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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.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.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).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. Pediatr Blood Cancer 2015;62:1381–1387. © 2015 Wiley Periodicals, Inc.