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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1602.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Identification of Coagulation Factor XI as a Ligand for Platelet Apolipoprotein E Receptor 2 (ApoER2)

Tara C. White-Adams; Michelle A. Berny; Erik I. Tucker; Jacqueline M. Gertz; David Gailani; Rolf T. Urbanus; Philip G. de Groot; András Gruber; Owen J.T. McCarty

From the Division of Biomedical Engineering (T.C.W.-A., M.A.B., E.I.T., J.M.G., A.G., O.J.T.M.), the Department of Cell and Developmental Biology (O.J.T.M.), and the Division of Hematology/Oncology (A.G.), School of Medicine, Oregon Health & Science University, Portland; the Department of Pathology and Medicine (D.G.), Vanderbilt University School of Medicine, Nashville, Tenn; and the Laboratory of Clinical Chemistry and Haematology (R.T.U., P.G.d.G.), University Medical Centre Utrecht, the Netherlands.

Correspondence to Owen J.T. McCarty, Division of Biomedical Engineering, Oregon Health & Science University School of Medicine, CHH-13B, 3303 SW Bond Ave, Portland, OR 97239. E-mail mccartyo{at}ohsu.edu

Objective— Factor XI (FXI) promotes hemostasis and thrombosis through enhancement of thrombin generation and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. The aim of this study was to investigate the mechanisms governing interactions between FXI and platelets.

Methods and Results— Platelet adhesion to immobilized FXI was abrogated in the presence of the low-density lipoprotein (LDL) receptor antagonist, receptor-associated protein (RAP), soluble recombinant apolipoprotein E receptor 2 (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. In the presence of shear, platelet aggregates formed on FXI or activated FXI (FXIa) surfaces, whereas the presence of RAP, binding domain 1 of ApoER2, or an anti-GPIb mAb blocked platelet adhesion to FXI or FXIa under shear. Soluble FXI bound to immobilized ApoER2' with an affinity of 61 nmol/L.

Conclusions— This study has identified apolipoprotein E receptor 2 (ApoER2, LRP8), a member of the LDL receptor family, as a platelet receptor for FXI. The interaction of FXI with other cell types that express ApoER2 remains to be explored.

FXI enhances thrombin generation and plays a role in the formation of occlusive thrombi in arterial injury models. FXI has been shown to bind to high affinity sites on the platelet surface, such as the receptor GPIb. This study identifies FXI as a ligand for ApoER2.

Key Words: platelets • GPIb • apolipoprotein E receptor 2 • LRP8 • factor XI

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