Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

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

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


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