Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reported incidence of thromboembolism in children with acute lymphoblastic leukemia (ALL) treated with L-asparaginase, vincristine, and prednisone varies from 2.4% to 11.5%. The present study was designed to prospectively evaluate the role of the TT677 methylenetetrahydrofolate reductase (MTHFR) genotype, the prothrombin G20210A mutation, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and increased lipoprotein (a) concentrations in leukemic children treated according to the ALL-Berlin-Frankfurt-Muenster (BFM) 90/95 study protocols with respect to the onset of vascular events. Three hundred and one consecutive leukemic children were enrolled in this study. Fifty-five of these 301 subjects investigated had one established single prothrombotic risk factor: 20 children showed the TT677 MTHFR genotype; 5 showed the heterozygous prothrombin G20210A variant; 11 were carriers of the factor V G1691A mutation (heterozygous, n = 10; homozygous, n = 1); 4 showed familial protein C, 4 protein S, and 2 antithrombin type I deficiency; 9 patients were suffering from familially increased lipoprotein (a) [Lp(a)] concentrations (>30 mg/dL). In addition, combined prothrombotic defects were found in a further 10 patients: the FV mutation was combined with the prothrombin G20210A variant (n = 1), increased Lp(a) (n = 3), protein C deficiency (n = 1), and homozygosity for the C677T MTHFR gene mutation (n = 1). Lp(a) was combined with protein C deficiency (n = 2) and the MTHFR TT 677 genotype (n = 2). Two hundred eighty-nine of the 301 patients were available for thrombosis-free survival analysis. In 32 (11%) of these 289 patients venous thromboembolism occurred. The overall thrombosis-free survival in patients with at least one prothrombotic defect was significantly reduced compared with patients without a prothrombotic defect within the hemostatic system (P <.0001). In addition, a clear-cut positive correlation (P <.0001) was found between thrombosis and the use of central lines. However, because the prothrombotic defects diagnosed in the total childhood population studied were all found within the prevalences reported for healthy Caucasian individuals, the interaction between prothrombotic risk factors, ALL treatment, and further environmental factors is likely to cause thrombotic manifestations.
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PMID:Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. 1200 2

Hereditary prothrombotic risk factors have been shown to increase the risk of venous thrombosis in children treated with the combination of E. coli asparaginase and steroids. In the present study the role of prothrombotic risk factors in children with ALL treated according to the COALL study protocol was investigated in 108 consecutively recruited childhood patients. The prevalence rates of prothrombotic risk factors [factor V G1691A mutation, the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, deficiencies of protein C, protein S, antithrombin, elevated lipoprotein (a)] in this cohort were within the range reported for healthy Caucasians, and comparable to previously reported data for other leukemic patients. Venous thromboembolism occurred in 3 of the 108 children (induction n = 1; reinduction n = 2: 2.8%), and none of these children carried a prothrombotic risk factor. The results of the present study, suggest that the role of hereditary and acquired disturbances of coagulation in the development of thromboses might depend on the treatment regimen.
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PMID:Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). 1089 35

Recently published data suggest that the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and elevated lipoprotein (a) concentrations were associated with venous thromboembolism in childhood patients treated according to the BFM protocol. To unravel the role of these prothrombotic risk factors and different treatment modalities, the present comparative study was performed in childhood leukemia patients of the same living population. Four hundred and twenty consecutively recruited leukemic children (BFM n=300; COALL n=120) were enrolled in this study with respect to the presence of prothrombotic risk factors and the occurrence of symptomatic venous thrombosis. No significant difference was found in the prevalence rates of thrombotic risk factors in the Caucasian populations studied. Symptomatic venous thromboembolism occurred in 11.6% of BFM patients compared with 2.5% in the COALL treatment group [odds ratio (OR)/95% confidence intervals (CI): 7.7/1.8-32.6; P=.005]. Including age, prothrombotic risk factors, central venous lines, treatment protocols, and anti-leukemic drugs in a logistic regression model, only the concomitant Escherichia coli asparaginase/prednisone administration in leukemic children suffering from a prothrombotic risk factor was found to increase the rate of thrombotic manifestations during leukemia treatment in patients of the same Caucasian origin (OR/95% CI: 34.5/4.39-271.42; P=.0008). Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases.
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PMID:Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. 1167 78

One of the hirudin variants HV3 was efficiently expressed in Escherichia coli using the L-asparaginase II signal sequence and the product was secreted into the culture medium. For the secretory manufacture of HV3, the L-asparaginase II signal sequence containing a single NheI restriction site at its 3' end was designed using the degenerate codons and PCR-amplified from E. coli chromosomal DNA. The synthetic HV3 coding sequence was fused to the signal sequence in-frame by its 5' NheI restriction site. The above signal-HV3 fusion gene was inserted into an expression vector pTA, which was derived from pkk223-3 such that its expression was under the control of the tac promotor. The resulting HV3 secretion expression vector pTASH thus constructed was introduced into an E. coli host cell AS1.357 with high L-asparaginase II producing level. After inducing with IPTG, the expression product was efficiently secreted into the culture medium and shake-flask culturing gave a yield of approximately 5 x 10(5)ATU/L (approximately 60mg/L). The secreted HV3 was easily purified from culture supernatant using ultrafiltration, ion-exchange column chromatography, and FPLC reverse-phase chromatography. The purified rHV3 from the culture supernatant had the expected N-terminal amino sequence and strong antithrombin activity, suggesting that the signal sequence was completely removed and the product was processed accurately during the secretion process.
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PMID:Efficient expression and secretion of recombinant hirudin III in E. coli using the L-asparaginase II signal sequence. 1218 23

Alterations in hemostasis leading to symptomatic thromboembolism have been observed in patients with acute lymphoblastic leukemia (ALL) receiving Escherichia coli asparaginase (CASP) combined with steroids. Moreover, hereditary prothrombotic risk factors are associated with an increased risk for venous thromboembolism in pediatric ALL patients treated according to the BFM 90/95 protocols (including CASP combined with prednisone during induction therapy). To assess whether the thromboembolic risk associated with established prothrombotic risk factors is modified by treatment modalities (prednisone or dexamethasone), the present analysis was performed. Three hundred thirty-six consecutively recruited leukemic children treated according to different BFM protocols (PRED group, n = 280, 60 mg/m(2) prednisone; DEXA group, n = 56, 10 mg/m(2) dexamethasone during induction therapy) were studied. Study end point was the onset of symptomatic vascular accidents during induction therapy. Cumulative thromboembolism-free survival was significantly reduced in children in the PRED group (thrombosis frequency, 10.4%) compared with children in the DEXA group (thrombosis frequency, 1.8%; P =.028). Although no significant difference was found in the overall prevalence of prothrombotic risk factors, 46.5% of patients in the PRED group who experienced thromboembolic events were carriers of a prothrombotic risk factor, whereas no carrier in the DEXA group had a thromboembolism. At the time of maximum CASP activity, fibrinogen and activities of antithrombin, plasminogen, and protein S were significantly reduced in the PRED group. No significant correlation could be found between CASP activity and levels of coagulation factors. In conclusion, the use of dexamethasone instead of prednisone, administered with CASP, significantly reduced the onset of venous thromboembolism.
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PMID:Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. 1251 8

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.
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PMID:Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. 1288 62

Thromboembolism (TE) is a known complication of L-asparaginase (ASP) therapy of acute lymphoblastic leukemia (ALL), possibly attributable to reduced synthesis of natural anticoagulants, in particular antithrombin (AT). This retrospective single institution study was performed to determine the TE incidence among adults undergoing induction with contemporary, ASP-containing regimens. Ten of 54 (18.5%) consecutive adults developed symptomatic, objectively confirmed TE, at a median of 5.5 days after the first ASP dose. These were notable for CNS and upper extremity localization, varied significantly according to ALL immunophenotype (precursor B: 11% vs. T cell: 33%), without apparent effect of schedule or total dose of ASP. Median baseline AT level was 94% and fell to a nadir of 47% (P < 0.0001) during ASP therapy. Prophylactic AT had been given to 17 during ASP therapy. None of these developed TE vs. 10/37 (27%) without replacement (P = 0.021). These observations merit further study to gain insight into disease and/or therapy-specific pathogenesis of TE in this population and call for the prospective evaluation of appropriate prophylactic interventions.
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PMID:Thromboembolism in adults with acute lymphoblastic leukemia during induction with L-asparaginase-containing multi-agent regimens: incidence, risk factors, and possible role of antithrombin. 1537 Feb 5

This review is based on pediatric reports (- January 2004) on the presence of symptomatic thrombosis in children with hematologic malignancies, mainly acute lymphoblastic leukemia, treated with different treatment protocols and associated with acquired and inherited prothrombotic risk factors (factor V G1691A, factor G20210A, MTHFR C677T genotypes, protein C, protein S, antithrombin, elevated levels of lipoprotein(a), and homocysteine). The interactions of treatment modalities, study designs, ethnical backgrounds and associated central lines are discussed. Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases. In addition, primary preventive anticoagulant/antithrombotic strategies are discussed.
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PMID:Thrombosis in children with hematologic malignancies. 1602 68

Asparaginase is essential in the treatment of lymphoproliferative malignancies, but it is associated with several side effects. The objective of this study was to compare asparaginase-induced alterations of the coagulation inhibitors and the impact on central line-associated thrombosis in children treated according to 2 different asparaginase regimens. The study enrolled 30 children treated for acute lymphoblastic leukemia, and they were divided into 2 groups with respect to asparaginase preparation and protocol (NOPHO ALL-1992 versus NOPHO ALL-2000). The coagulation inhibitors antithrombin, protein C, and proteins S were measured prior to and during asparaginase therapy, and incidence of central line-associated thromboses was compared to evaluate the protocols' thrombogenicity. Thirteen children received Erwinia asparaginase and 17 children received E. coli asparaginase. Independent of protocol, the coagulation inhibitors were significantly reduced during asparaginase therapy (p < .001), and central line-associated thromboses were frequent. Four children developed thrombosis in the course of asparaginase therapy, and there was a correlation between asparaginase-induced fall of antithrombin and occurrence of new thromboses (p = .01).
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PMID:Thrombotic effects of asparaginase in two acute lymphoblastic leukemia protocols (NOPHO ALL-1992 versus NOPHO ALL-2000): a single-institution study. 1651 37

Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, l-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of alpha1-antitrypsin. l-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, l-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for alpha1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. l-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and alpha1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.
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PMID:L-asparaginase-induced antithrombin type I deficiency: implications for conformational diseases. 1681 68


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