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We have described an autoantibody against β3 (GPIIIa49–66), a region of platelet integrin αIIbβ3 that is unique. It induces platelet fragmentation in the absence of complement via antibody activation of platelet NADPH oxidase and 12-lipoxygenase to release reactive oxygen species, which destroy platelets. To study the mechanism of anti-GPIIIa antibody-induced platelet fragmentation, we screened a human single chain Fv antibody library with the GPIIIa49–66 peptide. Nine monoclonal antibodies were identified that were capable of binding to GPIIIa49–66. Surprisingly, binding avidity for GPIIIa49–66 did not correlate with activity of induction of platelet fragmentation. We therefore investigated the requirements for platelet fragmentation. Mutations were introduced into the heavy chain complementary-determining region-3 of clones 11, 43, and 54 by site-directed mutagenesis. The capability of these clones to induce platelet fragmentation or bind to GPIIIa49–66 subsequently changed. Molecular modeling of these clones with their mutants revealed that the ability to induce platelet fragmentation is affected by the side chain orientation of positively charged amino acids in the heavy chain of residues 99–102. Thus, a structural change in the conformation of anti-GPIIIa49–66 antibody contributes to its binding to the β3 integrin and subsequent antibody-induced platelet fragmentation and aggregate dissolution.