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J. Biol. Chem., Vol. 278, Issue 36, 33831-33838, September 5, 2003

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Dimers of ₂-Glycoprotein I Increase Platelet Deposition to Collagen via Interaction with Phospholipids and the Apolipoprotein E Receptor 2'^*

Bianca C. H. Lutters  , Ronald H. W. M. Derksen ¶, Winnie L. Tekelenburg , Peter J. Lenting  , Jef Arnout || and Philip G. de Groot   **

From the Departments of Haematology and ^¶Rheumatology and Clinical Immunology, University Medical Center, 3508GA Utrecht, Institute of Biomembranes, Utrecht University, 3508GA Utrecht, The Netherlands, and the ^||Center for Molecular and Vascular Biology, University of Leuven, B-3000 Leuven, Belgium

Patients with prolonged clotting times caused by lupus anticoagulant (LAC) are at risk for thrombosis. This paradoxal association is not understood. LAC is frequently caused by anti-₂-glycoprotein I (₂GPI) antibodies. Antibody-induced dimerization of ₂GPI increases the affinity of ₂GPI for phospholipids, explaining the observed prolonged clotting times. We constructed dimers of ₂GPI that mimic effects of ₂GPI-anti-₂GPI antibody complexes, and we studied their effects on platelet adhesion and thrombus formation in a flow system. Dimeric ₂GPI increased platelet adhesion to collagen by 150% and increased the number of large aggregates. We also observed increased platelet adhesion to collagen when whole blood was spiked with patient-derived polyclonal anti-₂GPI or some, but not all, monoclonal anti-₂GPI antibodies with LAC activity. These effects could be abrogated by inhibition of thromboxane synthesis. A LAC-positive monoclonal anti-₂GPI antibody, which did not affect platelet adhesion, prevented the induced increase in platelet adhesion by ₂GPI dimers. Furthermore, increased platelet adhesion disappeared after preincubation with receptor-associated protein, a universal inhibitor of interaction of ligands with members of the low density lipoprotein receptor family. Using co-immunoprecipitation, it was shown that dimeric ₂GPI can interact with apolipoprotein E receptor 2 (apoER2'), a member of the low density lipoprotein receptor family present on platelets. These results demonstrate that dimeric ₂GPI induces increased platelet adhesion and thrombus formation, which depends on activation via apoER2'.

Received for publication, December 12, 2002 , and in revised form, June 13, 2003.

^* This work was supported by Netherlands Heart Foundation Grant 98.060. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: University Medical Center Utrecht, Thrombosis and Haemostasis Laboratory, Dept. of Haematology (G03.647), P. O. Box 85.500, 3508 GA Utrecht, The Netherlands. Tel.: 31-30-250-77-69; Fax: 31-30-251-18-93; E-mail: ph.g.degroot{at}azu.nl.

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