GPVI signaling is compromised in newly formed platelets after acute thrombocytopenia in mice.

Blood
Shuchi GuptaBernhard Nieswandt

Abstract

At sites of vascular injury, exposed subendothelial collagens trigger platelet activation and thrombus formation by interacting with the immunoreceptor tyrosine-based activation motif (ITAM)-coupled glycoprotein VI (GPVI) on the platelet surface. Platelets are derived from the cytoplasm of megakaryocytes (MKs), which extend large proplatelets into bone marrow (BM) sinusoids that are then released into the bloodstream, where final platelet sizing and maturation occurs. The mechanisms that prevent activation of MKs and forming proplatelets in the collagen-rich BM environment remain largely elusive. Here, we demonstrate that newly formed young platelets (NFYPs) released after antibody-mediated thrombocytopenia in mice display a severe and highly selective signaling defect downstream of GPVI resulting in impaired collagen-dependent activation and thrombus formation in vitro and in vivo. The diminished GPVI signaling in NFYPs is linked to reduced phosphorylation of key downstream signaling proteins, including Syk, LAT, and phospholipase Cγ2, whereas the G protein-coupled receptor and C-type lectin-like receptor 2 signaling pathways remained unaffected. This GPVI signaling defect was overcome once the platelet counts were restored to...Continue Reading

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Citations

Mar 10, 2018·Blood·J Rivera, E E Gardiner
Jun 18, 2019·Journal of Thrombosis and Haemostasis : JTH·Catherine AngénieuxBlandine Maître
Jun 16, 2018·F1000Research·Kirk A Taylor, Michael Emerson
Sep 16, 2020·Proceedings of the National Academy of Sciences of the United States of America·Shuchi GuptaLawrence F Brass
Aug 4, 2021·Blood Advances·Nathan EatonHervé Falet

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