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-beta(2)-glycoprotein I (beta(2)GPI) antibodies. Antibody-induced dimerization of beta(2)GPI increases the affinity of beta(2)GPI for phospholipids, explaining the observed prolonged clotting times. We constructed dimers of beta(2)GPI that mimic effects of beta(2)GPI-anti-beta(2)GPI antibody complexes, and we studied their effects on platelet adhesion and thrombus formation in a flow system. Dimeric beta(2)GPI 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-beta(2)GPI or some, but not all, monoclonal anti-beta(2)GPI antibodies with LAC activity. These effects could be abrogated by inhibition of thromboxane synthesis. A LAC-positive monoclonal anti-beta(2)GPI antibody, which did not affect platelet adhesion, prevented the induced increase in platelet adhesion by beta(2)GPI 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 beta(2)GPI 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 beta(2)GPI induces increased platelet adhesion and thrombus formation, which depends on activation via apoER2'.