title: L-Asparaginase lowers plasma antithrombin and mannan-binding-lectin levels: Impact on thrombotic and infectious events in children with acute lymphoblastic leukemia.
abstract: BACKGROUND
  L-asparaginase, a key therapeutic agent in the management of patients with acute lymphoblastic leukemia (ALL), dramatically impairs hepatic protein synthesis. We investigated the effects of prolonged exposure to L-asparaginase on antithrombin (AT), fibrinogen and mannan-binding-lectin (MBL) levels, and on the occurrence of thrombotic events (TE) and febrile neutropenia episodes (FN) in pediatric patients.
  
  
  METHODS
  Protein levels were measured in 97 children during 30 weeks of chemotherapy with L-asparaginase and up to 1 year following remission. TE and FN episodes were recorded during this period.
  
  
  RESULTS
  Median AT level decreased from 0.96 IU/mL prior to treatment (range: 0.69-1.38) to 0.55 IU/mL (0.37-0.76) during therapy. Fibrinogen and MBL decreased from 3.18 g/L (1.29-7.28) and 1,177 ng/mL (57-5,343) to 1.56 g/L (0.84-2.13) and 193 ng/mL (57-544), respectively. All three proteins had recovered 1-4 weeks after L-asparaginase cessation. TE were reported in 22 (23%) patients. Of these, 11 occurred after a median of 10 administrations of L-asparaginase. Fifty-one FN were associated with infections, of which 36 occurred during treatment with L-asparaginase. Patients with low levels of MBL at diagnosis were at higher risk of FN associated with infections (RR = 1.59, 95%CI: 1.026-2.474). Both AT and MBL decreases were moderately correlated with fibrinogen (r = 0.51 and 0.58, respectively).
  
  
  CONCLUSIONS
  Children with ALL are exposed to significant decrease in AT, fibrinogen and MBL levels, and concomitant increased risk of thrombosis and FN with infection during L-asparaginase treatment. Measuring plasma levels of these liver-derived proteins could help predict the occurrence of adverse events.
authors.affiliation: Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
authors.forename: Clémence
authors.initials: C
authors.lastname: Merlen
authors.affiliation: Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bonnefoy
authors.affiliation: Immunology / Histocompatibility laboratory, CHU de Quebec and Department of Microbiology, Infectious Diseases and Immunology, Laval University, Quebec, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Department of Hematology and Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dedeken
authors.affiliation: Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Leclerc
authors.affiliation: Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.affiliation: Division of Hematology / Oncology, CHU Sainte-Justine, Montréal, QC, Canada.
authors.forename: Georges-Etienne
authors.initials: GE
authors.lastname: Rivard
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000991:Antithrombins / Q000097:blood*; D001215:Asparaginase / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D064147:Febrile Neutropenia / Q000209:etiology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D037601:Mannose-Binding Lectin / Q000097:blood*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood*; D013927:Thrombosis / Q000209:etiology*
chemical_list: D000970:Antineoplastic Agents; D000991:Antithrombins; D037601:Mannose-Binding Lectin; D005340:Fibrinogen; D001215:Asparaginase
keywords: L-asparaginase; acute lymphoblastic leukemia; infections; mannan-binding-lectin; thrombosis