Ex Vivo Thrombin Generation Assessment of Four Anticoagulants in Children with Acute Lymphoblastic Leukemia

Venous thromboembolic events (VTE) are a serious complication in children with acute lymphoblastic leukemia (ALL). Currently, there is no consensus regarding anticoagulant treatment or prevention in this setting, and the role of direct oral anticoagulants (DOACs) has not been extensively studied. The recent approval of DOACs for the treatment of VTE in children supports their further evaluation in pediatric patients with ALL. We prospectively evaluated the effects of four anticoagulant agents in 67 pediatric patients with ALL, compared with healthy controls, using the global coagulation assay thrombin generation (TG). The first 21 patients formed the calibration cohort, and we performed the primary TG analysis in the subsequent 46 patients. Measurements were performed before and after asparaginase therapy, with and without ex vivo spiking of the different anticoagulants. Low-molecular-weight heparin demonstrated preserved anticoagulant activity both before and after asparaginase therapy, with reductions of 29% and 31% in thrombin peak height, respectively, similar to healthy controls. However, the direct factor Xa inhibitors apixaban and rivaroxaban showed minimal anticoagulant effect (7%-13% reduction in thrombin peak height compared with reductions of 48%-59%, in controls). Notably, dabigatran, an oral direct thrombin inhibitor, demonstrated substantial anticoagulant activity before and after asparaginase therapy, with 180% and 134% prolongation of lag time, respectively, comparable to controls. These ex vivo pharmacodynamics findings support the anticoagulant activity of LMWH and dabigatran. The clinical efficacy of dabigatran in pediatric patients with ALL should be further investigated and confirmed in prospective in vivo studies.