% was 3,500 units per week during second and third trimesters, but more frequent administration was necessary around delivery. In recent reports, pregnant women with hereditary AT-III deficiency had been treated with heparin or warfarin except for during abortion and delivery, in which time AT-III concentrate was widely utilized. But the use of heparin or warfarin during gestation is occasionally harmful, AT-III concentrate should be chosen for management in pregnancy in women with hereditary AT-III deficiency.

Adult↗

PubMed1990

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group.

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Adult↗

PubMed1987

[Antithrombin III determination in horses. Reference values and acquired antithrombin III deficiency].

Antithrombin III (AT III) determinations were done in healthy and sick horses using the chromogenic substrate Chromozym TH. Reference values for adult horses at 25 degrees C were 18-25 IU AT III per ml plasma and 84-118% AT III activity of normal horse plasma, respectively. Precision and accuracy were good (intra assay coefficient of variation less than 2%, accuracy 10%). Surgical operations on healthy horses led to a biphasic decrease in AT III activity touching the lower border of the reference values on the second postoperative day. Other reasons for acquired AT III deficiencies included disseminated intravascular coagulation (DIC), liver disease and glomerulonephritis. Using follow-up studies, differences in the dynamics of acquired AT III deficiency and coagulation promoting factors were demonstrated. 12 of 35 horses with decreased AT III values suffered from phlebothrombosis of the jugular veins. It was presumed that acquired AT III deficiencies promote development and progression of phlebothrombosis/thrombophlebitis in horses.

Animals↗

PubMed1994

Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis.

Inherited type 1 antithrombin (AT) III deficiency is characterized by a decrease of immunoreactive and functional protein levels to about 50%. The disorder is associated with a significantly increased risk of thromboembolism. We have investigated the molecular basis of type 1 AT deficiency in a Belgian family. The diagnosis of the disease was primarily made in a newborn girl with unusually severe thrombotic complications. Using the polymerase chain reaction and single-strand conformation polymorphism analysis, followed by direct sequencing of AT gene fragments, we identified a novel point mutation in exon 6. We detected a G to C substitution in the first position of codon 424 leading to a glycine to arginine substitution. The modification at this highly conserved position in the serine protease inhibitor gene family probably leads to an unstable mutant-gene product. The mutation creates a unique restriction site for the enzyme Hha I in exon 6. This change permitted a rapid and accurate screening of the kindred with identification of the molecular defect in five other family members.

Adult↗

PubMed1993

An antithrombin III assay based on factor Xa inhibition provides a more reliable test to identify congenital antithrombin III deficiency than an assay based on thrombin inhibition.

OBJECTIVES: To determine whether functional antithrombin III (AT-III) levels measured by a factor Xa inhibition (AT-III-Xa) assay identifies AT-III deficient individuals more reliably than functional AT-III levels measured by a thrombin inhibition (AT-III-IIa) assay. STUDY DESIGN: Cross-sectional study. PATIENT POPULATION: Sixty-seven members of a large family with type 2 AT-III deficiency. INTERVENTION: DNA analysis was used as the reference diagnostic standard for AT-III status and subjects were classified as AT-III deficient or non deficient according to these results. Functional AT-III levels were measured in all subjects using: 1) a chromogenic substrate for thrombin and added human thrombin (AT-III-IIa), and 2) a chromogenic substrate for factor Xa and added bovine factor Xa (AT-III-Xa). Functional heparin cofactor II (HC-II) levels were measured using a commercially available kit. The proportions of 125I-alpha-thrombin complexed to AT-III and HC-II were measured by polyacrylamide gel electrophoresis and autoradiography. RESULTS: Thirty-one (46%) individuals were classified as AT-III deficient and 36 (54%) as AT-III non deficient. AT-III-Xa assay measured a significantly lower mean AT-III value and a narrower range for individuals classified as AT-III deficient than the AT-III-IIa assay. Using the AT-III-IIa assay, six subjects had borderline AT-III levels compared to none with the AT-III-Xa assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗