Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2'.
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-beta2-glycoprotein I (beta 2GPI) antibodies. Antibody-induced dimerization of beta 2GPI increases the affinity of beta 2GPI for phospholipids, explaining the observed prolonged clotting times. We constructed dimers of beta 2GPI that mimic effects of beta 2GPI-anti-beta 2GPI antibody complexes, and we studied their effects on platelet adhesion and thrombus formation in a flow system. Dimeric beta 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-beta 2GPI or some, but not all, monoclonal anti-beta 2GPI antibodies with LAC activity. These effects could be abrogated by inhibition of thromboxane synthesis. A LAC-positive monoclonal anti-beta 2GPI antibody, which did not affect platelet adhesion, prevented the induced increase in platelet adhesion by beta 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 beta 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 beta 2GPI induces increased platelet adhesion and thrombus formation, which depends on activation via apoER2'.
Lutters
Bianca C H
BC
Department of Haematology, University Medical Center, and Institute of Biomembranes, Utrecht University, 3508GA Utrecht, The Netherlands.
Derksen
Ronald H W M
RH
Tekelenburg
Winnie L
WL
Lenting
Peter J
PJ
Arnout
Jef
J
de Groot
Philip G
PG
D000911:Antibodies, Monoclonal / Q000737:chemistry; D016736:Antiphospholipid Syndrome / Q000276:immunology; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D005260:Female; D005340:Fibrinogen / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D008856:Microscopy, Fluorescence; D010477:Perfusion; D010743:Phospholipids / Q000737:chemistry; D010974:Platelet Aggregation; D011233:Precipitin Tests; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D014162:Transfection; D053482:beta 2-Glycoprotein I
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D006023:Glycoproteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D010743:Phospholipids; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D013931:Thromboxanes; D053482:beta 2-Glycoprotein I; C098773:low density lipoprotein receptor-related protein 8; D005340:Fibrinogen; D003094:Collagen