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/m2/day IV x 3 days) in children with newly diagnosed ALL.


METHODS
Children (>1 to < or = 18 years of age) enrolled on DFCI 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 microg/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.
Athale
Uma
U
Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada. athaleu@mcmaster.ca
Moghrabi
Albert
A
Nayiager
Trishana
T
Delva
Yves-Line
YL
Thabane
Lehana
L
Chan
Anthony K C
AK
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008775:Methylprednisolone / Q000009:adverse effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D013917:Thrombin / Q000187:drug effects*; D013927:Thrombosis / Q000139:chemically induced; D014841:von Willebrand Factor / Q000187:drug effects*
D005938:Glucocorticoids; D014841:von Willebrand Factor; D013917:Thrombin; D008775:Methylprednisolone