Thrombogenicity of β2-glycoprotein I–dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster

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Abstract
We previously showed that β2-glycoprotein I (β2GPI)–dependent lupus anticoagulants (LAs) form bivalent antigen-antibody complexes with high affinity for phospholipids; these complexes are responsible for their in vitro anticoagulant effect. We now studied the role of these bivalent complexes in arterial thrombosis in the hamster. Three monoclonal antibodies (mAbs) raised against human β2GPI were selected on the basis of their cross-reactivity with hamster β2GPI. Two of these, one with LA activity, 5H2, and one with only anticardiolipin properties, 11E8, were infused at 0 to 10 mg/kg prior to photochemically induced vessel damage. 5H2 promoted thrombus formation dose dependently, raising the thrombus size from 6.0 arbitrary units (AU) in controls (n = 9) to 65.0 AU in the high-dose group (10 mg/kg, n = 6, P = .007). The LA−mAb 11E8 and mAb 27A8, reactive with human β2GPI exclusively, did not significantly promote thrombus formation. In a second set of experiments, intact mAb 5H2 was compared to its fragments. Intact mAb 5H2 at 3.3 mg/kg and the equimolar dose of F(ab′)2 fragments (2.2 mg/kg) promoted thrombus formation equally well (55.8 AU, n = 8 and 62.5 AU, n = 7, respectively); mAb 5H2-derived Fab′ fragments were inactive. Immunohistochemical analysis showed platelet-rich thrombi, with 5H2 or its F(ab′)2fragments mainly bound to individual platelets. Our results indicate that bivalent immune complex formation plays an important role in the genesis of arterial thrombosis by certain antiphospholipid antibodies. Cellular activation via the Fc portion of these immune complexes, however, is not essential, because F(ab′)2 fragments of 5H2 still promote thrombus formation.

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