Age-Related Changes in Hemostasis in Children with Acute Lymphoblastic Leukemia; Influences of Peg-Asparaginase Upfront and Native E Coli Asparaginase during Remission Induction Therapy.

Alterations in hemostasis are frequently observed in children with ALL. Although increased thrombin generation is already present at diagnosis, thromboembolism is reported only after initiation of antileukemic therapy and mainly in children older than 10 years, indicating a relationship between disease, age and antileukemic treatment. During their development children will undergo physiological changes in hemostasis. These age-related changes might be related to the risk for symptomatic thrombo-embolic disease. The current report presents the results of a prospective study on coagulation and fibrinolysis parameters in 121 children with newly diagnosed ALL. The DCOG (Dutch Childhood Oncology Group) ALL-9 remission induction protocol consists of weekly vincristine injections and oral dexamethasone 6 mg/m2 during 4 weeks. From day 29, the dexamethasone dose is tapered and E. coli Asparaginase Paronal® is introduced, twice weekly at 6000 IU/m2 iv for 2 weeks. 64 children were studied according to this protocol, 57 children additionally received 1000 IU/m2 PEG-Asparaginase iv before the start of remission induction chemotherapy. Blood samples were collected at diagnosis (day -5) and 5 days after the PEG-Asparaginase administration at the start of regular induction chemotherapy (day 0), and immediately before each Paronal® infusion to analyze procoagulant (fibrinogen, F II, F V, F VII, F IX, F X) and anticoagulant factors (AT, prot C, prot S) and parameters of thrombin generation (F1+2, TAT) and fibrinolysis (a2-antiplasmin, plasminogen, PAP, D-dimer). At diagnosis a situation of enhanced thrombin generation was found (elevated levels of F1+2 and TAT) and signs of consumption coagulopathy (increased D-dimer together with hypofibrinogenemia). The effect of one dose of 1000 IU/m2 PEG-Asparaginase resulted five days later in a decrease of procoagulant and anticoagulant proteins; thrombin generation decreased, fibrinolysis did not increase further. 1000 IU/m2 PEG-Asparaginase induced an asparagine depletion lasting 4 weeks. The asparagine depletion did not result in a persistent inhibition of coagulation protein synthesis as all coagulation parameters at day 29 and at day 43 did not differ between patients who did or did not receive PEG-Asparaginase window-treatment. If we divided the children in three age groups (1–5, 6–10 and 11–16 years) the 11–16 year old children showed a greater decline in procoagulant and in anticoagulant factor levels compared to the younger children during Paronal® treatment. Also the fibrinolytic potential (a2-antiplasmin and plasminogen) was significantly more decreased in children older than 11 years during Paronal® treatment. Activation markers concerning thrombin generation and fibrinolysis did not change along time after day 29.

Conclusion: Age-related changes in hemostasis underline the increased risk of thrombosis during ALL induction treatment for children between 11 and 16 years of age compared to younger children.