Low plasma levels of hemostatic proteins during the induction phase in children with acute lymphoblastic leukemia: A retrospective study by the JACLS

Background : Thromboembolic and bleeding events are serious complications associated with the administration of L-asparaginase (ASP) during the induction phase in children with acute lymphoblastic leukemia (ALL). Prophylactic supplementation of plasma-derived coagulation products remains controversial. The purposes of this study were to examine the plasma levels of hemostatic proteins during the induction phase and the efficacy of prophylactic replacement of plasma-derived products. Methods : A multicenter retrospective survey on the incidence of hemostatic complications and the frequency of prophylactic replacement of plasma-derived products among children with ALL who underwent ASP therapy was conducted. All patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-97 protocol. Results : Thirty-six (67%) of the 54 JACLS-treatment centers responded and provided information on 127 patients. Clinically relevant hemostatic complications occurred in two patients (1.6%; 2/127); one patient suffered intracranial bleeding 5 days after beginning the protocol, and the second patient suffered an ischemic attack during an ASP treatment. The administration of ASP (10 000 u/m(2) x six doses) led to significant reductions in the plasma fibrinogen (180 +/- 74 to 105 +/- 57 mg/dL), antithrombin III (AT III) (126 +/- 21 to 73 +/- 18%), and plasminogen levels (97 +/- 17 to 52 +/- 18%). These laboratory parameters returned to normal levels 2 weeks after completion of the ASP treatment. Forty-eight patients (38%) received AT III concentrate (AT III-supplement group). The AT III level of the AT III-supplement group was significantly lower than that of the AT III non-supplement group, not only during the ASP therapy, but also prior to the ASP therapy. A greater percentage of patients in the AT III-supplement group received fresh-frozen plasma and in greater amounts than those in the AT III non-supplement group. Conclusions : Severe hemorrhage and thrombosis were uncommon in the ALL patients who underwent ASP therapy in comparison with the degree of coagulation changes. Prophylactic administration of AT III concentrate or fresh-frozen plasma did not demonstrate clear beneficial effects in the treatment of ALL in preventing thromboembolic events.