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PubMed1991

Novel point mutations leading to type 1 antithrombin deficiency and thrombosis.

Direct sequencing of antithrombin III (AT) gene fragments specifically amplified by the polymerase chain reaction was utilized to identify the molecular basis of type 1 AT deficiency in two unrelated kindreds, both with thrombotic disease. Two novel point mutations were identified, deletion of a T from the second position of codon 81 in one propositus and insertion of a G in codon 424 in the second kindred. The AT 81(-T) frameshift mutation leads to a premature stop signal in codon 89, while the AT 424(+G) allele has a premature stop only one codon short of the normal gene. The latter mutation changes the eight carboxy terminal residues of AT, including 429Cys, and increases the proportion of polar amino acids in this region. We suggest that altered folding of the mutant protein may explain the AT deficiency.

Adult↗
PubMed1991

Molecular basis for hereditary antithrombin III quantitative deficiencies: a stop codon in exon IIIa and a frameshift in exon VI.

Antithrombin III (AT III) is an inhibitor of serine protease (serpin) comprising 432 amino acids. Quantitative AT III deficiencies are associated with a high risk of thrombotic disease. Although this risk is smaller in patients with qualitative AT III deficiencies, the molecular defects characterizing the latter have been the subject of many studies. However, in quantitative AT III deficiencies, only three mutations have been described: Pro 407 to Leu and A1a404 to Thr (both located in the C-terminal part of the AT III molecule) and also a frameshift in exon IIIa. Using the asymmetric polymerase chain reaction (PCR) and genomic DNA analysis by direct sequencing, we detected two mutations in three unrelated families: (i) a C----T transition in exon IIIa in two families, leading to the replacement of the codon corresponding to Arg 129 by a stop codon, and (ii) in the third family, insertion of an adenine in the codon corresponding to Phe 408, a highly conserved serpin amino acid. This insertion altered the reading frame and led to the appearance of a premature stop signal. Patients of all three families were heterozygous for their abnormality. These results show that asymmetric PCR and genomic DNA analysis by direct sequencing permit fast identification of the molecular basis of quantitative AT III deficiencies. It is concluded that in many cases the absence of AT III gene product probably results from point mutation, as previously observed for another serpin, alpha-1-antitrypsin.

Adolescent↗
PubMed2006

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study.

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.

Adolescent↗
PubMed1990

Sensitivity of the thrombin clotting time and activated partial thromboplastin time to low level of antithrombin III during heparin therapy.

The thrombin clotting time (TCT) has been used at our institution, along with the activated partial thromboplastin time (aPTT), for monitoring heparin therapy. We have observed that, in some patients, a discrepancy develops between the heparin levels predicted by the TCT and the aPTT with the TCT consistently predicting a lower heparin level than the aPTT. An inverse relationship was noted between the functional antithrombin III (AT-III) level and the magnitude of this discrepancy.

Antithrombin III↗
PubMed1985

A pasteurized antithrombin III concentrate for clinical use.

A method for large-scale production of a pasteurized antithrombin III (AT III) concentrate for therapeutic use has been adapted from published methods. It includes the following steps: (1) batchwise adsorption onto heparin-Sepharose from plasma depleted of cryoprecipitate and prothrombin complex; (2) chromatographic elution at high salt concentration; (3) pasteurization for 10 h at 60 degrees C in the presence of added citrate ion; (4) desalting on Sephadex G-25, and (5) sterile filtration and freeze-drying. Seven batches prepared in this manner gave a mean yield of 269 U AT III/kg plasma. The product passed all the usual animal safety and pyrogenicity tests and has been used successfully in several courses of treatment of congenital deficiencies.

Adsorption↗
PubMed1987

Clinical use of antithrombin III concentrates.

The biochemical and biological properties of antithrombin III (AT III) and the clinical consequences of a deficiency of this inhibitor are described. Therapy with concentrates of purified AT III has been carried out for about 10 years and the present experience is reviewed. In a relatively small number of patients with congenital AT III deficiency it is necessary, under certain condition to substitute AT III. A considerably more frequent use of AT III concentrates has been made in acquired AT III deficiency, especially in shock and diffuse intravascular coagulation (DIC). This therapy was shown to be promising since the duration of DIC could be considerably shortened and the frequency of fatal events could be significantly diminished. No undesirable side effects of substitution with virus-sterilized AT III concentrates have been hitherto observed.

Antithrombin III↗
PubMed1984

Familial deficiency of antithrombin III: evidence for heterogeneity existing within the family.

An Australian family with familial antithrombin III (AT III) deficiency is described. The deficiency inherited in an autosomal co-dominant manner is characterised by proportionate reduction in antigenically and biologically measured AT III. Some members with AT III deficiency have had major venous thromboses, and the deficiency has possibly been the cause of death in two individuals in the family. Heterogeneity was observed in laboratory and clinical findings in this family.

Adult↗
PubMed2004

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice.

Venous thromboembolic disease is a major cause of morbidity and mortality, necessitating antithrombotic therapy. A human monoclonal anti-factor (F)VIII antibody, LCL-mAb-LE2E9, produced by a lymphoblastoid cell line derived from a hemophilia A patient with inhibitor to wild-type but not mutant self FVIII, was previously reported to achieve efficient inhibition of thrombosis in an experimental vena cava thrombosis model in mice. Here, the antithrombotic efficacy of a recombinant DNA-derived version of this anti-FVIII antibody (rec-mAb-LE2E9) was tested in mice which carry a type II heparin binding site antithrombin deficiency mutation and display spontaneous chronic thrombosis in several sites including the penile vein of sexually active males. The recombinant anti-FVIII antibody (100 microg, repeated after 3 days) prevented thrombotic priapism in all treated males, whereas all control animals treated with saline (group of four animals) developed priapism within 6 days after mating (P < 0.05 for treated vs. saline). The rec-mAb-LE2E9 and the original LCL-mAb-LE2E9 were equally effective (five and seven males/group, respectively). These results confirm that FVIII inhibition represents a potent antithrombotic strategy, and show that both LCL-mAb-LE2E9 and rec-mAb-LE2E9 efficiently prevent thrombosis in a physiological model representative of thrombosis in patients with a severe prothrombotic risk.

Animals↗
PubMed1976

Heparin cofactor activity and antithrombin III concentration in plasma related to age and sex.

Heparin cofactor activity and antithrombin III (At-III) concentration were measured in plasma from 219 healthy men and 177 women. Narrow ranges for heparin cofactor activity and At-III concentration were found. The standard deviation for heparin cofactor activity in men and women was 8.6 and 10.1, respectively, for At-III concentration 10.4 and 12.5. In men, mean heparin cofactor activity and mean At-III concentration decreased significantly with increasing age. In women, mean heparin cofactor activity and mean At-III concentration tended to be lower in fertile age. Hereditary At-III deficiency was detected in one individual.

Adolescent↗
PubMed1980

Familial functional antithrombin III deficiency.

A family with a tendency to thrombosis and decreased antithrombin III (AT III) activity in plasma, but normal immunoreactive AT III is reported. 7 members of the family had the AT III defect, 4 of whom have had thrombotic episodes. The importance of biological determination of AT III when studying patients with recurrent thrombotic episodes is emphasized.

Adult↗
PubMed1996

Aortic thrombosis in a neonate with hereditary antithrombin III deficiency: successful outcome with thrombolytic and replacement treatment.

We report the case of a newborn male who presented an aortic thrombosis during the neonatal period and was subsequently diagnosed as having antithrombin III (AT III) hereditary deficiency type I. This hypercoagulable condition is known to predispose young adults to venous thrombosis, but in our patient the primary thrombotic incident affected the arterial vessels within the first few days of life. Combined treatment with thrombolytic agents and AT III concentrates recovered aortic permeability, suggesting that the use of AT III may be beneficial for the treatment of thrombotic complications during the first few days of life.

Angiography, Digital Subtraction↗
PubMed1992

Antithrombin III deficiency and cerebrovascular accidents in young adults.

A young man with antithrombin III (AT-III) deficiency sustained a cerebellar venous infarct and recovered following treatment with AT-III concentrate. A family study showed that other members were affected. AT-III deficiency in this family was found to be due to a new variant AT-III TRURO 1. Young patients with strokes should be screened for thrombophilia.

Adult↗
PubMed1977

Familial thrombosis due to antithrombin III deficiency in a Greek family.

A Greek family with hereditary antithrombin III (AT III) deficiency associated with venous thrombosis is reported. 5 members of the family were affected. In these patients, AT III and heparin cofactor activities were decreased. Immunoreactive AT III showed a positive correlation to both AT III and heparin cofactor activities. alpha2-Macroglobulin and alpha1-antitrypsin were normal. The pattern of inheritance of the defect is autosomal dominant.

Adult↗
PubMed1977

The anticoagulant effect of heparin + antithrombin III using purified fibrinogen as substrate.

The anticoagulant effect of heparin in test systems composed of purified factors [antithrombin III (AT-III), fibrinogen and thrombin] was studied. As expected, the sensitivity to heparin depended on the concentrations of AT-III and thrombin, whereas the fibrinogen level was less decisive. In addition, qualitative differences proved important. Thus, the sensitivity to heparin was greater with crude bovine thrombin than with highly purified thrombin from the same species. Further, the sensitivity to heparin increased following removal of cold-insoluble material from the fibrinogen preparation. Finally, during storage of purified AT-III at +4 degrees C for more than 4 weeks, the sensitivity to heparin decreased more rapidly than expected from the amidolytic AT-III assays. Smaller amounts of heparin were required to give a prolonged thrombin clotting time than in whole plasma, indicating that components of normal platelet-poor plasma (besides AT-III and fibrinogen) interfere with the anticoagulant effect of heparin. The present test systems may prove suitable for the detection and evaluation of factors of importance for the so-called heparin tolerance.

Animals↗
PubMed1980

Antithrombin III, heparin cofactor and antifactor Xa in relation to age, sex and pathological condition.

Antithrombin III (At-III) activity and protein, heparin cofactor activity, antifactor Xa activity were determined in 200 healthy adults, evenly distributed within age and sex groups, in 60 patients with cerebral thrombosis and in 20 oral contraceptive users. There was a positive correlation between At-III protein and its activities in normal subjects and in patients with cerebral thrombosis. The mean At-III protein and heparin cofactor activity values decreased with age in men and in women of fertile age. The mean values of At-III protein and its activities did not show any variation in the patients with cerebral thrombosis when compared with the normals. In oral contraceptive users a positive correlation was also found between At-III protein and its activities, antifactor Xa activity excepted. The mean antifactor Xa activity value in these women decreased during treatment, whereas the other At-III activities and At-III protein were unchanged.

Adult↗
PubMed1985

Treatment of familial antithrombin-III deficiency with danazol.

3 individuals from 2 unrelated families with recurrent thromboses and quantitative deficiencies of antithrombin III (AT-III) were treated with danazol, 600 mg daily for 4 months. Significant increases of AT-III (p less than 0.025) measured as heparin cofactor activity were noted in 1 female and 1 male patient. Failure to augment levels in the other male patient may have been due to poor absorption of the drug following small bowel resection for mesenteric infarction. Side effects of estrogen deficiency necessitated dosage reduction in the female patient. The 2 males experienced no adverse side effects except for prolongation of the prothrombin time in 1 who was receiving oral anticoagulants. We conclude that danazol causes a significant increase in some individuals with familial AT-III deficiency. Additional studies are necessary to determine whether this form of therapy may prove to be a suitable alternative to long-term anticoagulation and to assess the long-term clinical benefits in individuals with recurrent thrombosis.

Adolescent↗
PubMed1983

Severe acquired antithrombin III deficiency in relation to hepatic and renal insufficiency and intrauterine fetal death in late pregnancy.

Acute fatty liver (AFLP) is a rare complication of late pregnancy. The maternal and fetal mortality has earlier been reported to be about 75%, but during the last decade a reduced mortality to about 30 and 50%, respectively, has been reported in the literature. Disseminated intravascular coagulation (DIC) has been suggested as a contributing cause to the high mortality. The treatment of DIC has long been under debate, and recently the administration of antithrombin III (AT) concentrate in addition to other supportive treatment has been reported successful. This paper presents the survival of 1 patient with severe liver and renal failure indicating AFLP complicated by severe disturbances in blood coagulation and fibrinolysis. The patient was treated with AT concentrate and small doses of heparin, blood coagulation factors, large amounts of glucose intravenously and supportive intensive care. The pregnancy was terminated by cesarean section. The child was stillborn and 75% of the placental parenchyma was fibrosed.

Acute Kidney Injury↗
PubMed2000

Familial antithrombin-III deficiency during cardiopulmonary bypass: a case report.

The serine protease inhibitor antithrombin-III (AT-III) is the principal in vivo inhibitor of blood coagulation, inactivating mainly thrombin, but also other serine proteases. Binding of AT-III to heparin dramatically increases its inhibitory effect. AT-III deficiency during cardiopulmonary bypass (CPB) can lead to insufficient anticoagulation which cannot be treated by higher doses of heparin. A 60-year-old male with familial AT-III deficiency was admitted to our hospital for coronary artery bypass surgery and aortic valve replacement. Four days before the operation, acenocoumarol was stopped and anti-Xa nadroparincalcium (Fraxiparine) was started. AT-III activity at that time was 56%. Two hours before the operation, a single dose of 4500 IU AT-III concentrate was administered. Heparinization was performed with 400 IU/kg of porcine mucosal heparin, increasing the activated coagulation time (ACT) from a baseline of 115 to 549 s. AT-III activity at that time was above 100% and the plasma D-dimer concentration was 230 ng/l. ACTs during CPB remained above 999 s, whereas the AT-III activity dropped to 54% and the D-dimer increased up to 500 ng/l at the end of CPB. CPB was terminated uneventfully. Heparin was reversed with 3 mg/kg protamine chloride, decreasing the ACT to 155 s. In the intensive care unit (ICU), the patientreceived prophylactic Fraxiparine and 1500 IU AT-III, increasing the AT-III activity to 84%. Postoperatively, there was continued blood loss, which necessitated the administration of whole blood and eventually re-exploration. The case presented illustrates an uneventful treatment of a patient with a hereditary AT-III deficiency undergoing CPB. In spite of an uneventful treatment with AT-III pre-CPB, administration of prophylactic AT-III concentrate after surgery should be considered with caution, as this might increase the postoperative morbidity.

Animals↗