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)

We report 2 new cases of thrombosis occurring in a cohort of 21 consecutive patients with acute lymphocytic leukemia treated with L-asparaginase (L-ase), 6,000 U/die s.c. or i.m. days 15-21 from start of chemotherapy, according to the GIMEMA LAL 0288 protocol. The first patient died of massive diffuse thromboembolism (thrombosis of sagittal sinus and of suprahepatic veins and pulmonary arteries; multiple hepatic and splenic infarctions) associated with markedly reduced levels of protein C, antithrombin III and plasminogen. In the second patient, portal vein thrombosis developed soon after the completion of L-ase. Antithrombin III was reduced, whereas protein C level was normal. Therapy with fresh frozen plasma and subcutaneous calcium heparin (12,500 U twice daily) proved successful, and 8 days later abdominal echotomography revealed the complete disappearance of the thrombus. The incidence of thrombosis is similar to that previously found in a cohort of consecutive patients treated at our Department with a different schedule and dosage of L-ase administration, and similar to that reported in previous series.
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PMID:Thrombotic complications during L-asparaginase treatment for acute lymphocytic leukemia. 209 99

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

12 children affected by acute lymphoblastic leukemia had higher baseline levels of Normotest, Antithrombin III activity (AT III:A) and antigen (AT III:Ag) than those found in the control group, due to increased liver protein synthesis, as shown by the higher values of 305llbumin. Treatment with L-asparaginase (L-Asp) induced a marked decrease in fibrinogen and plasminogen and only a slight but significant reduction in AT III:A, AT III:Ag, protein C and alpha 2 antiplasmin levels. Platelet counts progressively increased. Each single L-Asp administration acutely induced (as recorded in the 2-hour postadministration samples) a significant increase in fibrinopeptide A values and reduction in several factors and inhibitors, due to activation of coagulation and consumption phenomena. It is suggested that these acute changes, but not the marked and selective reduction in fibrinogen and plasminogen, were partly compensated during L-Asp treatment by an overall increase in clotting and nonclotting protein synthesis in the liver.
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PMID:Intravascular coagulation phenomena associated with prevalent fall in fibrinogen and plasminogen during L-asparaginase treatment in leukemic children. 318 17

Two short-lived vitamin K-dependent factors, factor VII and protein C, were measured by both functional and antigenic techniques in 3 hematological conditions known for their risk of hepatotoxicity: Following use of asparaginase and bisantrene, and patients at high risk of hepatic veno-occlusive disease after allogenic bone marrow transplantation for relapse of acute leukemia of accelerated phase of evoluted chronic myelogenic leukemia. In these 3 conditions functionally measured levels of protein C and factor VII, and antigenically measured levels of both these factors proved to be early markers of incipient hepatic involvement. These tests were easy to use routinely were reproducible, and proved to be predictive of veno-occlusive disease in grafted patients at the preconditioning stage. In the follow-up of bone marrow grafted patients plasma markers of endothelial function (von Willebrand's factor, tissue type plasminogen activator, and plasma activity of angiotensin converting enzyme) were significantly altered at the time of overdose with cyclosporin A, probably due to a drug-induced in vivo lesion of the endothelium. In the search for cytoprotective drugs for the prevention of veno-occlusive disease in bone marrow grafted patients prostaglandin E1 (PGE1) was given prior to and for at least 4 weeks after transplantation and proved to be effective by biological criteria (the level of protein C mainly). This deserves further study in a prospective clinical trial of the potential usefulness of PGE1 in preventing liver veno-occlusive disease in bone marrow grafted patients.
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PMID:[Hemostasis tests as markers of hepatic and endothelial toxicity in chemotherapy]. 329 Aug 34

Protein C is, after activation by thrombin, a potent inhibitor of blood coagulation. An isolated deficiency of protein C increases the risk of thrombosis. The two forms of protein C deficiency, the heterozygous and the homozygous deficiency state, have different clinical features. Patients with heterozygous protein C deficiency are at a high risk to develop venous thrombosis and pulmonary embolism. In newborns with homozygous protein C deficiency with very low protein C levels (1%) a purpura fulminans like syndrome was observed. Heparin and coumarin derivatives are effective drugs in heterozygous protein C deficiency, homozygous patients may be treated either by replacement of protein C or coumarin derivatives. Decreased protein C levels were observed in various other diseases: Chronic and acute liver disease, disseminated intravascular coagulation, malignancy, postoperatively and during treatment with asparaginase. The role of protein C in these diseases to trigger thrombosis is not yet established.
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PMID:Clinical relevance of protein C. 352 11

The use of L-asparaginase during remission induction in patients with leukemia is associated with coagulation abnormalities, which may present either as thrombosis or hemorrhage. However, because of the multiple pharmacologic and hematologic variables present in these patients, the exact contribution of L-asparaginase to these coagulation abnormalities is unclear. We studied platelet function and plasma coagulation parameters in 12 pediatric patients with acute lymphoblastic leukemia (ALL) receiving daily L-asparaginase as a single agent when in complete remission. Changes in the prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen, while statistically significant, remained within or close to the normal range during the study. Platelet function also remained normal during the study. In contrast, levels of protein C antigen decreased to a mean of 42%, a significant change from pretreatment values. Levels of antithrombin III (AT III) were likewise depressed to 15 mg/dL (34% of pretreatment value). Despite these changes in the levels of physiologic inhibitors of coagulation, this schedule of L-asparaginase administration was associated with only rare clinical thrombosis, and this study suggests that the development of this complication may be dependent on the presence of additional factors.
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PMID:Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia. 357 67


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