The ADAMTS13 cleavage site (the Y1605-M1606 bond) in the VWF A2 domain is buried within the native, folded structure of VWF multimers and is not accessible to cleavage by the metalloprotease [3] [4] [5] . Although a report found that recombinant VWF-A2 peptide (a.a.1481-1668) was sensitive to proteolysis by ADAMTS-13 under physiological pH and non-denaturing conditions [17] , most of studies have shown that even for the isolated A2 domain, unfolding by high fluid shear stress or chemical denaturants such as urea and guanidine-HCl is required for proteolysis by ADAMTS13 [10, 18] . Thus, for VWF with its multi-domain structure, not only the inter-domain but also the intra-domain A2 structural changes have regulatory roles in ADAMTS13-mediated cleavage of VWF. Our data demonstrate that the epitope of SZ34, a mAb raised against native VWF multimers, is located within the A1555-G1595 region, which comprises the a2-helix and a3-helix according to the crystal structure of VWF A2 domain [19] . It is possible that part or all of the a2-helix and a3-helix structure of A2 domain is constitutively exposed on the native VWF multimers and is involved in the regulation of VWF proteolysis by ADAMTS13. Previous studies, however, considered that the A2 domain of VWF is normally sandwiched between the much larger A1 and A3 domains [19, 20] , and the D1596-R1668 region in VWF A2 domain (the so called VWF73) is the minimal substrate for ADAMTS13 [21] .