Sequence of events leading to cellular activation by β₂GPI-antibody complexes. β₂GPI is not recognized by pathologic anti-β₂GPI antibodies in the circulation. When negatively charged, phospholipids become exposed, and β₂GPI will bind to this surface and change conformation. This step exposes a cryptic epitope in domain I that is recognized by the pathologic antibodies. The antibody fixes β₂GPI in this conformation, and the antibody–β₂GPI complex can subsequently interact with several surface receptors, such as glycoprotein Ibα (GPIbα), LRP8, annexin A2, and several members of the TLR family (TLR2, -4, and -8). Because receptor and phospholipid binding are mutually exclusive, the β₂GPI–antibody complex probably dissociates from the surface before it can interact with a surface receptor.