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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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Submitted October 23, 2006
Accepted May 1, 2007
Beta2-Glycoprotein I inhibits von Willebrand factor-dependent platelet adhesion and aggregation
Janine J.J. Hulstein, Peter J. Lenting, Bas de Laat, Ron H.W.M. Derksen, Rob Fijnheer, and Philip de Groot*
Dept of Clinical Chemistry & Haematology, Laboratory for Thrombosis and Haemostasis, University Medical Centre Utrecht, Utrecht, Netherlands
Dept. of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands
Department of Internal Medicine, Jeroen Bosch Hospital, Hertogenbosch, Netherlands
* Corresponding author; email: ph.g.degroot{at}umcutrecht.nl.
Patients with the antiphospholipid syndrome are characterized by the association of thrombosis or pregnancy morbidity and the presence of anti-phospholipid autoantibodies. Particularly, anti- 2-glycoprotein I (2GPI) autoantibodies correlate with thrombosis, suggesting an antibody-induced gain-of-prothrombotic function and/or an antibody-induced loss-of-antithrombotic function of 2GPI. In search for potential antithrombotic properties of 2GPI, we found that 2GPI 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 2GPI (p<.03). 2GPI binds to the A1-domain of VWF, but preferably when the A1-domain is in its active Glycoprotein Ibalpha-binding conformation. Anti-2GPI antibodies isolated from a subset of antiphospholipid-syndrome patients neutralized the 2GPI-VWF interactions and thus the inhibitory activity of 2GPI. In comparison to healthy individuals, the amounts of active VWF in circulation were increased 1.5-fold (p<.0001) in patients positive for lupus anticoagulant (LAC) due to anti-2GPI antibodies. Thus, 2GPI is a biological relevant inhibitor of VWF function by interfering with VWF-dependent platelet adhesion. Anti-2GPI autoantibodies neutralize this inhibitory function, and are associated with in increased levels of active VWF. This mode of action could contribute to the thrombosis and consumptive thrombocytopenia observed in patients with anti-2GPI antibodies.
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