Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor

Transgenic mouse lines were created that express Fc gamma 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 a ntibody activated platelets of Fc gamma RIIA transgenic (tg) mice and, foll owing injection in vivo, caused more rapid severe thrombocytopenia than non activating antiplatelet antibody Anti-CD9 injected into Fc gamma RIIA tg cr ossed with FcR gamma -chain knockout (gamma -KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. The shock depended on plate let Fc receptor density and antibody dose. On histologic examination, the l ung vasculature of anti-CD9-treated Fc gamma RIIA tg x gamma -KO mice conta ined extensive platelet-fibrin thrombi. Thrombosis and shack in Fc gamma RI IA tg mice in the context of the FcR gamma -chain knockout suggested the im portance of the interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically (splenectomy) or funct ionally (monoclonal antibody treatment) also facilitated anti-CD9-mediated shock in Fc gamma RIIA tg mice. The spleen, which clears wnonactivating ant ibody-coated platelets leading to thrombocytopenia, appears to play a prote ctive role in the thrombosis and shock observed with activating antiplatele t antibody. The data indicate that antibodies, which activate platelets in an Fc gamma RIIA-dependent manner, can lead to thrombosis, shock, and death . Furthermore, antibody titer, platelet Fc receptor density, and splenic cl earance are likely important determinants of the outcome. (C) 2000 by The A merican Society of Hematology.