1 Von Willebrand factor biosynthesis, secretion & clearance: connecting the far ends

To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life-cycle, from synthesis to secretion and ultimately its clearance. Von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles both intra- and extracellular that implicate a wide range of other proteins: its presence is required for the formation and the regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), while VWF is also a key-determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life-cycle will help us to gain insight into the pathogenesis of von Willebrand disease, to design alternative treatment options to prolong the factor VIII half-life and to delineate the role of VWF and co-residents of the WPBs in the pro-thrombotic and pro-inflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion and clearance is provided and we will discuss how they can be affected by the presence of protein defects