Role of FcγRIIB in regulating antibody-induced ectodomain shedding of platelet GPVI. (A) New studies (Stegner et al) have now shown that depletion of platelet surface GPVI by the anti-GPVI antibody JAQ1 depends on expression of an inhibitory Fc receptor, FcγRIIB, expressed on LSEC. WT mice or mice deficient in the activating Fc receptor, FcγRIIA (FcγRIIA^−/−), treated with JAQ1 showed entrapment of platelets in the liver and increased GPVI shedding as demonstrated by elevated levels of sGPVI in plasma. In contrast, WT mice treated with JAQ1 F(ab′)₂ fragments or mice deficient in FcγRIIB (FcγRIIB^−/−) did not show these effects. (B) Human, but not mouse, platelets express FcγRIIA providing a potential pathway for antibody-induced GPVI shedding in peripheral blood (dashed line), whereas potential mechanisms for antibody-induced GPVI shedding in mice mediated by FcγRIIB in the liver might involve FcγRIIB/IgG-dependent clustering of GPVI and involvement of a sheddase derived from LSEC. LSEC, liver sinusoidal endothelial cells; PLT, platelet; WT, wild-type.