Affiliation:
1. From the Division of Cardiovascular Research, Department of Biochemistry, and the Division of Transfusion Medicine, Department of Haematology, University of Cambridge; the National Blood Service, Cambridge, United Kingdom; the Departments of Biochemistry and Human Biology, CARIM, University of Maastricht, Netherlands; and the Laboratory for Thrombosis Research, IRC, KU Leuven, Belgium.
Abstract
AbstractThe platelet glycoproteins (GPs) Ib, integrin α2β1, and GPVI are considered central to thrombus formation. Recently, their relative importance has been re-evaluated based on data from murine knockout models. To examine their relationship during human thrombus formation on collagen type I fibers at high shear (1000 s–1), we tested a novel antibody against GPVI, an immunoglobulin single-chain variable fragment, 10B12, together with specific antagonists for GPIbα (12G1 Fab2) and α2β1 (6F1 mAb or GFOGER-GPP peptide). GPVI was found to be crucial for aggregate formation, Ca2+ signaling, and phosphatidylserine (PS) exposure, but not for primary adhesion, even with more than 97% receptor blockade. Inhibiting α2β1 revealed its involvement in regulating Ca2+ signaling, PS exposure, and aggregate size. Both GPIbα and α2β1 contributed to primary adhesion, showing overlapping function. The coinhibition of receptors revealed synergism in thrombus formation: the coinhibition of adenosine diphosphate (ADP) receptors with collagen receptors further decreased adhesion and aggregation, and, crucially, the complete eradication of thrombus formation required the coinhibition of GPVI with either GPIbα or α2β1. In summary, human platelet deposition on collagen depends on the concerted interplay of several receptors: GPIb in synergy with α2β1 mediating primary adhesion, reinforced by activation through GPVI, which further regulates the thrombus formation.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
145 articles.
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