Blood, 1 July 2002, Vol. 100, No. 1, pp. 143-147
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Factor VIII expression in azoxymethane-induced murine fulminant
hepatic failure
Christopher B. Doering,
Cassandra D. Josephson,
Heather
N. Craddock, and
Pete Lollar
From the Winship Cancer Institute, Emory University,
Atlanta, GA.
Fulminant hepatic failure (FHF) in humans produces a bleeding
diathesis due in large part to a reduction in the biosynthesis of
liver-derived coagulation factors. Remarkably, factor VIII procoagulant
activity is elevated in most of these patients despite widespread liver
cell death. FHF can be modeled in mice by administration of
azoxymethane, the active ingredient found in cycad palm nuts. We
compared the expression of factor VIII to other hepatic hemostatic factors in azoxymethane-induced murine FHF. Mice displayed
dose-dependent decreases in all coagulation factor activities measured,
including factors V, VII, VIII, and IX. At the highest dose of
azoxymethane (50 µg/g body weight), factor VIII activity in plasma
decreased by 98% within 36 hours after treatment, which was associated
with an 80% reduction in hepatic factor VIII messenger RNA (mRNA). In
contrast, factor VIII mRNA levels in spleen, kidney, and lung tissue of
azoxymethane-treated mice were unchanged. Cellular damage in these mice
appeared to be limited to hepatocytes as evident by histologic
examination. This finding is supported by 2 observations. First,
hepatic mRNA levels of von Willebrand factor, which is synthesized by
liver sinusoidal endothelial cells but not hepatocytes, were unchanged.
Second, von Willebrand factor was detected antigenically in liver
sections of azoxymethane-treated mice by immunofluorescence. These
results indicate that the contribution of the liver to factor VIII
biosynthesis is not replaced or significantly supplemented by other
tissues in this model of FHF.
