Model for annexin A2–dependent endothelial cell activation induced by β₂GPI and anti-β₂GPI antibodies, or anti–annexin A2. In this model, annexin A2 (green) embedded in the outer plasma membrane of the endothelial cell may be directly cross-linked by anti–annexin A2 antibodies, or, alternatively, through the binding of anti-β₂GPI antibodies bound to β₂GPI (yellow) bound to annexin A2. We hypothesize that annexin A2 cross-linking may promote the aggregation of an annexin A2–associated transmembrane “adaptor” protein, perhaps with receptor tyrosine kinase activity (dashed line, blue extracellular domains), potentially leading to phosphorylation of this protein (P) and assembly of additional intracellular signaling proteins (red). Activation of endothelial cells by either scenario would be blocked by anti–annexin A2 Fab fragments.