Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies

Patients with antiphospholipid antibodies (APLAs) are at increased risk for arterial and venous thrombosis. Many APLAs associated with these events react with beta2 glycoprotein I (beta2GPI), and endothelial cell reactive antibodies that activate endothelial cells in a beta2GPI-dependent manner occur commonly in these patients. We previously reported that beta2GPI binds with high affinity to annexin A2 on the endothelial surface, though the relevance of this interaction to APLA/anti-beta2GPI antibody-induced endothelial activation has not been determined. In this report, we confirm that anti-beta2GPI antibodies activate endothelial cells in the presence of beta2GPI, and demonstrate that anti-annexin A2 antibodies directly cause endothelial cell activation of a similar magnitude and with a similar time course. Moreover, bivalent anti-annexin A2 F(ab')2 fragments also caused endothelial cell activation, whereas monomeric Fab fragments not only did not cause activation, but blocked activation induced by anti-annexin A2 antibodies and F(ab')2 fragments, as well as that caused by anti-beta2GPI antibodies in the presence of beta2GPI. These observations suggest a novel pathway for endothelial activation induced by APLA/anti-beta2GPI antibodies that is initiated by cross-linking or clustering of annexin A2 on the endothelial surface.