title: Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression.
abstract: Platelet P-selectin plays important roles in inflammation and contributes to thrombosis and hemostasis. Although it has been reported that von Willebrand factor (VWF) affects P-selectin expression on endothelial cells, little information is available regarding regulation of platelet P-selectin expression. Here, we first observed that P-selectin expression was significantly decreased on platelets of fibrinogen and VWF double-deficient mice. Subsequently, we identified this was due to fibrinogen deficiency. Impaired P-selectin expression on fibrinogen-deficient platelets was further confirmed in human hypofibrinogenemic patients. We demonstrated that this impairment is unlikely due to excessive P-selectin shedding, deficient fibrinogen-mediated cell surface P-selectin binding, or impaired platelet granule release, but rather is due to decreased platelet P-selectin content. Fibrinogen transfusion completely recovered this impairment in fibrinogen-deficient (Fg(-/-)) mice, and engagement of the C-terminus of the fibrinogen gamma chain with beta3 integrin was required for this process. Furthermore, Fg(-/-) platelets significantly increased P-selectin expression following transfusion into beta3 integrin-deficient mice and when cultured with fibrinogen. These data suggest fibrinogen may play important roles in inflammation, thrombosis, and hemostasis via enhancement of platelet P-selectin expression. Since human fibrinogen levels vary significantly in normal and diseased populations, P-selectin as an activation marker on platelets should be used with caution.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Sean
authors.initials: S
authors.lastname: Lang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhai
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Pingguo
authors.initials: P
authors.lastname: Chen
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkić
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Spring
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni