Model for a mechanism of anxA5 reduction on the surface of phospholipid membranes leading to thrombosis in APS. Panel Ai shows anionic phospholipids exposed at the surface of endothelial cells and platelets after activation/damage of or to the cells. Subsequently AnxA5 becomes positioned above the damaged site and thereby prevents further clotting (panels Aii and Aiii). Monomeric β2GPI does not have a sufficient affinity to compete with AnxA5 for binding. When damage occurs to the endothelial surface of an APS patient with antibodies against epitope G40-R43 on domain I of β2GPI, β2GPI initially binds the anionic phospholipids with a rather low affinity (panel Bi). However, following binding, β2GPI undergoes a conformational change that enables the antibody to bind the epitope g40-R43 of 2 β2GPI molecules (panels Bii and Biii). This dimerized β2GPI has a high affinity for the anionic phospholipids at the surface of the damaged cell.²¹  Panel Biv shows that due to the dimerization of β2GPI, it has a high enough affinity to compete with AnxA5 for the exposed anionic phospholipids. The reduced AnxA5 concentration on the damaged cell may lead to excessive clotting (panel Bv) and subsequently thrombosis.