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 changes in plasma levels of the vitamin K-dependent natural anticoagulants protein C (PC) and protein S (PS) and procoagulant factors II, IX and X were evaluated in 8 adult patients during treatment with L-asparaginase (L-ase i.v. 120,000 U/m2 over 10 days). PC anticoagulant activity and factor IX, X and II coagulant activity decreased proportionally to their half-lives to a nadir of 50-60% of pretreatment values after 2-5 L-ase infusions, suggesting that inhibition of protein synthesis rather than consumption is the main mechanism responsible for the observed changes. Free PS antigen levels declined at a rate similar to total PS antigen, reaching a nadir of 56% of pretreatment values after 3 L-ase infusions; however due to C4b-binding protein levels higher than total PS levels (p less than 0.05), they were constantly lower than the corresponding total PS antigen levels (0.05 less than p less than 0.001). This implicates that total PS antigen levels cannot be taken as an indicator of PS activity. No differences between the antigenic levels and the anticoagulant activities of PC and free PS could be observed suggesting that L-ase does not affect the mechanisms of vitamin K-dependent carboxylation of Gla-residues. The faster rate of decline of PC and PS activities relative to that of factor II may be responsible for the onset of an hypercoagulable state during the early phase of L-ase treatment.
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PMID:L-asparaginase treatment reduces the anticoagulant potential of the protein C system without affecting vitamin K-dependent carboxylation. 214 29

To evaluate the occurrence of hypercoagulability during treatment with L-asparaginase (L-ase), thrombin-antithrombin complex (TAT) and D-dimer levels in plasma were serially measured in 15 consecutive adult patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma who had recently completed a chemotherapy cycle with cytosine arabinoside and methotrexate. The first eight patients (group A) received i.v. L-ase alone (20,000 U/m2 on alternate days over 10 d); the last seven patients (group B) received, in addition to L-ase, bolus injection of antithrombin concentrate (2000 U) on alternate days for a total of six administrations, beginning with the second L-ase infusion. Increased levels of TAT (P less than 0.05) and D-dimer (P less than 0.01) were observed prior to L-ase, possibly related to inflammation and cytolysis secondary to previous chemotherapy. In patients treated with L-ase alone, further elevation of TAT (P less than 0.05) and persistence of increased D-dimer were observed, associated with marked reduction of the anticoagulant activities of protein C, protein S and antithrombin III. At variance, in patients receiving antithrombin III supplementation there was no increase of TAT and a normalization of D-dimer levels occurred during L-ase treatment. In these patients, mean plasma antithrombin III activity was maintained at levels higher than 70% of normal throughout the treatment. The rate of decline of fibrinogen, factor IX, protein C and protein S was unaffected by antithrombin III supplementation, indicating that hypercoagulability has little if any relevance for the reduction of coagulation factors and inhibitors induced by L-ase treatment. The usefulness of antithrombin III concentrates in preventing thromboembolic complications in patients submitted to L-ase treatment remains to be determined.
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PMID:Hypercoagulability during L-asparaginase treatment: the effect of antithrombin III supplementation in vivo. 218 89

Hemostatic changes were evaluated in ten patients with acute lymphoblastic leukemia and lymphoma who received chemotherapy with L-asparaginase, vincristine, and prednisolone for 1 week. Following treatment, prothrombin time and activated partial thromboplastin time were significantly prolonged, while a marked decrease in fibrinogen levels was observed. The values for cross-linked fibrin degradation products, however, remained within normal limits during treatment, which excluded the possibility of disseminated intravascular coagulation. The concentrations of coagulation inhibitors (antithrombin III, protein C, and protein S), plasminogen, and alpha 2 antiplasmin also significantly decreased; however, levels of both tissue-type plasminogen activator and plasminogen activator inhibitor, which are synthesized in endothelial cells, increased during the treatment. Although a decrease was observed in concentrations of many coagulation factors, including subunits A and B of factor XIII, the activity and antigenicity of factor VII significantly increased following the treatment. From this study, we concluded that these hemostatic abnormalities caused by the administration of L-asparaginase produced a labile condition that easily inclines to bleeding or thrombosis.
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PMID:Changes in hemostatic and fibrinolytic proteins in patients receiving L-asparaginase therapy. 275

Vitamin K-dependent proteins were measured sequentially by immunoassay in eight patients with acute lymphoblastic leukemia receiving L-asparaginase (1000 U/kg/day) for 10 days as induction therapy, in combination with vincristine or vindesine, daunorubicin, cyclophosphamide, and prednisone. The level of each protein was significantly decreased during L-asparaginase therapy, but both the time course of change and the severity of decrease differed among the proteins. The decrease in protein C, factor IX, and factor X was observed earlier than the decrease in protein S and factor II. In the first days of L-asparaginase therapy the protein C level was significantly lower than those of the other vitamin K-dependent proteins. The transient imbalance in the levels of plasma vitamin K-dependent proteins observed in the first days of treatment may contribute to the risk of thrombosis associated with L-asparaginase therapy.
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PMID:Effect of L-asparaginase therapy for acute lymphoblastic leukemia on plasma vitamin K-dependent coagulation factors and inhibitors. 293 29

Plasma levels of protein C and protein S antigens were measured in eight children who developed thrombosis following asparaginase-prednisone-vincristine treatment for acute lymphoblastic leukaemia and in nine similarly treated children without this complication. Protein C antigen levels were below normal in three of the eight patients with thrombosis and in three of the nine patients without the complication (P = 0.38). Low protein S antigen levels were found in five of six patients with thrombosis and in two of seven patients without thrombosis (P = 0.10). Plasma factor IX and factor X antigen levels, other vitamin K dependent factors, were also measured in the two groups of patients. In general, reduced levels of protein C, protein S or both antigens (anticoagulant vitamin K dependent proteins) were associated with reduced levels of factor IX, factor X, or both of these factors (procoagulant vitamin K dependent clotting proteins). The ratios of protein C and protein S antigens to each other and to factor IX and factor X antigens did not differ between the two groups. Thus, there is no clear evidence that reduced levels of protein C and (or) protein S cause thrombosis in leukaemia patients treated with this drug combination.
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PMID:Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. 294 15

Thrombotic events have been reported in acute lymphoblastic leukaemia patients, especially during or after L-asparaginase administration. A so-called L-asparaginase associated coagulopathy has been well recognized, being characterized by a hypercoagulable state (decrease of antithrombin III, plasminogen, protein C, protein S and increase of prothrombin fragment F1 + 2, thrombin-antithrombin complexes and fibrinopeptide A). The aim of this study was to determine whether the supplementation of antithrombin III (AT-III) concentrates could improve the L-asparaginase associated coagulopathy, thereby blocking the activation of the haemostatic system. In 25 adult patients with acute lymphoblastic leukaemia (M 19, F6, mean age 34 years) antithrombin III (AT-III) concentrates were administered at daily doses of 50 U/kg for 10 consecutive days from the beginning of L-asparaginase therapy (6,000 U/m2/day s.c. for 7 days), given according to the GIMEMA ALL 0288 trial. A marked increase of antithrombin III was recorded on days IV-VIII-XI (P < 0.001). No changes in protein C, protein S, plasminogen, alpha 2-antiplasmin, factor VII and platelet count were observed and there was no increase in markers of hypercoagulability. There was no evidence of disseminated intravascular coagulation. In conclusion, AT-III concentrate supplementation during L-asparaginase therapy, by the achievement of high levels of antithrombin III, is associated with a lack of activation of the haemostatic system and appears to overcome the complex coagulopathy associated with L-asparaginase.
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PMID:Antithrombin III infusion suppresses the hypercoagulable state in adult acute lymphoblastic leukaemia patients treated with a low dose of Escherichia coli L-asparaginase. A GIMEMA study. 751 43

Blood coagulation abnormalities induced by administration of E. coli L-asparaginase were investigated in 25 patients with acute lymphoblastic leukemia treated according to the GIMEMA ALL 0288 trial. Dosage of L-asparaginase was relatively low (6,000 U/m2/day for 7 days total dose 42,000 U/m2) as compared to the conventional dosages (120,000-140,000 U/m2 over 10-14 days). A significant decrease in fibronogen, plasminogen, alpha2-antiplasmin and antithrombin III was observed from day IV of L-asparaginase and it was maximum on day VIII, with return to the baseline levels on day XV. Protein C levels had only a borderline reduction, while no modification of protein S or factor VII was observed. Two of the patients investigated developed thrombosis. The presence of a prothrombotic state induced even by this low dosage of E. coli L-asparaginase was suggested by a significant increase of sensitive markers of hypercoagulability such as fibrinopeptide A, thrombin-antithrombin complexes, and prothrombin fragment F1 + 2.
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PMID:Evidence of a hypercoagulable state in patients with acute lymphoblastic leukemia treated with low dose of E. coli L-asparaginase: a GIMEMA study. 844 31

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

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2 (PF 1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 19 patients with acute lymphoblastic leukemia, (ALL) receiving combined chemotherapy including L-asparaginase (L-ASP) and high dose methylprednisolone (HDMP). HDMP was administered in doses of 30 mg/kg/day for 7 days, and 20 mg/kg/day for another 7 days. In order to evaluate the effect of HDMP on the hemostatic system, the 8 patients studied here received HDMP (30 mg/kg/day) therapy for 4 days before the combined chemotherapy. These parameters were also studied in 12 healthy children as a control group. PC levels were normal in the patients while PS levels were decreased both before and after combined chemotherapies. Patients with ALL have laboratory signs of coagulation activation such as PF 1,2, TAT prior to initiation of chemotherapy. With combined chemotherapy, TAT levels were found to be normal while PF1,2 were not. TM levels were found to be increased both before and after therapies whereas HCFII and vWF levels were not different from those of the control group. The short course of HDMP therapy did not prominently influence these hemostatic parameters. These results indicate that both the malignant process and the drugs used in combined chemotherapy cause a decrease in natural inhibitors and an increase in procoagulant activity and endothelial injury. These hemostatic changes may contribute to a thrombotic tendency in the patients with ALL.
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PMID:Changes of hemostatic factors in children with acute lymphoblastic leukemia receiving combined chemotherapy including high dose methylprednisolone and L-asparaginase. 1022 16

Cerebral sinus thrombosis associated with acquired free protein S deficiency is very rare. We report the case of an adult patient with acute lymphoblastic leukemia who presented with repeated transient ischemic attacks followed by a seizure during consolidation treatment with L-asparaginase. Magnetic resonance of the brain showed a small cortical hemorrhagic infarct. Superior sagittal sinus thrombosis was demonstrated by cerebral angiogram. A marked decrease of the free form of protein S was documented. One month later, when the patient was free of symptoms, the follow-up free protein S antigen level was restored to the normal range. We suggest that the sagittal sinus thrombosis in this patient was caused by acquired, transient free protein S deficiency. This case also extends the clinical spectrum of cerebral sinus thrombosis to include recurrent transient ischemic attacks alternating with seizures.
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PMID:Sagittal sinus thrombosis associated with transient free protein S deficiency after L-asparaginase treatment: case report and review of the literature. 1071 1


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