Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a crucial role in hemostasis and thrombosis. VWF synthesis is restricted to endothelial cells (ECs) and megakaryocytes. VWF circulates in the blood either in plasma or in platelets. Although biochemical differences between plasma and platelet-derived VWF have been described in vitro, the exact contribution of both VWF compartments in thrombotic and hemostatic processes in vivo still remains unclear. This information, however, is crucial for the efficient treatment of thrombotic events and hemorrhages. In the first part of this project the role of VWF, and especially the role of VWF present in platelets, in thrombosis and hemostasis will be studied. Therefore we will generate chimeric VWF-/- mice expressing VWF only in platelets. Reconstitution of the plasma VWF compartment will be realised through the hydrodynamic injection of a VWF expression plasmid. The construction of a VWF-/- mouse that expresses VWF in all blood cells provides a first step in the development of a potential gene therapeutic strategy for the treatment of VWD, which will be examined in the second part of the project. To achieve this goal, hematopoietic stem cells isolated from VWF-/- mice will be ex vivo modified with (non-) viral vectors that express VWF under the control of a CMV promoter and infused into irradiated VWF-/- mice.