ABSTRACTvon Willebrand factor (vWf) deficiency causes severe von Willebrand disease 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 Willebrand antigen II) were detectable in plasma, platelets, or endothelial cells of the homozygous mutant mice. The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in Ϸ10% 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 mutant mice was also evident in an in vivo model of vascular injury. In this model, the exteriorized mesentery was superfused with ferric chloride and the accumulation of f luorescently labeled platelets was observed 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 models.

Megakaryocytopoiesis is the cellular developmental process that leads to platelet production. At least two humoral growth factors may be necessary for megakaryocyte proliferation and maturation. One is a megakaryocyte-colony stimulating factor (MK-CSF) which induces the proliferation and differentiation of megakaryocyte progenitors, and the second, thrombopoietin, is a megakaryocyte maturation factor. Neither of these factors has been fully characterized. The proto-oncogene c-mpl, an orphan member of the haematopoietin receptor family, is specifically involved in megakaryocyte regulation. Here we present evidence that the c-mpl-encoded receptor binds a ligand (c-Mpl ligand) which is a humoral factor implicated in platelet homeostasis. Our results suggest that c-Mpl ligand, thrombopoietin and MK-CSF might be the same molecule.