In conditions of high shear blood flow, ULVWF multimers secreted from stimulated endothelial cells (18-19) are anchored in string-like formations by the P-selectin molecules exposed on the surface of activated endothelium . They are then cleaved by ADAMTS13 between Tyr1605-Met1606 residues located within the A2 domain. More specifically, ADAMTS13 binds under flow conditions to accessible A3 domains in the monomeric subunit of VWF and then cleaves the Tyr 1605-Met1606 peptide bond in the adjacent A2 domain.

As a consequence of ADAMTS13 deficiency, ULVWF multimers are not cleaved after their secretion from endothelial cells, but remain anchored to the cells. Passing platelets adhere via their GpIb and GpIIb/IIIa to the A1 and the A3 domains of the monomeric subunits of ULVWF strings anchored to P-selectin to form large, potentially occlusive, platelet thrombi.