When histamine-stimulated endothelial cells are perfused with platelets in buffer, the platelets form long beads-on-a-string structures on the surface of the cells. The strands connecting the platelets are composed of ultralarge multimers of von Willebrand factor (ULVWF) and can be rapidly cleaved when perfused with normal plasma or purified ADAMTS-13 metalloprotease, but not with plasma from patients with either congenital or acquired thrombotic thrombocytopenic purpura (TTP). These ULVWF strings anchor to the surface of the endothelial cell at least partly through P-selectin, as their formation is prevented by either soluble P-selectin or P-selectin antibodies. They are also able to support the attachment of beads coated with ADAMTS-13. The metalloprotease binds to both the A1 and A3 domains of VWF, the latter with higher affinity. This attachment docks the enzyme close to its substrate site within the A2 domain. We propose that attachment of newly released ULVWF to the endothelial cell surface facilitates its cleavage by ADAMTS-13 by allowing tensile force to be applied to the A2 domain, thereby exposing the ADAMTS-13 cleavage site.