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Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginase-treated children
U Nowak-Göttl1, N Kuhn, J E Wolff
1Department of Paediatrics, University Hospital, Münster, Germany.
Insights
Acquired antithrombin deficiency during leukemia treatment can cause thrombosis. Antithrombin substitution in children with acute lymphoblastic leukemia improved AT levels and reduced clot markers, suggesting a potential clinical benefit.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Acquired antithrombin (AT) deficiency is a significant side effect of L-asparaginase (ASP) treatment in acute lymphoblastic leukemia (ALL).
- This deficiency can lead to thrombosis, posing a risk to patients undergoing ALL therapy.
Purpose of the Study:
- To investigate the efficacy of antithrombin (AT) substitution in children with ALL treated with ASP.
- To evaluate the impact of AT concentrate administration on AT levels and markers of coagulation activation.
Main Methods:
- A prospective, non-randomized study of 27 children with ALL treated with the ALL-BFM-90 protocol.
- AT substitution was administered to 15 patients when plasma AT levels fell below 60% of normal, accompanied by increased D-dimer formation.
- Plasma AT concentrations and markers of thrombin generation (D-dimer, plasminogen activator inhibitor 1) were monitored post-administration.
Main Results:
- AT substitution successfully increased plasma AT concentrations, which remained elevated for up to 72 hours.
- Following AT concentrate administration, markers of thrombin generation, D-dimer formation, and plasminogen activator inhibitor 1 decreased towards normal levels.
- Laboratory findings suggest a potential benefit of AT substitution during ASP treatment.
Conclusions:
- Antithrombin substitution appears effective in restoring AT levels and mitigating markers of hypercoagulability in children with ALL receiving ASP.
- Further randomized trials are necessary to confirm the clinical benefit of prophylactic AT administration in preventing thromboembolic events in pediatric leukemia.
Abstract:
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.