B2GPI is the major antigen for pathogenic antibodies in antiphospholipid syndrome (APS). The presence of anti-b2GPI antibodies correlates with increased risk for thrombosis and pregnancy loss in patients with APS. In animal models of thrombosis, anti-b2GPI antibodies cause the increase in thrombus size after injury to the vessel wall. We engineered a molecule, A1-A1, that prevents the binding of b2GPI to anionic phospholipids and ApoER2, and studied how it inhibits prothrombotic properties of anti-b2GPI antibodies in vivo using the laser-induced arterial thrombosis model. Lupus-prone (NZWxBXSB)F1 male mice express chronic autoimmune anti-b2GPI antibodies. In (NZWxBXSB)F1 mice, infusion of A1-A1 at a dose of 4 ug/g of body weight caused a decrease in thrombus size of more than 85% as compared to thrombus size in the absence of A1-A1. Similarly, A1-A1 inhibits prothrombotic properties of b2GPI/anti-b2GPI antibody complexes in wild type mice following acute infusion with anti-b2GPI positive APS IgG. The thrombus reduction was due to the binding of A1-A1 to b2GPI, because infusion of LA6, a structural homologue of A1 that does not bind b2GPI, did not affect thrombus size. We did not observe thrombus inhibition by A1-A1 in the absence of anti-b2GPI antibodies, indicating that A1-A1 does not affect normal thrombus formation in the absence of anti-b2GPI antibodies.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.