Determinants of von Willebrand Factor Function

Abstract SCI-17 Platelet thrombus formation is a multistep process involving a number of molecular players, including von Willebrand factor (vWF). vWF is an adhesive multimeric protein that acts as a molecular bridge between the subendothelium and the glycoprotein Ib/IX/V receptor complex on platelets. Furthermore, vWF promotes the expansion of the platelet plug by cross-linking platelets via binding to integrin αIIbβ3. It is important to keep in mind that before participating in the formation of platelet-rich thrombi, vWF and platelets coexist in the circulation without interacting with each other. For optimal function, it is essential that vWF-platelet interactions occur in a timely way, that is, not too early and not too late. In the former case, spontaneous interaction may lead to intravascular thrombosis, while in the latter, hemorrhagic complications may arise. In order to reach this fine balance of regulation, a number of mechanisms are in place that contribute to control vWF function. In the last few years, considerable progress has been made in either revealing or better understanding such determinants. Physiologically, most of these mechanisms are dedicated to the prevention of excessive vWF-platelet interactions. These include shear-stress-mediated vWF conformational changes that lead to exposure or nonexposure of the platelet-binding site and cleavage sites on the vWF molecule. Intramolecular shielding of the vWF-platelet binding domain by adjacent domains also contributes to vWF reactivity. A major determinant of vWF function is related to its multimeric size, which can be controlled by proteolysis by ADAMTS13 and by other proteases, such as granzyme B or neutrophil elastase. The thiol reductase activity of ADAMTS13 toward vWF also contributes to multimer regulation. Finally, interaction of vWF with plasma proteins such as β2-glycoprotein I, or with endothelial proteins such as osteoprotegerin and galectins, can also participate in keeping vWF from binding excessively to platelets. Pathologically, dysregulations of the above-mentioned mechanisms may lead to either an overly active form of vWF or, in contrast, to an inactive protein. Additional determinants can also become prominent, such as the presence of mutations in the vWF sequence, leading to the genetic bleeding disorder known as von Willebrand disease. Determinants affecting vWF-platelet function have been studied extensively, as vWF participation in platelet thrombus formation is its best known and most important role. However, rather fascinating mechanisms have been identified that can modulate other functions of vWF. An example thereof is the recent identification of vWF cleavage by ADAM28 expressed by carcinoma cells in order to escape the proapoptotic action of vWF on such cells. Another example is the regulation of the Factor VIII binding capacity of vWF that can be controlled by cleavage by granzyme M. Identification of these various regulatory pathways now opens new avenues to act upon in order to better control the fine balance between the prohemostatic and the prothrombotic roles of vWF. Disclosures: No relevant conflicts of interest to declare.