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At least 1,423 records · Page 79Linked to original sources
PubMed2006

Antithrombin deficiency and its relationship to severe burns.

Antithrombin (AT) is an important endogenous anticoagulant and exhibits marked anti-inflammatory properties. To evaluate the incidence of AT deficiency in severe burn and its correlation to the variables of the abbreviated burn severity index (ABSI), length of hospital stay (LOS) and mortality we collected data on the substitution of human plasma-derived AT concentrate in 201 consecutive patients suffering from severe burn. One hundred and eight patients (54%) developed AT deficiency during their hospitalisation and, according to our institutional practice, received substitution therapy by continuous infusion to maintain physiological plasma activity (70-120%). The mean administered dose served as a measure of AT deficiency. The percentage of patients in an AT deficient state was highest within the first 5 days after injury. It was 26% on day 1 and between 38% and 41% on days 2-5 and thereafter decreased constantly over time. A multiple regression analysis between the dependent variable mean administered dose of AT concentrate and the independent variables age, total body surface area burned (TBSA), gender, inhalation injury (INHAL), full thickness burn (FTB), LOS and mortality was performed. Age, gender and FTB showed no significant influence on the development of AT deficiency. Increasing TBSA and INHAL clearly increase the risk of developing AT deficiency (p-values 0.0001 and 0.037). The analysis also identified AT deficiency as an independent predictor of LOS and mortality (p-values 0.036 and 0.003). Development of AT deficiency is a frequent event after burn with significant correlation to TBSA and INHAL, increased mortality rates and longer hospital stays.

Anticoagulants↗
PubMed2005

Identification of a novel amino acid deletion mutation and a very rare single nucleotide variant in a Japanese family with type I antithrombin deficiency.

We studied a Japanese family with type I antithrombin (AT) deficiency and identified a novel in-frame deletion mutation (-ATG at nucleotide position of 2771-2773) in the AT gene, which predicted loss of a methionine (Met) at amino acid number of 103. In addition, we found a single base replacement of G to A at nucleotide position of 67 (4 base upstream to the initial codon) in the mutant allele. Since the G67A substitution in the AT gene was very rare, this family was the second case, in which the nucleotide change was transmitted. To elucidate the mechanism of AT deficiency, we transiently expressed wild type and the mutant AT (DeltaM103) in HuH-7 human hepatoma cells and performed pulse-chase studies. The experiments revealed that the mutant AT (DeltaM103) hardly secreted into the medium and underwent partial intracellular degradation. In addition, we performed luciferase reporter assay to examine the effect of G67A substitution on the AT gene expression, and found that the substitution did not reduce the luciferase activity. These results suggested that secretion defect and intracellular degradation of the variant molecule with the deletion of Met 103 were responsible for AT deficiency in this family.

Adult↗
PubMed2001

Antithrombin deficiency in Brazilian patients with venous thrombosis: molecular characterization of a single splice site mutation, an insertion and a de novo point mutation.

The prevalence of antithrombin (AT) deficiency in 342 unselected Brazilian patients with venous thrombosis was 1.16%, which increased to 3% when only patients under the age of 50 or with a familial history of thrombosis were considered. In two patients, a clinical (contraceptive use) or genetic risk factor (factor V Leiden and C677T in the methylene tetrahydrofolate reductase gene [MTHFR]) was identified and corroborated the hypothesis that an interaction of factors accounted for the appearance of thrombosis. However, no risk factor other than AT deficiency was identified in one patient with an important clinical and family history of spontaneous thrombosis. Three mutations were identified in these patients: a G-->A transition in intron 5 at position +1 (5'-->3'), three base insertions corresponding to arginine at position 5383 in exon 3A, and a G-->A transition at 13328, corresponding to an Ala404Thr de novo mutation. The polymorphisms in the genes coding for coagulation factors XII and XIII and fibrinogen normally associated with an increased risk for venous thrombosis were not related to thrombosis in these patients. This is the first study in South America to assess the prevalence of AT deficiency and to report the molecular characterization of the mutations involved.

Adult↗
PubMed1982

[Prevention of thrombosis by Hemoclar. Preliminary results of a test in a patient with antithrombin III deficiency].

We report here preliminary results of a study comparing the effect of Hemoclar and antithrombin III (AT III) in a patient with an AT III congenital deficiency. Both drugs inhibit thrombin generation in the patient's plasma. Unlike AT III, Hemoclar also inhibits factor Xa generation. This led us to propose the use of Hemoclar, which acts via an AT III independent pathway, to prevent thrombosis in A III deficient patients.

Adult↗
PubMed1990

[Hereditary deficiency of antithrombin III, protein C and protein S. A study of 31 patients from 8 unrelated families].

The families of eight unrelated patients were studied with regard to a hereditary deficiency in antithrombin III (ATIII), protein C, or protein S. These deficiencies were recognized in the course of investigations for deep-vein thrombosis (DVT) in the eight patients. A group of 31 individuals (patients and family members), mostly less than 40-year-old was explored. Two cases of AT III deficiency were discovered, as well as 21 of protein C deficiency, and seven of protein S. Ten of the 30 have had recurrent venous thrombosis at the time of bedrest, trauma, surgery, pregnancy, postpartum or during oral contraceptive treatment. Spontaneous DVT occurred in three cases. Seventeen patients had remained asymptomatic till then. Such patients need antithrombotic treatment during surgery or pregnancy. Prophylactic treatment with enoxaparin in one patient (deficiency in protein C) during her second pregnancy is discussed. It seems that low molecular weight heparin may be a safe alternative to unfractionated heparin. Oral anticoagulants are efficient in preventing reoccurring venous thromboembolism in patients with AT III deficiency. The questions of whether oral anticoagulants should be continued in the long-term in patients with protein C or protein S deficiency who have had a DVT, and whether asymptomatic deficient patients should be given any antithrombotic treatment outside circumstances likely to induce a DVT, remain as yet unanswered.

Adolescent↗
PubMed1993

Cerebral vein thrombosis due to hereditary antithrombin III deficiency.

Cerebral vein thrombosis, also called superior sagittal sinus thrombosis, is a well recognized clinical and radiologic entity associated with a variety of medical disorders. We report a patient with fatal cerebral vein thrombosis following myelography, in whom the cause was familial antithrombin III (AT3) deficiency. Unsuspected AT3 deficiency should be considered in cases of unexplained cerebral venous thromboses.

Adult↗
PubMed1997

Regulation of thrombosis and hemostasis by antithrombin.

In this article, three cases, with antithrombin (AT) abnormality "Toyama" (type IIb), AT abnormality "Aomori" (type IIa), and congenital AT deficiency (type I) with pregnancy and delivery managed with administration of both AT concentrates and low-molecular-weight heparin, are described. Additionally, a case of AT-producing hepatocellular carcinoma, the first case in the world literature, is reported. Following these clinical reports, the development of AT studies on heparin cofactor II, characteristics of the vessel wall related to coagulation-fibrinolysis, and the development of the treatment of thrombosis with low-molecular-weight heparin and herbal drugs are discussed.

Anticoagulants↗
PubMedDate not supplied

hsp70, hsp32, and grp78 are increased in thermally injured skin with and without antithrombin(human) concentrate infusion.

An acquired deficiency of antithrombin (AT), an anti-inflammatory protein, develops in patients with thermal injuries. Skin thermotolerance is regulated by heat shock protein (hsp) genes. hsp70, hsp32, hsp27, and glucose-regulated protein78 (grp78) were studied in burned and unburned human skin to determine whether correction of the AT deficiency modulated the intensity of expression of these proteins. Fifty-four human skin samples were prepared by Western blot analysis: 11 unburned and 22 burned control skin samples and 7 unburned and 14 burned skin samples from patients treated with AT(Human), or AT(H). The intensity of hsp32 expression in burned AT(H)-treated skin (P < .001) and in burned control skin (P < .01) was significantly increased compared with unburned control skin. The intensity of expression of hsp70 was statistically significant in burned AT(H)-treated skin compared with unburned control skin (P < .02), as was that of grp78 (P < .01). Thermally injured skin with or without AT(H) treatment had an increased expression of hsp70, hsp32, and grp78 compared with unburned control skin.

Adolescent↗
PubMed2002

Antithrombin supplementation III in childhood acute lymphoblastic leukemia treated with L-asparaginase.

The change of plasma antithrombin III (AT) levels after supplementation of AT concentrates was examined in ALL children with acquired AT deficiency following L-asparaginase (ASP) administration. The patients received AT concentrates of 34.5 +/- 7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 +/- 0.62% and 0.70 +/- 0.16 mg/dL per unit AT infused per kilogram of body weight, respectively. The activity decreased to 62.0 +/- 7.7% of the peak values by 48 hours after supplementation. The administration of AT concentrates constantly increased the plasma AT activity in ALL children treated with ASP, which may minimize the acquired prothrombotic state.

Adolescent↗
PubMed1985

Protection against venous thrombosis in an antithrombin-III deficient patient suffering from episodes of arterial thrombosis requiring major surgery. Effects of oral stanozolol in combination with subcutaneous heparin and intravenous AT-III.

In an antithrombin-III (AT-III) deficient patient suffering from recurrent episodes of venous and arterial thrombosis requiring major surgery an attempt was made to institute antithrombotic protection by long-term stanozolol treatment supplemented during periods of thrombogenic exposure with subcutaneous heparin and, when needed, infusion of AT-III as plasma or concentrate. Stanozolol raised the plasma levels of AT-III, demonstrating a sparing effect on the AT-III needed. Despite the repeated exposures to major surgery, protection against venous thrombosis was complete, but the arterial disease progressed and led to the demise of the patient.

Administration, Oral↗
PubMed2005

Mutation study of antithrombin: the roles of disulfide bonds in intracellular accumulation and formation of russell body-like structures.

Antithrombin (AT) is a major plasma protease inhibitor with three intramolecular disulfide bonds and a deficiency of it is associated with venous thrombosis. Recently, we prepared CHO cells overexpressing a novel mutant, AT(C95R), with a disulfide bond removed, and revealed that this mutant remained for a long time in the endoplasmic reticulum (ER) without being degraded and also accumulated in newly formed membrane structures that resembled Russell bodies (RB) [Tanaka, Y. et al. (2002) J. Biol. Chem. 277, 51058-51067]. In this study, we replaced each of the individual cysteine residues of AT with an arginine and also two paired cysteine residues with arginines. We stably expressed these mutant ATs in CHO cells, and examined the roles of each cysteine residue or disulfide bond in the accumulation of mutant ATs and the formation of RB-like structures. In pulse-chase experiments, the secretion of mutant ATs with single mutations decreased approximately 1/5-1/50 times compared to that of the wild type AT. All of the mutant ATs were retained in the ER and were also found to accumulate in the RB-like structures. On the other hand, the fates of mutant ATs with double mutations fell into two categories. Secretion of mutant AT(C8R,C128R) decreased only approximately 1/2 times and no RB-like structures appeared. Mutants AT(C21R,C95R) and AT(C247R,C430R) exhibited similar secretion kinetics to the mutant ATs with the single mutations and were found in RB-like structures. On a sucrose gradient, all of the mutant ATs that induced RB-like structures migrated as oligomeric structures, whereas wild type AT and AT(C8R,C128R) migrated as monomers. Further, to clarify the morphological pathway through which RB-like structures are formed, we prepared CHO cells in which the expression of AT(C95R) was controlled by the Tet-On system. During expression of AT(C95R), RB-like structures formed through expansion of the ER. These results suggest that the correct folding with each disulfide bond is essential for the secretion of AT and oligomerization of mutant ATs in the ER is involved in the formation of RB-like structures.

Animals↗
PubMed1995

Thrombocytopenia, antithrombin deficiency and extensive thromboembolism in pregnancy: treatment with low-molecular-weight heparin.

Pregnancy limits the therapeutic options for managing thrombocytopenia which occurs in 5% of patients on heparin. We describe a case of extensive thromboembolism associated with antithrombin (AT) deficiency complicated by thrombocytopenia which resolved when low-molecular-weight heparin was instituted. A primigravid woman presented at 11 weeks gestation with bilateral femoral occlusive thrombi extending above the renal veins. Investigations revealed AT deficiency, thrombocytopenia and renal infarction. After low-molecular-weight heparin was substituted for unfractionated heparin, the thrombocytopenia resolved and although the pregnancy was lost, the patient made a full recovery.

Adult↗
PubMed1996

Low thrombosis rate seen in blood donors and their relatives with inherited deficiencies of antithrombin and protein C: correlation with type of defect, family history, and absence of the factor V Leiden mutation.

We have previously identified a group of blood donors with inherited deficiencies of either antithrombin (AT) or protein C who appear to have a relatively low thrombosis rate. In the 5 years that have elapsed since initial identification of these individuals, resistance to activated protein C (APC resistance), which is associated with the factor V Leiden gene mutation, has emerged as an important and highly prevalent inherited thrombophilic risk factor. We have followed 28 donors/relatives with deficiency of AT (median age 48 years, range 16-77) and 23 with deficiency of protein C (median age 44 years, range 15-79) over a period of 5 years. During the study period only one individual, who was previously symptomatic, has suffered a thrombotic event which occurred spontaneously whilst on warfarin. We have now excluded coinheritance of APC resistance due to the factor V Leiden mutation in our cohort. Our findings demonstrate that individuals with single inherited thrombophilic defects are not uncommon and are frequently asymptomatic. The absence of the factor V Leiden mutation may in part explain the low thrombosis rate observed, and lends support to the hypothesis that multiple thrombophilic defects may be necessary for the development of thrombosis.

Adolescent↗
PubMed2002

The use of coagulation activation markers (soluble fibrin polymer, TpP, prothrombin fragment 1.2, thrombin-antithrombin, and D-dimer) in the assessment of hypercoagulability in patients with inherited and acquired prothrombotic disorders.

A total of 260 consecutive patients, referred for hypercoagulable assessment, was included in this study. Four coagulation activation markers were utilized to assess these patients [enzyme-linked immunosorbent assays for soluble fibrin polymer (TpP), prothrombin fragment 1.2, thrombin-antithrombin complex, and D-dimer]. The mean levels of the activation markers directly correlated with the number of hypercoagulable abnormalities. The percentage of patients with increased TpP levels for each group was lower than the other activation markers. The findings indicate that activation markers reflect the number of underlying thrombophilic abnormalities. Our data suggest that there is a utility in performing a panel of coagulation activation markers to assess the thrombotic risk. The measurement of soluble fibrin polymer may be more reflective of an impending vascular event.

Activated Protein C Resistance↗
PubMed1975

Investigations on antithrombin III in normal plasma and serum.

Studies on antithrombin III (AT-III) were made by a modification of the two dimensional crossed immunoelectrophoresis technique and gel filtration. Mixing various quantities of heparin with agarose in the first phase of electrophoresis, AT-III from normal human plasma and serum revealed a heterogeneity which depended on the heparin concentration in the agarose gel. At heparin concentrations higher than 16 u/ml, AT-III displayed three components with different electrophoretic mobilities. The component with the highest mobility (designated immunoantithrombin III1 : IAT-III1) dominated in plasma. In normal serum, however, the quantity of this component was decreased and the two other peaks with a slower electrophoretic mobility (IAT-III2 and IAT-III3) became more evident. Normal human plasma and serum were filtered on Sephadex G-200 and the AT-III concentration measured in the fractions by rocket immunoelectrophoresis. The peaks of AT-111 were found in the same fractions for both plasma and serum and were coincident with the albumin peak of the plasma proteins. However, in the case of serum the AT-III concentration decreased less sharply in those fractions with higher molecular weight than in the corresponding plasma fractions. Analysis of these fractions by crossed immunoelectrophoresis revealed that the two components with slower electrophoretic mobility (IAT-III2 and IAT-III3) had higher molecular size than IAT-III1, that the concentration of IAT-III2 and IAT-III3 was significantly higher in serum, and that the high molecular weight components in plasma and serum were qualitatively identical. It is concluded that high molecular weight complexes between AT-III and activated coagulation factors may be present in normally circulating blood and that their detection and possibly quantitation can be achieved using the heparin/agarose crossed immunoelectrophoresis system.

Antithrombin III↗
PubMed1982

Treatment of congenital antithrombin III deficiency with concentrates.

Antithrombin III concentrates were administered to a patient with hereditary AT III deficiency undergoing orthopaedic surgery. The plasma AT III level (heparin cofactor activity) was maintained at values in excess of 100% postoperatively. A mean dose of 0.74 u/kg (range 0.64 - 0.83) of AT III resulted in a 1% increase in AT III level after concentrate infusion. The half-life of AT III (mean 66 h; range 58-76) was shorter during surgery and in the early postoperative period suggesting an increased consumption of the inhibitor. At III antigen was consistently higher than heparin cofactor activity during the first 24 h after concentrate infusions. This discrepancy was associated with the presence in the patient's plasma of an AT III fraction showing a slower mobility than the main AT III peak on two-dimensional immunoelectrophoresis in the presence of heparin. A biological assay is preferred to an immunological assay in monitoring replacement therapy with AT III concentrates.

Adult↗
PubMed1984

Management of planned pregnancy in a patient with congenital antithrombin III deficiency.

Long-term warfarin therapy was changed to subcutaneous heparin to cover a planned pregnancy in a patient with congenital antithrombin III (AT III) deficiency. Satisfactory anticoagulation was easily maintained in spite of low levels of biologically active AT III. Delivery and the puerperium were covered by a reduced dose of heparin and alternate day infusions of AT III concentrate. A mean dose of 0.77 U/kg of AT III concentrate produced a rise of 1% in AT III and the half-life was of the order of 24 h, with no evidence of increased consumption during labour and delivery. Pregnancy and labour were uncomplicated and resulted in delivery of a healthy female infant. The importance of early and adequate anticoagulation during pregnancy is emphasized.

Adult↗