Platelet GPVI (Glycoprotein VI) and Thrombotic Complications in the Venous System

Abstract

The immunoglobulin receptor GPVI (glycoprotein VI) is selectively expressed on megakaryocytes and platelets and is currently recognized as a receptor for not only collagen but also a variety of plasma and vascular proteins, including fibrin, fibrinogen, laminin, fibronectin, and galectin-3. Deficiency of GPVI is protective in mouse models of experimental thrombosis, pulmonary thromboembolism as well as in thromboinflammation, suggesting a role of GPVI in arterial and venous thrombus formation. In humans, platelet GPVI deficiency is associated with a mild bleeding phenotype, whereas a common variant rs1613662 in the GP6 gene is considered a risk factor for venous thromboembolism. However, preclinical studies on the inhibition of GPVI-ligand interactions are focused on arterial thrombotic complications. In this review we discuss the emerging evidence for GPVI in venous thrombus formation and leukocyte-dependent thromboinflammation, extending to venous thromboembolism, pulmonary thromboembolism, and cancer metastasis. We also recapitulate indications for circulating soluble GPVI as a biomarker of thrombosis-related complications. Collectively, we conclude that the current evidence suggests that platelet GPVI is also a suitable cotarget in the prevention of venous thrombosis due to its role in thrombus consolidation and platelet-leukocyte complex formation.

Keywords: embolism; glycoprotein; inflammation; thrombosis; venous thromboembolism.

Figure.

GPVI (glycoprotein VI) structure and natural variants. A, Schematic presentation of the human GP6 gene structure. The first seven exons encode for the protein extracellular domain, with exons 3-4 encoding for domains D1 and D2, respectively. Exon 8 encodes for the transmembrane and short intracellular region. B, Cartoon showing the human GPVI protein domains with amino acid positions of the nine GPVI natural variants and mutations indicated. C, Representation of crystal structure of the GPVI binding site interacting with CRP (collagen-related peptide). D, Table of reported effects of GPVI variants on protein expression and platelet functions.^– FcR γ indicates Fc receptor γ; and VTE, venous thromboembolism.