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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-05-1310.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 157-162
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Thrombogenicity of  2-glycoprotein
I-dependent antiphospholipid antibodies in a photochemically
induced thrombosis model in the hamster
Milosz Jankowski,
Ingrid Vreys,
Christine Wittevrongel,
Doris Boon,
Jos Vermylen,
Marc. F. Hoylaerts, and
Jef Arnout
From the Center for Molecular and Vascular Biology,
University of Leuven, Leuven, Belgium.
We previously showed that  2-glycoprotein I
(2GPI)-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 2GPI were selected on the basis of their cross-reactivity with hamster 2GPI. 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 2GPI
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')2
fragments 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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