von Willebrand factor Jedi knight of the bloodstream
When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF) with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended threadlike in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational forcepropagated through the length of VWF in its thread like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF duringbiosynthesis.A2domainunfolding by hydrodynamic force enables postsecretion regulationofVWFlength.Mutations in VWF in vonWillebrand disease contribute to and are illuminatedbyVWFbiology. I attempt to integrate classic studies on the physiology of hemostatic plug formation intomodernmolecularunderstanding, and point out what remains to be learned. (Blood. 2014;124(9):1412 1425)