ADAMTS13 activity in normal and thrombotic thrombocytopenia purpura (TTP) plasma.

(A) In normal individuals, ADAMTS13 enzyme molecules from the plasma attach to, and then cleave, unusually large von Willebrand factor (ULVWF) multimers that are secreted in long “strings” from stimulated endothelial cells.

(B) The ULVWF multimeric strings may be anchored in the endothelial cell membrane to P-selectin molecules that are secreted concurrently with the ULVWF multimers from Weibel-Palade bodies. P-selectin molecules are retained in the endothelial cell membrane by a transmembrane portion. Each ADAMTS13 molecule may dock via one or both of its C-terminal CUB domains, possibly along with one or more thrombospondin-1-like domains, to exposed A3 domains in ULVWF monomeric subunits. The attached ADAMTS13 molecules then cleave Tyr 842–843 Met peptide bonds in the adjacent A2 domains of ULVWF monomeric subunits. The smaller VWF forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood flow.

(C) Absent or severely reduced activity of ADAMTS13 in patients with TTP prevents the timely cleavage of ULVWF multimers secreted by endothelial cells. Uncleaved ULVWF multimers induce the adhesion and subsequent aggregation of platelets in flowing blood. Congenital deficiencies of ADAMTS13 activity caused by gene mutations or acquired defects of ADAMTS13 caused by autoantibodies result in TTP.