A MOUSE MODEL OF SEVERE VON-WILLEBRAND-DISEASE - DEFECTS IN HEMOSTASIS AND THROMBOSIS

von Willebrand factor (vWf) deficiency causes severe von Willebrand di sease in humans. We generated a mouse model for this disease by using gene targeting. vWf-deficient mice appeared normal at birth; they were viable and fertile. Neither vWf nor vWf propolypeptide (von Willebran d antigen II) were detectable in plasma, platelets, or endothelial cel ls of the homozygous mutant mice. The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous blee ding events in approximate to 10% of neonates, As in the human disease , the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf. Defective thrombosis in mu tant mice was also evident in an in vivo model of vascular injury, In this model, the exteriorized mesentery was superfused with ferric chlo ride and the accumulation of fluorescently labeled platelets was obser ved by intravital microscopy, We conclude that these mice very closely mimic severe human von Willebrand disease and will be very useful for investigating the role of vWf in normal physiology and in disease mod els.