Fc-receptor dependent platelet aggregation induced by monoclonal antibodies against platelet glycoprotein Ib or von Willebrand factor

In this paper we describe two pathways leading to platelet activation by cr osslinking glycoprotein (GP) Ib alpha to the platelet Fc-receptor (Fc gamma RII). First the monoclonal antibody (MoAb) 9C8, raised against human plate let GPIb alpha, dose-dependently induced platelet aggregation of citrate-an ticoagulated platelet-rich plasma, an effect that can be inhibited by sever al activation inhibitors. The Fc gamma RII-inhibitory MoAb IV.3 was able to prevent the aggregatory effects of MoAb 9C8, indicating that crosslinking of the antigen GPIba to the Fc gamma II-receptor is necessary for the activ ating effect. Secondly we observed a synergistic activating effect of two a nti-von Willebrand factor (VWF) MoAbs 1C1E7 and B724, both known to enhance vWF binding to GPIb alpha in the presence of shear or ristocetin. When the se antibodies are added together to PRP, platelet aggregation is induced wi thout further need for an additional modulator. This effect can be blocked by either MoAb IV.3 or an inhibitory anti-GPIb MoAb, indicating that again the platelet activation results from signaling through Fc gamma RII crossli nked to vWF bound to GPIb alpha. In addition, both the anti-GPIb MoAb 9C8, or the two anti-vWF MoAbs 1C1E7 and B724 induce genuine platelet activation , as evidenced by the secretion of ATP and protein tyrosine phosphorylation . These findings with both anti-GPIb and anti-vWF MoAbs add further proof t o recent reports demonstrating an interaction between the platelet receptor s GPIb and Fc gamma RII, suggesting a role for the Fc gamma II-receptor in GPIb-related signaling.