Dimers of β2-Glycoprotein I Increase Platelet Deposition to Collagen via Interaction with Phospholipids and the Apolipoprotein E Receptor 2

Patients with prolonged clotting times caused by lupus anticoagulant (LAC) are at risk for thrombosis. This paradoxal association is not understood. LAC is frequently caused by anti-β2-glycoprotein I (β2GPI) antibodies. Antibody-induced dimerization of β2GPI increases the affinity of β2GPI for phospholipids, explaining the observed prolonged clotting times. We constructed dimers of β2GPI that mimic effects of β2GPI-anti-β2GPI antibody complexes, and we studied their effects on platelet adhesion and thrombus formation in a flow system. Dimeric β2GPI increased platelet adhesion to collagen by 150% and increased the number of large aggregates. We also observed increased platelet adhesion to collagen when whole blood was spiked with patient-derived polyclonal anti-β2GPI or some, but not all, monoclonal anti-β2GPI antibodies with LAC activity. These effects could be abrogated by inhibition of thromboxane synthesis. A LAC-positive monoclonal anti-β2GPI antibody, which did not affect platelet adhesion, prevented the induced increase in platelet adhesion by β2GPI dimers. Furthermore, increased platelet adhesion disappeared after preincubation with receptor-associated protein, a universal inhibitor of interaction of ligands with members of the low density lipoprotein receptor family. Using co-immunoprecipitation, it was shown that dimeric β2GPI can interact with apolipoprotein E receptor 2 (apoER2′), a member of the low density lipoprotein receptor family present on platelets. These results demonstrate that dimeric β2GPI induces increased platelet adhesion and thrombus formation, which depends on activation via apoER2′.