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)

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

It is well known that L-asparaginase (L-Ase) treatment may cause thrombotic events in patients with acute lymphoblastic leukemia (ALL). The mechanism of this effect is not well understood although a reduction in plasma antithrombin III (AT III) levels is observed. In our study, a group of patients treated with L-Ase received AT III concentrates as adjuvant treatment. This adjuvant treatment reduced the levels of plasma D-dimer and thrombin-antithrombin complex, which are considered as early markers of a hypercoagulability state. These preliminary data suggest that large randomized trials will have to be conducted to improve our understanding of the role of AT III concentrates in ALL therapy.
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PMID:L-asparaginase in acute lymphoblastic leukemia treatment: the role of human antithrombin III concentrates in regulating the prothrombotic state induced by therapy. 772 51

Three out of 21 patients treated at the Children's Hospital of Eastern Switzerland for ALL or NHL with the respective BFM-90 protocols experienced thrombotic complications during Erwinia L-asparaginase therapy. We therefore investigated the development of the haemostatic imbalance in six children during the induction phase of both protocols. In the average, elevated thrombin generation was found simultaneously to an increase in fibrinogen, cross-linked fibrin degradation products and platelet counts between protocol days 28 to 35. This period thus seems to harbour an increased potential of hypercoagulability which could explain the accumulation of thrombotic complications described by Sutor et al. Moreover, day to day investigations just before and one day after L-asparaginase administration did not show any relevant change in the above named parameters, thus rather indicating a cumulative than a single dose effect of Erwinia L-asparaginase therapy on the coagulation system. These findings lead to the question if the prophylactic use of anticoagulants might reduce the hypercoagulability seen during L-asparaginase therapy, which is currently under investigation in our institutions.
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PMID:Increased thrombin generation during fibrinogen and platelet recovery as an explanation for hypercoagulability in children with L-asparaginase therapy for ALL or NHL: a preliminary report. 796 34

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

L-Asparaginase treatment of leukemia patients causes hemostatic problems. To investigate whether L-asparaginase influences coagulation studies, 63 blood samples of 21 healthy male donors were incubated with L-asparaginase for 30 min at room temperature. After treatment with 100 IU/ml L-asparaginase plasma fibrinogen (P = 0.002), plasma antithrombin (P = 0.0002), plasma protein C (P = 0.0004), and plasma plasminogen (P = 0.0039) were decreased compared with controls. In contrast, a significant increase in plasma von Willebrand factor antigen (P = 0.08) and plasma thromboglobulin (P = 0.005) was observed. The decrease in plasma anti-thrombin (P = 0.001), plasma protein C (P = 0.0003), and plasma plasminogen (P = 0.0043) was also measurable after 0.05 IU/ml asparaginase treatment. The incubation with L-asparaginase was similar to the normal time from blood sampling to testing and hence the results suggest that L-asparaginase may directly attack proteins of the coagulation system during the interval between sampling and assay.
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PMID:Asparaginase decreases clotting factors in vitro: a possible pitfall? 856 77

A prospective longitudinal study was conducted to determine whether single-donor fresh frozen plasma (FFP) substitution was able to influence L-asparaginase-associated hypoproteinemia. Within a 36-month period, 20 of 42 children with ALL received a total of 42 prophylactic FFP doses at a median of 10 (5-20) mliter/kg when fibrinogen levels decreased to < 60 mg/dL and thrombin time was lengthened. Laboratory monitoring before, during and after FFP substitution showed no short-term improvements and demonstrated only a minimal increase in fibrinogen and alpha 2-antiplasmin. Plasma levels of antithrombin and plasminogen remained unchanged. Furthermore, administration of FFP had no influence on thrombin generation, the plasmin/alpha 2-antiplasmin complex or enhanced D-dimer formation.
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PMID:Inefficacy of fresh frozen plasma in the treatment of L-asparaginase-induced coagulation factor deficiencies during ALL induction therapy. 864 57

Acquired deficiency of antithrombin (AT), which in some patients could lead to thrombosis, has been a serious side effect of protocols which incorporate E. coli L-asparaginase (ASP) for the treatment of acute lymphoblastic leukaemia (ALL). In a longitudinal, prospective, non-randomized study children with ALL (n=27) were treated according to the protocol ALL-BFM-90. During the induction phase using prednisone, vincristine, daunorubicin and ASP, AT substitution was performed in 15/27 patients, when their plasma concentration decreased below 60% of normal with a concomitant increase of D-dimer formation. After the administration of the AT concentrate the patients, plasma concentration of AT increased and remained elevated after 18, 48, and 72 h. In addition, the plasma concentration of enhanced thrombin generation, D-dimer formation and plasminogen activator inhibitor 1 decreased towards normal levels. Although the observed laboratory findings may serve as evidence for a possible clinical benefit of AT substitution during ASP treatment, further randomized studies are requested to evaluate whether the use of prophylactic AT administration could reduce the incidence of thromboembolic events in childhood acute leukaemia.
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PMID:Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginase-treated children. 859 91

Thromboembolic events (TE) are serious complications of treatment for childhood acute lymphoblastic leukemia (ALL) that result in significant morbidity and occasionally mortality. These events are strongly associated with the administration of L'asparaginase (ASP). There have been many studies reporting TE and assessing the coagulopathy associated with treatment. The intention of these studies was to determine a potential mechanism for thrombosis. This article reviews the current literature in this area. First, data on thrombotic complications in terms of incidence, location, diagnosis, and timing of events are summarized. The second section discusses the coagulopathy associated with the disease and treatment. To minimize the effects of confounding treatments, the data are divided into sections covering pretreatment, after ASP only, after combination chemotherapy without ASP, and after combination chemotherapy with ASP. In addition, the effects of glucocorticoid steroids on the hemostatic system are discussed. As thrombin regulation is critically important to hemostasis, the next section of the review discusses the regulation of thrombin in children with ALL, both in vitro and in vivo, and the link between impaired thrombin regulation and TE in this population. Finally current hypothesis on mechanisms for TE and proposed preventative strategies are examined.
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PMID:Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease and treatment. 874 2

The influence of two different E. coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood ALL was recently reported, demonstrating a clearly significant association between ASP activity and haemostatic changes. Since the Bayer preparation is no longer available for treatment of large series of patients with ALL, the present study was designed to prospectively evaluate coagulation and fibrinolytic changes in leukaemic children receiving different doses of Medac ASP, which is now available for treatment of childhood ALL. Leukaemic children in whom ASP Medac was administered at 3 d intervals in a two-step dose reduction (5000 IU/m2, n = 10; 2500 IU/m2, n = 15) were compared with children who had received Bayer ASP 10,000 IU/m2 in the same time schedule in a former randomized trial; at the same venipuncture, blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacokinetic monitoring. Compared with Bayer ASP 10,000 IU/m2, patients receiving Medac ASP 5000 IU/m2 showed significantly decreased values of fibrinogen, plasminogen, and alpha 2-antiplasmin, along with significantly enhanced thrombin generation. Improvement occurred in children treated with 2500 IU/m2 Medac ASP; alpha 2-antiplasmin and D-dimer no longer differed from the Bayer group. Since both patient groups showed complete asparagine depletion during the course of ASP administration, the lower dosage of 2500 IU/m2 administered at 3 d intervals should guarantee the specific metabolic therapy for ALL, leading to depletion of the circulating pool of asparagine.
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PMID:Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation. 885 48

We attempted to administer PEG-L-asparaginase (PEG-L-A) following hematologic recovery to 38 patients undergoing autologous or allogeneic marrow transplantation for acute lymphoblastic leukemia (ALL). Twenty-four patients (12 of 22 receiving allogeneic and 12 of 16 receiving autologous transplants) received between one and 12 doses of PEG-L-A, including nine who completed the planned 12 doses of therapy. The toxicities encountered were similar to those observed in non-transplanted patients undergoing therapy with PEG-L-A and included allergic reactions, pancreatitis, weight loss, hypoalbuminemia, and low levels of anti-thrombin III. Of the 24 who received the drug, eight remain in remission. Of 12 patients in second remission at the time of transplantation who received PEG-L-A, five of seven who received allogeneic and two of five who received autologous transplants remain in remission, 16+ to 46+ months from transplant. While PEG-L-A could be administered to most of the patients undergoing marrow transplantation for ALL, most patients either relapsed while receiving the drug or developed toxicities which resulted in abbreviated courses. At this time, we cannot recommend PEG-L-A as single agent, post-BMT chemotherapy.
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PMID:Toxicity, pharmacology and feasibility of administration of PEG-L-asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia. 961 79


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