Identification of a Role for Apolipoprotein E Receptor 2 as a Platelet Receptor for Factor XI

Factor XI (FXI) promotes hemostasis and thrombosis through the enhancement of thrombin generation, and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. Although the binding of FXI to platelets has been demonstrated, the role that FXI binding might play in platelet activation has not been studied. It is also unknown if FXI-platelet binding is solely mediated by GPIbα or if other platelet receptor(s) exist that can support interactions with FXI. This study has identified apolipoprotein E receptor 2 (ApoER2, LRP8), a member of the low-density lipoprotein (LDL) receptor family, as a platelet receptor for FXI. Surface-bound FXI supported platelet spreading and elevation of intracellular Ca²⁺, while platelet spreading on FXI was eliminated in the presence of either Src-kinase or PI3-kinase inhibitors. Platelet adhesion to immobilized FXI was abrogated in the presence of the universal LDL receptor antagonist, receptor-associated protein (RAP), soluble recombinant ApoER2′ or the LDL-binding domain 1 or 2 of ApoER2. FXI supported wild-type murine platelet binding; in contrast, ApoER2-deficient murine platelets did not adhere to FXI. Soluble FXI binding to immobilized platelets or purified recombinant ApoER2′ was abrogated in the presence of binding domain 1 of ApoER2 or RAP, respectively. These results identify FXI as a novel ligand for the platelet receptor ApoER2. While many of the details regarding the role of FXI in vivo are still undetermined, the ability of FXI to bind and activate platelets via ApoER2 suggests that FXI may contribute to hemostasis and thrombosis in a manner unrelated to contact activation or thrombin generation. Furthermore, these findings suggest that FXI may play a role in promoting cell signaling in other cells that express ApoER2, such as neurons, immune system cells and smooth muscle cells.