title: beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation.
abstract: Patients with antiphospholipid syndrome are characterized by the association of thrombosis or pregnancy morbidity and the presence of antiphospholipid autoantibodies. Particularly, anti-beta(2)-glycoprotein (beta(2) GPI) autoantibodies correlate with thrombosis, suggesting an antibody-induced gain of prothrombotic function and/or an antibody-induced loss of antithrombotic function of beta(2) GPI. In the search for potential antithrombotic properties of beta(2) GPI, we found that beta(2) GPI inhibits von Willebrand factor (VWF)-induced platelet aggregation. In addition, platelet adhesion to a VWF-coated surface was decreased by 50% in the presence of beta(2) GPI (P < .03). beta(2) GPI binds to the A1 domain of VWF but preferably when the A1 domain is in its active glycoprotein Ibalpha-binding conformation. Anti-beta(2) GPI antibodies isolated from a subset of antiphospholipid syndrome patients neutralized the beta(2) GPI-VWF interactions and thus the inhibitory activity of beta(2) GPI. In comparison to healthy individuals, the amounts of active VWF in circulation were increased 1.5-fold (P < .001) in patients positive for lupus anticoagulant (LAC) due to anti-beta(2) GPI antibodies. Thus, beta(2) GPI is a biologically relevant inhibitor of VWF function by interfering with VWF-dependent platelet adhesion. Anti-beta(2) GPI autoantibodies neutralize this inhibitory function and are associated with increased levels of active VWF. This mode of action could contribute to the thrombosis and consumptive thrombocytopenia observed in patients with anti-beta(2) GPI antibodies.
authors.affiliation: Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Janine J J
authors.initials: JJ
authors.lastname: Hulstein
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.forename: Ron H W M
authors.initials: RH
authors.lastname: Derksen
authors.forename: Rob
authors.initials: R
authors.lastname: Fijnheer
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
mesh_terms: D016736:Antiphospholipid Syndrome / Q000276:immunology*; D005260:Female; D006801:Humans; D016682:Lupus Coagulation Inhibitor / Q000276:immunology*; D010973:Platelet Adhesiveness / Q000276:immunology*; D010974:Platelet Aggregation / Q000276:immunology*; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology*; D013927:Thrombosis / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology*; D014841:von Willebrand Factor / Q000276:immunology*
chemical_list: D016682:Lupus Coagulation Inhibitor; D053482:beta 2-Glycoprotein I; D014841:von Willebrand Factor