VWF string characteristics. (A) A representative VWF string with VWF A1 (yellow circles), VWF A2 (blue circles), and with VWF A3 domains (green circles) in folded and unfolded parts of the VWF multimer (blue line). Attachment sites are represented by purple Y-shaped symbols. Platelets (gray circles) bind to open and accessible A1 domains. ADAMTS13 (red scissors) can digest unfolded VWF A2-domains. (B) VWF string length in vitro. Top: VWF multimers may consist of multiple self-associated multimers. Bottom: Occasionally, extraordinary long VWF strings (> 1 mm) are observed. Hence, these strings are probably formed by end-to-end self-association of different VWF multimers. (C) Platelet binding to VWF strings. Platelets bind to open VWF A1 domains (yellow circles) via their GPIb receptors. This binding does not result in a rolling movement of the platelets but in a firm adhesion to VWF strings. Bound platelets become activated as evidenced by the presence of P-selectin and activated αIIbβ3 on their surface.⁵¹  (D) Anchorage of VWF strings to endothelial cells. VWF strings are expelled from the WPB and remain anchored to the endothelial cells. P-selectin and αvβ3 have been identified as possible receptors involved in VWF string attachment in vitro, whereas these receptors do not seem to play a role in vivo. (E) ADAMTS13-mediated proteolysis of VWF strings. Top: ADAMTS13 (red scissors) mediated proteolysis of VWF strings is regulated by conformational changes in VWF and unfolding of its A2 domain (blue circle) induced by shear stress. Proteolysis occurs preferentially at sites of local elongations of VWF strings, which can be monitored by an increase in interplatelet distances (arrows).⁴³  Bottom: ADAMTS13 cannot access the cleavage site in VWF A2 domains (blue circle) that are folded or cannot bind when TSP-1 (orange circle) interacts with the VWF A2-A3 domains.