We found that SZ34, a mAb against the A2 domain of human VWF, reduces the susceptibility of VWF to proteolysis by ADAMTS13 under fluid shear stress. However, this effect was not observed under static and chemically denaturing conditions. Seven other mAbs against VWF including SZ129 and SZ130 (two mAbs against VWF A1), SZ29 (another mAb against VWF A2), SZ123 and SZ125 (two mAbs against VWF A3) and 1C1E7 and 75H4B12 (two mAbs against VWF D'D3) exhibited no effects on ADAMTS13-mediated VWF proteolysis under either shear stress or denaturing conditions. The epitope mapping shows that the epitope of SZ-34 is located within the A1555-G1595 region of the A2 domain of native VWF, suggesting that this region may directly interact with ADAMTS13. Furthermore, the mAb SZ-34 is a conformation-sensitive mAb because it preferentially binds to native VWF. VWF-D'D3 no effect no effect 75H4B12 25 VWF-D'D3 no effect no effect SZ129 26 VWF-A1 no effect no effect SZ130 26 VWF-A1 no effect no effect SZ29 28 VWF-A2 no effect no effect SZ34 27,28 VWF-A2 inhibition no effect SZ123 27 VWF-A3 no effect no effect SZ125 27 VWF-A3 no effect no effect doi:10.1371/journal.pone.0022157.t001 Only two reports have been published showing the inhibitory effects of VWF antibodies on the proteolysis of VWF by ADAMTS13, but the mechanism of inhibition by SZ34 may be different from that of the two other mAbs VP-1 and RU8 reported by Tsai et al [15] and Zanardeli et al [16] , respectively. The mAb VP-1, which was directly against residues 1591-1605 (inside VWF A2 domain) of VWF polypeptide, inhibited the susceptibility of the recombinant type 2A VWF mutants R1606W and R1606Q to proteolytic cleavage by ADAMTS13 under the static condition. But they did not examine whether VP-1 inhibited native pVWF or wild-type recombinant VWF proteolysis by ADAMTS13 [15] . Because VP-1 was raised against the synthetic VWF peptide (residues 1591-1605) and reacted poorly with the intact subunit (250 kDa fragment) of VWF in reduced SDS-PAGE followed by immunoblotting [3, 15] , we speculated that VP-1 could not bind to native VWF and could not affect its proteolysis by ADAMTS13 without denaturization or under shear stress. In addition, Zanardelli et al [16] reported the inhibition of VWF proteolysis by ADAMTS13 under shear by using RU8, a mAb directed against the VWF D4 domain. They suggested that a binding site in the Cterminal region (D4CK) of VWF is constitutively exposed and participates at the initial step of a multi-step interaction, ultimately leading to proteolysis of VWF by ADAMTS13. Thus, RU8 may inhibit VWF proteolysis by inhibiting the initial binding of the distal domains of ADAMTS13 to the C-terminal region of VWF. We found that the mAb, SZ34, bound to native VWF better than pre-denatured VWF at the central A2 domain, and decreased the cleavage of native VWF under shear stress, but not pre-denatured VWF under static conditions. These findings suggest that SZ34 binds native VWF-A2 domain, which may block the conformational change of VWF or block the access of ADAMTS13 to the ancillary binding site and cleavage bond located at the central A2 domain under fluid shear stress.