title: Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome.
abstract: Antiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy losses. β2-glycoprotein I (β2GPI) is the major antigen for clinically relevant antibodies in APS. We engineered a molecule, A1-A1, which interferes with 2 prothrombotic mechanisms in APS: the binding of β2GPI to negatively charged cellular surfaces and ApoE receptor 2. We studied how A1-A1 affects arterial thrombosis in vivo in lupus-prone (NZW × BXSB)F1 male mice. For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in vivo in the presence of chronic autoimmune anti-β2GPI antibodies. We have shown that A1-A1 interferes with thrombotic properties of β2GPI/antibody complexes and does not affect normal thrombus formation in the absence of anti-β2GPI antibodies. A1-A1 inhibits prothrombotic properties of β2GPI/antibody complexes in wild-type mice after acute infusion with anti-β2GPI antibodies, as well as in mice expressing persistent autoimmune anti-β2GPI antibodies. A1-A1 reduced thrombus size in a mouse model of APS in the presence of lupus features, suggesting that A1-A1 might effectively interfere with thrombosis not only in primary APS but also in APS secondary to lupus. Our results suggest that A1-A1 could be a prototype for an antithrombotic drug in APS.
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kolyada
authors.forename: Andrew
authors.initials: A
authors.lastname: Porter
authors.forename: Natalia
authors.initials: N
authors.lastname: Beglova
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000009:adverse effects* / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013927:Thrombosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D007074:Immunoglobulin G; D026502:LDL-Receptor Related Proteins; D053482:beta 2-Glycoprotein I; C098773:low density lipoprotein receptor-related protein 8