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 Blood, 1 September 2007, Vol. 110, No. 5, pp. 1483-1491.
Prepublished online as a Blood First Edition Paper on May 8, 2007; DOI 10.1182/blood-2006-10-053199.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

β2-Glycoprotein I inhibits von Willebrand factor–dependent platelet adhesion and aggregation

Janine J. J. Hulstein1, Peter J. Lenting1, Bas de Laat1, Ron H. W. M. Derksen2, Rob Fijnheer1,3, and Philip G. de Groot1

1 Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology; 2 Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht; 3 Jeroen Bosch Hospital, Department of Internal Medicine, Hertogenbosch, the Netherlands

Patients with antiphospholipid syndrome are characterized by the association of thrombosis or pregnancy morbidity and the presence of antiphospholipid autoantibodies. Particularly, anti-β2-glycoprotein (β2 GPI) autoantibodies correlate with thrombosis, suggesting an antibody-induced gain of prothrombotic function and/or an antibody-induced loss of antithrombotic function of β2 GPI. In the search for potential antithrombotic properties of β2 GPI, we found that β2 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 β2 GPI (P < .03). β2 GPI binds to the A1 domain of VWF but preferably when the A1 domain is in its active glycoprotein Ib{alpha}-binding conformation. Anti-β2 GPI antibodies isolated from a subset of antiphospholipid syndrome patients neutralized the β2 GPI-VWF interactions and thus the inhibitory activity of β2 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-β2 GPI antibodies. Thus, β2 GPI is a biologically relevant inhibitor of VWF function by interfering with VWF-dependent platelet adhesion. Anti-β2 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-β2 GPI antibodies.


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