Reduced antithrombin III levels during L‐asparaginase therapy

Buchanan, George R.; Holtkamp, Christine A.

doi:10.1002/mpo.2950080103

Cited by 35 publications

(13 citation statements)

References 28 publications

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“…The asparaginase-induced courses of fibrinogen, anthrombin 111, triglycerides and cholesterin are in accordance with other studies [6,7,[12][13][14][15]17,18].…”

Section: Discussionsupporting

confidence: 79%

Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects

Ollenschläger¹,

Roth²,

Linkesch³

et al. 1988

Eur J Clin Investigation

121

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Abstract. Several side-effects of asparaginase therapy have been said to be a consequence of the glutaminase activity of Escherichia coli asparaginase, especially the deleterious influence on the liver function. We report here the drug-induced impairments of asparagine and glutamine metabolism in correlation to concentrations changes of plasma proteins, synthesized in the liver, in patients with acute lymphatic leukaemia. One hour after asparaginase application, plasma glutamine decreased to 5% (0-39%: median, range) of the initial values, with a subsequent rise to concentrations slightly lower than those prior to therapy. During the 14 days of drug application the fasting plasma concentrations of glutamine fell to a median of 63% of the pre-therapeutic levels, indicating a depletion of the glutamine pools. Two days after the end of asparaginase application, in one patient the glutamine concentrations increased to the pre-therapeutic range. Plasma concentrations of fibrinogen and antithrombin I11 decreased to 46% and 56%, respectively, of the initial values, with a slight increase 2 days after the end of therapy. The changes of plasma protein concentrations followed the course of plasma glutamine and asparagine. From that we deduce that the hepatic synthesis of the plasma proteins might be influenced by asparagine and glutamine depletion as a consequence of the therapy with E. coli asparaginase.

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“…The asparaginase-induced courses of fibrinogen, anthrombin 111, triglycerides and cholesterin are in accordance with other studies [6,7,[12][13][14][15]17,18].…”

Section: Discussionsupporting

confidence: 79%

Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects

Ollenschläger¹,

Roth²,

Linkesch³

et al. 1988

Eur J Clin Investigation

121

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“…L‐asparaginase can also alter synthesis of proteins such as antithrombin (AT) and fibrinogen, leading to severe acquired deficiencies . Recently, AT activity was proposed as an indicator of L‐asparaginase activity during the induction phase (8 doses of E. coli L‐asparaginase) in children with ALL treated according to the ALL IC‐BFM 2002 protocol …”

Section: Introductionmentioning

confidence: 99%

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

Merlen

Bonnefoy

Afeich

et al. 2019

Pediatric Blood & Cancer

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Background L‐asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L‐asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L‐asparaginase activity. Methods Fibrinogen, von Willebrand factor antigen (VWF:Ag), total protein, and albumin levels as well as antithrombin (AT) and L‐asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L‐asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L‐asparaginase activity. Results Median E. coli L‐asparaginase activity was 220 IU/L (range, 0–1308) throughout the treatment period. L‐asparaginase activity was below 100 IU/L in 23% of measured samples. L‐asparaginase activity was inversely associated with AT activity, fibrinogen, total protein, and albumin levels (r = −0.63, −0.62, −0.57, and −0.45, respectively; P < 0.0001), but not with VWF:Ag. ROC curve analyses showed an intermediate accuracy of AT activity (area under the ROC curve [AUC] = 0.77) to detect specimens with subtherapeutic level of L‐asparaginase. An optimal accuracy was found when AT and fibrinogen were combined (AUC = 0.82; sensitivity = 75%; specificity = 82%; positive predictive value = 55%; negative predictive value = 92%) with cutoff values of 0.73 IU/mL and 1.85 g/L, respectively. Conclusions AT combined with fibrinogen levels could be used as a proxy to identify patients with therapeutic level of L‐asparaginase activity in the absence of real‐time asparaginase measurement during prolonged exposure to L‐asparaginase.

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“…These abnormalities are responsible for the development of hemorrhage and thrombosis. 7,[11][12][13]16 In our national ALL treatment protocol, L-Ase is given in 6 courses (6000μ/m 2 ) by intravenous infusion, modified from the international standard ALL protocol which uses 9 courses of L-Ase. This modification was done since the limited availability and high cost of the drug.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10] Significant reductions of fibrinogen, prothrombin, plasminogen, a 2 -antiplasmin, antithrombin (AT) III, and activated protein C (PCa) have been consistently reported and is also responsible for abnormal platelet aggregation. 4,7,[8][9][10][11][12][13][14][15] The reduction of AT III level is due to the decrease of its synthesis in the liver. [11][12][13] It is also reported that the tissue plasminogen activator and the plasminogen-activator inhibitor are reduced.…”

Section: Resultsmentioning

confidence: 99%

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Coagulation abnormality as a complication of L-asparaginase therapy in childhood lymphoblastic leukemia

Gatot¹,

Pringgardini²,

Suradi³

2016

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Background Bleeding, one of the most common symptoms of acute leukemia in untreated patients, is mostly due to thrombocytopenia as a result of myeloinvasion by leukemic cells. Nevertheless, a further contributory factor for the additional hemorrhagic complication during intensive chemotherapy is the myelosuppressive effect of most active drugs. L-asparaginase, one of the cytostatics used during remission induction therapy for childhood of acute lymphoblastic leukemia (ALL), is widely reported to impair the hemostatic system.

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Reduced antithrombin III levels during L‐asparaginase therapy

Cited by 35 publications

References 28 publications

Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects

Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects

Antithrombin and fibrinogen levels as predictors for plasma L‐asparaginase activity in children with acute lymphoblastic leukemia

Coagulation abnormality as a complication of L-asparaginase therapy in childhood lymphoblastic leukemia

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