Von Willebrand Factor and Thrombin Activation in Children With Newly Diagnosed Acute Lymphoblastic Leukemia: An Impact of Peripheral Blasts

Background. The pathogenesis and the impact of therapy on thrombin activation in children with acute lymphoblastic leukemia (ALL) are unknown. Steroids may contribute to ALL-associated thrombosis. We explored the hemostatic effects of methylprednisolone monotherapy (MpMT) (32 mg/m(2)/day IV x 3 clays) in children with newly diagnosed ALL. Methods. Children (>1 to <= 18 years of age) enrolled on DEO ALL05-01 protocol (n = 30; mean age 6.3 years), without prior steroid therapy, were eligible for study. Overnight fasting pre- and post-MpMT samples were analyzed for coagulation factors [FVIII:C, von Willebrand factor antigen (vWF:Ag) and fibrinogen] and parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin antithrombin complex (TAT), and D-dimer] Results. At diagnosis F1.2 (1.5 nmol/L), TAT (10.9 mu g/L), and D-dimers (2,766 ng/ml) levels were increased indicating endogenous thrombin activation. Patients with peripheral blasts (n = 17) had higher levels of vWF:Ag (1.89 vs. 1.14 P=0.001), TAT (15.39 vs. 5.02 P=0.038), and D-dimer (3,640 vs. 1,623 P=0.019) compared to those without peripheral blasts. Following MpMT the blast count decreased significantly from 24% to 3.5% (P < 0.001) with reduction in level of vWF:Ag (1.5, P < 0.01), TAT (8.9, P=0.42), and D-dimer (P=0.018) despite 30% increase in FVIII:C levels (P=0.005). However, patients without peripheral blasts had no significant change in vWF:Ag levels (1.14 vs. 1.25; P=0.142) and had an increase in thrombin generation parameters. Conclusions. We postulate that peripheral blasts through endothelial activation stimulate vWF:Ag production/secretion causing coagulation activation. Methylprednisolone therapy reduces the blast count and indirectly suppresses the coagulation activation. Future studies are required to confirm these findings. Pediatr Blood Cancer 2010;54:963-969. (C) 2010 Wiley-Liss, Inc.