VWF-dependent platelet adhesion and TTP. VWF multimers adhere to endothelial cell surfaces or to subendothelial connective tissue through A1 or A3 domains (orange) in each VWF subunit. Platelets adhere to the VWF A1 domain through platelet membrane glycoprotein Ib (GPIb, blue). Flowing blood exerts a force on the platelet that stretches the attached VWF multimer. A1 and A3 domains have a disulfide bond (SS) that stabilizes them against this force. Without such a disulfide bond, the A2 domain unfolds and exposes the Tyr¹⁶⁰⁵-Met bond to cleavage by ADAMTS13, which releases adherent platelets and prevents microvascular thrombosis. Without sufficient ADAMTS13 activity, thrombi grow large enough to cause TTP. ADAMTS13 consists of metalloprotease (M), disintegrin-like (D), thrombospondin 1-like (T), cysteine-rich (C), spacer (C), and CUB [complement C1r/C1s, Uegf, Bmp1] domains.