Histidine‑rich Glycoprotein Modulates Platelet Adhesion and Aggregation by Binding to GPIbα and GPIIb/IIIa

Histidine-rich glycoprotein (HRG) is a 75-kDa plasma protein produced by the liver and circulating at about 2 µM, with an additional pool in platelets that is released upon activation. Previously, we demonstrated that HRG downregulates the contact system by binding polyanions and reducing their capacity to activate factor (F) XII. Although HRG localizes on the platelet surface, its role in platelet biology remains uncertain. Accordingly, we investigated whether HRG directly engages platelet receptors to regulate adhesion and aggregation. Using human and murine platelets, we show that HRG (a) binds to glycoprotein (GP)Ibα on resting and activated platelets and to GPIIb/IIIa on activated platelets, (b) competes with von Willebrand factor (VWF) for binding to GPIbα on resting platelets and with fibrinogen for binding to GPIIb/IIIa on activated platelets, and (c) attenuates platelet agglutination, aggregation, and platelet-mediated thrombus growth. Furthermore, in an endothelial-platelet flow system or a collagen-coated microperfusion chamber, HRG reduced VWF-mediated platelet string formation and attenuated platelet deposition under high-shear conditions. Plasma HRG levels in patients with sepsis or COVID-19 were about half those of healthy controls, and reducing HRG to these levels in vitro promoted a hyperreactive platelet phenotype. Therefore, HRG not only modulates coagulation but also platelet adhesion and aggregation by competing with VWF and fibrinogen for binding to GPIbα and GPIIb/IIIa.