Structure of VWF and ADAMTS13. VWF multimers may contain ≥40 ∼250 kDa subunits linked together by disulfide bonds between C-terminal cystine-knot (CK) domains and N-terminal D3 domains. The VWF subunit is composed mostly of repeated A, C, and D domains and has binding sites for many proteins, including factor VIII, platelet GPIb, and collagens (Col) 1, 3, and 6. The A2 domain has a globular structure in native VWF, but unfolds in response to fluid shear stress to expose a Tyr-Met bond (red triangle) that is cleaved by ADAMTS13. ADAMTS13 is a multidomain protein with metalloprotease (M), disintegrin-like (D), thrombospondin type 1, Cys-rich, spacer, 7 more thrombospondin type 1 repeats, and 2 CUB domains. A molecular model of the proximal domains shows sites (shaded red) that interact with the extended sequence of the A2 domain.