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 antibody activated platelets of Fc gamma RIIA transgenic (tg) mice and, following injection in vivo, caused more rapid severe thrombocytopenia than nonactivating antiplatelet antibody. Anti-CD9 injected into Fc gamma RIIA tg crossed 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 platelet Fc receptor density and antibody dose. On histologic examination, the lung vasculature of anti-CD9-treated Fc gamma RIIA tg x gamma-KO mice contained extensive platelet-fibrin thrombi. Thrombosis and shock in Fc gamma RIIA tg mice in the context of the FcR gamma-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 Fc gamma RIIA 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 Fc gamma RIIA-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. (Blood. 2000;96:4254-4260)
Taylor
S M
SM
Hematology/Oncology Research, A. I. duPont Hospital for Children, Wilmington, DE 19899, USA.
Reilly
M P
MP
Schreiber
A D
AD
Chien
P
P
Tuckosh
J R
JR
McKenzie
S E
SE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D012769:Shock / Q000276:immunology*; D013154:Spleen / Q000276:immunology*; D013156:Splenectomy; D060245:Tetraspanin 29; D013921:Thrombocytopenia / Q000276:immunology*; D013927:Thrombosis / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D060245:Tetraspanin 29