1/19. Familial overexpression of beta antithrombin caused by an Asn135Thr substitution.We have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (approximately 70% antigen and activity) of antithrombin. Direct sequencing of amplified dna showed a mutation in codon 135, AAC to ACC, predicting a heterozygous Asn135Thr substitution. This substitution alters the predicted consensus sequence for glycosylation, Asn-X-Ser, adjacent to the heparin interaction site of antithrombin. The antithrombin isolated from plasma of the proband by heparin-sepharose chromatography contained amounts of beta antithrombin (the very high affinity fraction) greatly increased (approximately 20% to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wild-type and variant protein were translated and exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represents a novel cause of antithrombin deficiency, removal of glycosylation concensus sequence, and highlights the potentially important role of beta antithrombin in regulating coagulation.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
2/19. budd-chiari syndrome and extrahepatic portal obstruction associated with congenital antithrombin iii deficiency.We report a patient with budd-chiari syndrome (BCS) and extrahepatic portal obstruction (EHO) associated with congenital antithrombin (AT) III deficiency. A 35-year-old man was admitted to Nishi Kobe Medical Center for evaluation of abnormal intrahepatic veins. By various imaging modalities, BCS and EHO were diagnosed. Laboratory data revealed parallel decreases in activity and antigen concentration of AT III despite normal liver function. Taken together, the etiology of both BCS and EHO was considered to be thrombosis, associated with congenital AT III deficiency. Two years after beginning warfarin therapy, the patient has no symptoms and his liver function remains normal. Anticoagulant therapy is considered useful for preventing progression of the disease.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
3/19. cerebral infarction in a heterozygote with variant antithrombin III.BACKGROUND: We report a heterozygous case of familial qualitative deficiency of antithrombin III associated with cerebral infarction. CASE DESCRIPTION: A 33-year-old man had a history of recurrent transient ischemic attacks from the age of 28. Cerebral computed tomography at age 29 disclosed a low-density area in the left frontal lobe, and an internal carotid angiogram showed branch occlusion of the right anterior cerebral artery and stenosis of the left middle cerebral artery. Occlusion of the right middle cerebral artery developed thereafter. The plasma antithrombin III antigen concentration and progressive antithrombin activity were normal, but plasma heparin cofactor activity was low in the patient and his father. Nucleotide sequence analysis of the proband's deoxyribonucleic acid showed no mutation in exons II and VI of antithrombin III. CONCLUSIONS: We conclude that abnormal antithrombin III with defective heparin binding, even though heterozygous, may cause ischemic stroke in young adults. We named this antithrombin III variant "Antithrombin III Nagasaki."- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
4/19. Congenital antithrombin iii deficiency (AT-III Kyoto): identification of a point mutation altering arginine-406 to methionine behind the reactive site.A Japanese patient with congenital antithrombin III (AT-III) deficiency, named AT-III Kyoto, is associated with reduced levels (60% of normal) of AT-III antigen, progressive activity and heparin cofactor activity. The antithrombin III gene of this patient was investigated by polymerase chain reaction (PCR) method followed by direct dna sequencing analysis, which revealed a G to T transitional mutation resulting in the conversion of arginine-406 to methionine in exon 6. arginine-406 is located at the 12th amino acid residue from the reactive site on the C-terminal side of AT-III in a core region of the molecule which has been highly conserved during evolution of serine protease inhibitor (serpin) family. It is concluded that AT-III Kyoto is a newly described mutation which is similar to AT-III utah and lends support to the idea that the conserved region near the reactive site is important in maintaining biological function of the AT-III molecule.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
5/19. The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease.210 patients, with a history of venous thrombosis, have undergone prothrombotic investigations. In nine cases a consistent deficiency of antithrombin was identified. In five there was a reduction in the plasma antigenic concentration of antithrombin and in a further four cases deficiency was due to the presence of a dysfunctional antithrombin variant. The variants have all been characterized by dna analysis and in three the mutations have been confirmed by peptide sequencing (antithrombin Basel (41 Pro to Leu). Hamilton (382 Ala to Thr). Cambridge I (384 Ala to Pro) and Cambridge II (384 Ala to Ser). The incidence of antithrombin deficiency in patients with a history of venous thrombosis has previously been quoted at between 2% and 3%: there is no published data available on the incidence of antithrombin variants. In our series 5% of patients who presented before the age of 40 years had antithrombin deficiency, and 2% of the total number of patients investigated had a dysfunctional variant. Our figures indicate that a significant number of cases of antithrombin deficiency are due to dysfunctional variants and that the true incidence of antithrombin deficiency in patients with a history of venous thrombosis is in the order of 5%.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
6/19. antithrombin iii deficiency: a report of 14 cases belonging to three different kindreds.A hereditary deficiency of AT III is described in 14 subjects belonging to three different kindreds. There is no consanguineity in any of the families investigated. The pattern of inheritance of defect appears autosomal dominant. Seven of the affected subjects presented thrombotic episodes (deep vein thrombosis, splanchnic thrombosis, pulmonary embolization). The main laboratory features were: normal routine clotting tests, decreased AT III activity in all assay systems and concomitantly reduced AT III antigen levels. Crossed immunoelectrophoresis showed only reduced peaks with respect to normal in both plasma and serum. No correlation was found between age of patients and AT III levels.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
7/19. association of hereditary heparin co-factor II deficiency with thrombosis.A family was investigated for heparin co-factor II deficiency. Three of the five members examined had had thrombosis and their levels of heparin co-factor II were reduced to 50%. All five members had antithrombin III levels within the normal range. Analysis on crossed immunoelectrophoresis showed no qualitative abnormality of patient heparin co-factor II antigen. Since heparin co-factor II activity and concentration were reduced to the same extent, the deficiency was due to reduced protein synthesis.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
8/19. AT III Barcelona: a familial quantitative-qualitative AT III deficiency.A quantitative and qualitative deficiency of antithrombin III (ATIII) was found in four members of a Spanish family with thrombotic tendency. In all affected members, levels of ATIII antigen and activity (heparin cofactor activity) were reduced to 50% of the normal range. When crossed immunoelectrophoresis (CIE) was performed in the presence of heparin, an abnormal slow-moving peak was found. Crossed immunoelectrofocusing (CIEF) from normal and affected individuals showed that normal ATIII migrated between pH 4.9-5.3 while the ATIII under study was asymmetrically distributed between two pH ranges: 4.9-5.3 and 4.6-4.8. Affinity adsorption of affected members' plasma to heparin-sepharose beads revealed one population of ATIII in the supernatant corresponding to the abnormal ATIII, devoid of heparin cofactor activity and showing a peak between pH range: 4.6-4.8 in CIEF. Our data supports the view that a quantitative-qualitative deficiency was present in the heterozygous state in all the affected family members. Both normal and abnormal ATIII were present in plasma of the affected individuals. This abnormal ATIII was characterized by a lack of affinity for heparin. This familial ATIII deficiency was named ATIII Barcelona.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
9/19. Antithrombin III Pescara: a defective AT III variant with no alterations of plasma crossed immunoelectrophoresis, but with an abnormal crossed immunoelectrofocusing pattern.An abnormal AT III variant was found in five members from a family where a high incidence of thromboembolism occurred. In all the affected subjects AT III antigen concentration was normal, whereas antithrombin and antifactor Xa progressive activities as well as heparin cofactor activities were low. Crossed immunoelectrophoresis performed either in absence or in presence of heparin showed a normal plasma pattern. Further chromatographic investigations showed a normal affinity to heparin. An abnormal plasma pattern was evidentiated by crossed immunoelectrofocusing throughout all the AT III pH range. These data are consistent with the presence of an abnormal AT III variant with a defective binding to serine proteases and clearly identifiable only by crossed immunoelectrofocusing. This variant appeared different from the other qualitative AT III defects so far described and was named 'Antithrombin III Pescara'.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
10/19. Hereditary antithrombin iii deficiency: case report and review of recent therapeutic advances.We report on a newly diagnosed family with hereditary antithrombin iii deficiency, with thromboembolic complications in the propositus. Both the propositus and his asymptomatic sister had decreased plasma levels of antithrombin III antigen and activity (28-52% of normal with good agreement between functional and immunologic assays). The propositus developed deep venous thrombosis, followed by massive pulmonary emboli despite heparin therapy and was treated with streptokinase and heparin with excellent results. Shortly thereafter, small bowel obstruction required surgical intervention, and antithrombin III concentrate, recently available in the united states as an investigational new drug (I.N.D.), was administered with no postoperative thrombotic complications. He was subsequently asymptomatic while on warfarin prophylaxis but twice developed venous thrombosis when he failed to take warfarin. The addition of danazol therapy led to a sustained rise in the antithrombin III level. Each of these therapeutic approaches is discussed and the literature reviewed with emphasis on the newer agents--streptokinase, antithrombin III concentrate, and danazol.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
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