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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4254-4260
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Thrombosis and shock induced by activating antiplatelet
antibodies in human Fc RIIA transgenic mice: the interplay among
antibody, spleen, and Fc receptor
Scott M. Taylor,
Michael P. Reilly,
Alan D. Schreiber,
Paul Chien,
Joseph R. Tuckosh, and
Steven
E. McKenzie
From Hematology/Oncology Research, A. I. duPont
Hospital for Children, Wilmington, DE; the Department of Pediatrics,
Thomas Jefferson University, Philadelphia, PA; and the Department of
Medicine, University of Pennsylvania School of Medicine, Philadelphia,
PA.
Transgenic mouse lines were created that express Fc RIIA on
platelets and macrophages at human physiologic levels, and they were
used to explore the consequences in vivo of activating antiplatelet antibodies. Anti-CD9 antibody activated platelets of FcRIIA
transgenic (tg) mice and, following injection in vivo, caused more
rapid severe thrombocytopenia than nonactivating antiplatelet antibody. Anti-CD9 injected into FcRIIA tg crossed with FcR -chain knockout (-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. The shock depended on platelet Fc receptor density and
antibody dose. On histologic examination, the lung vasculature of
anti-CD9-treated FcRIIA tg × -KO mice contained extensive platelet-fibrin thrombi. Thrombosis and shock in FcRIIA tg mice in
the context of the FcR -chain knockout suggested the importance of
the interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically (splenectomy) or
functionally (monoclonal antibody treatment) also facilitated anti-CD9-mediated shock in FcRIIA tg mice. The spleen, which clears
nonactivating antibody-coated platelets leading to thrombocytopenia, appears to play a protective role in the thrombosis and shock observed
with activating antiplatelet antibody. The data indicate that
antibodies, which activate platelets in an FcRIIA-dependent manner,
can lead to thrombosis, shock, and death. Furthermore, antibody titer,
platelet Fc receptor density, and splenic clearance are likely
important determinants of the outcome.
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