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)

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

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.
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PMID:Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups. 1112 98

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

At diagnosis, there is evidence of increased thrombin generation in children with acute lymphoblastic leukemia (ALL), the etiology of which is unclear. However, thromboembolism (TE) in children with ALL is most commonly reported after the initiation of antileukemic therapy indicating a possible interaction of the disease and therapy. Antileukemic therapy influences the haemostatic system either by direct effect of the chemotherapeutic agents or indirectly through the effect of supportive care, e.g. central venous line (CVL) or infectious complications secondary to immunosuppression. Asparaginase and steroids are shown to induce hypercoagulable state by suppression of natural anticoagulants, especially AT and plasminogen, and by elevations in F VIII/vWF complex, respectively. In addition, steroid therapy causes hypofibrinolytic state by dose-dependent increase in plasminogen activator inhibitor 1 (PAI-1) levels. Combination of these effects coupled with increased thrombin generation may be responsible for the increased incidence of TE observed with concomitant administration of asparaginase and steroids. Further studies to delineate the mechanism of increased thrombin in generation children with ALL and effects of various chemotherapeutic agents, in isolation and in combination, on haemostatic system are needed.
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PMID:Thrombosis in children with acute lymphoblastic leukemia. Part II. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of the disease and therapy. 1469 64

Alterations in hemostasis have frequently been observed in children with acute lymphoblastic leukemia. Thrombotic events are well documented in patients receiving L-asparaginase as a single agent or in combination with other chemotherapeutic drugs. The present prospective, randomized study evaluated the effect of two different L-asparaginase preparations, native Escherichia coli L-asparaginase (Crasnitin; Bayer AG, Leverkusen, Germany; n = 10) and L-asparaginase derived from Erwinia chrysanthemi (Erwinase; Porton Pruducts, London, UK; n = 10) on the changes in parameters concerning hypercoagulability. Patients were randomized to receive a total of eight doses of 10,000 IU/m2 L-asparaginase intravenously with intervals of 3 days during induction therapy. Before starting L-asparaginase treatment all patients had already demonstrated an increased thrombin generation shown by the elevated levels of prothrombin fragment 1+2 and thrombin antithrombin III, presumably due to therapy with prednisone, daunorubicin and vincristine. A significant decrease in alpha2-antiplasmin and plasminogen levels was measured in the E. coli L-asparaginase but not in Erwinase-treated patients. Increased thrombin generation combined with a decrease in alpha2-antiplasmin and plasminogen levels may lead to a state of increased risk for thrombosis due to a delay in fibrin elimination in E. coli L-asparaginase-treated patients only.
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PMID:Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases. 1647 96

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.
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PMID:Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study. 1685 90

Thromboembolism (TE) is an uncommon entity in childhood. Overall 25% of children with thrombosis and more than 40% of children with central venous line (CVL) -related TE enrolled on the Canadian Pediatric Thrombophilia Registry had underlying diagnosis of cancer. However, so far there are very little data describing the epidemiology of TE in children with cancer. Most of the available information in this area originates mainly from retrospective and some prospective observational cohort studies conducted in children with acute lymphoblastic leukemia (ALL). Although ALL has been the most common cancer reported in association with thrombosis in children, available data from small studies indicate that TE is equally common in children with acute myeloid leukemia and lymphoma. TE in association with leukemia and lymphoma seems to be a multifactorial entity. Potential risk factors include increased thrombin generation related to leukemia, age of the patients, use of CVL, chemotherapy including asparaginase and corticosteroids, infections, and inherited prothrombotic state. Management of TE in a child with cancer presents a unique challenge in terms of balancing risk versus benefit. Conservative therapy could lead to clot extension and risks of additional morbidity or mortality; however, chemotherapy-related thrombocytopenia and coagulopathy increase the risk of bleeding complications. In summary, TE is a frequent and serious complication in children with hematologic malignancies. More prospective studies are required to define the epidemiology, pathogenesis, and management of TE in children with hematologic malignancies.
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PMID:Thromboembolic complications in pediatric hematologic malignancies. 1752 99

Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1-3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis.
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PMID:Thrombosis and acute lymphoblastic leukaemia. 1760 66

We analyzed the clinical factors resulting in hypofibrinogenemia, which is defined as less than 100mg/dl of plasma fibrinogen values determined by a procedure based on the Thrombin-time method. Within a 12-month period, we assayed 5,746 patients (19,309 plasmas) and found 113 patients (1.97%) with hypofibrinogenemia. We categorized these patients as having decreased synthesis of fibrinogen (less than 3.0g/dl of albumin, 140 IU/l of Cholinesterase, and/or 50% on Hepaplastin Test), increased consumption of fibrinogen (more than 10 microg/ml of FDP D-dimer), known side effect of L-asparaginase administration, or other causes. Details are follows: 1) decreased synthesis: 26 patients, suspected of decreased synthesis (albumin: 3.1-3.4 g/dl): 4 patients, 2) increased consumption: 15 patients, suspected of increased consumption (FDP D-dimer: 5.0-9.9 g/dl): 1 case, 3) decreased synthesis combined with increased consumption: 24 patients, suspected of decreased synthesis and/or suspected of increased consumption: 14 patients, 4) side-effect of L-asparaginase administration: 24 patients, 5) heterozygous dysfibrinogenemia: 1 patient, 6) heterozygous fibrinogen deficiency: 1 patient, suspected of heterozygous fibrinogen deficiency: 1 patient, 7) unidentified: 2 patients with West syndrome treated with a combination of ACTH and valproic acid. Three patients with dysfibrinogenemia or fibrinogen deficiency showed normal or slightly prolonged PT values and normal APTT values. These data and our previous reports suggest that heterozygous patients with dysfibrinogenemia or fibrinogen deficiency do not demonstrate markedly prolonged PT and APTT values, differing from patients with afibrinogenemia.
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PMID:[Analysis of hypofibrinogenemias found on routine coagulation screening tests and identification of heterozygous dysfibrinogenemia or fibrinogen deficiency]. 1815 29

Unfractionated heparin has been used as antithrombotic therapy for many years. Its main effect is attributed to the activation of antithrombin (AT), the heparin/AT complex inactivating both factor IIa (thrombin) and factor Xa. Resistance to unfractionated heparin with clinical or biological expression is uncommon. The occurrence of venous or arterial thrombosis or the extension of thrombosis in a patient receiving unfractionated heparin, should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia (HIT type 2). HIT type 2 is not a true heparin resistance but an immune complication that requires heparin discontinuation and the use of alternative anticoagulants. Biological heparin resistance is suspected in the presence of a normal or not prolonged activated partial thromboplastin time despite the administration of increasing dose of heparin. Measurement of anti-Xa activity is useful to adjust heparin treatment. Isolated biological heparin resistance is encountered in several physiological and pathological situations including inflammatory and infectious disorders, pregnancy and thrombocytosis. It also occurs in acquired antithrombin deficiency of nephrotic syndrome, l-asparaginase treatment or cardiopulmonary bypass. Biological heparin resistance is relatively common, but clinically significant resistance to heparin is rare and should always raise suspicion of either AT deficiency or type 2 heparin-induced thrombocytopenia.
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PMID:[Resistance to curative treatment by unfractionned heparin]. 1881 40


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