The Efficacy of Prophylactic Use of Antithrombin with Unfractionated Heparin or Danaparoid Sodium to Prevent Venous Thromboembolism In Children with Acute Lymphoblastic Leukemia

Venous thromboembolism (VTE) is a severe complication that may occur during remission induction and intensification phases of treatment for childhood acute lymphoblastic leukemia (ALL). Previous studies have reported that the incidence of VTE in children with ALL ranges between 2.5–36.7%, and that risk factors for this condition comprise placement of central venous lines and L-asparaginase (L-ASP)-associated acquired antithrombin III (AT III) deficiency. We hypothesized that prophylactic replacement of AT III and use of heparin or heparinoid may reduce the incidence of VTE in children with ALL. In this study, we reviewed 72 consecutive children diagnosed with ALL at our institute to assess the strategy we used for preventing VTE. The strategy comprised prophylactic use of AT III concentrate and unfractionated heparin (UFH) or danaparoid sodium (DS, which catalyzes the inactivation of factor Xa and thrombin).

From January 2002 to April 2010, 69 children newly diagnosed with ALL and 3 children with relapsed ALL received conventional chemotherapy at our institute. This therapy included combined use of L-ASP (30000–48000 IU/m² in each phase) and prednisolone during both induction and intensification phases. During the treatment phase, 69 children received UFH (2000–3000 IU/m²/day) by continuous intravenous infusion, while 3 children with disseminated intravascular coagulation (DIC) syndrome received DS (70 IU/m²/day) twice daily by intravenous infusion. Plasma AT III activity was measured in all children at least thrice a week, and children in whom AT III activity tended to decrease below 80% were given AT III replacement.

The study included 47 boys and 25 girls who were aged between 1–15 years (median age, 4 years). The underlying diseases were B-cell precursor ALL (n = 62), T-cell ALL (n = 7), and relapsed ALL (n = 3). Complications observed at diagnosis were as follows: 15 children had infections, 3 had DIC, 2 had hypertension, and 1 had multiple organ failure. Complications observed during the induction phase were as follows: 24 children had infections, 3 had acute pancreatitis, 1 had pneumomediastinum, and 1 had glaucoma. These complications necessiated the suspension and delay of the induction phase in 12 of these children. During the intensification phase, although 13 children had infections and 1 had hemorrhagic cystitis, no children required suspension of the intensification phase. No one developed VTE in either of the two phases. Replacement of AT III was required 0–9 times (with a median of 2 times) and 0–6 times (with a median of 2 times) during induction and intensification phases, respectively. A hemorrhagic event (greater than CTCAE grade 3) was not observed during either of the phases.

Our observations suggest that prophylactic use of AT III concentrate with UFH or DS are safe and effective treatments for preventing VTE in children with ALL. Further randomized studies on these treatments are therefore warranted.

No relevant conflicts of interest to declare.