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

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 normal in the circulation. Overall, these results indicate that the GPVI-ITAM signaling machinery in NFYPs after antibody-mediated thrombocytopenia only becomes fully functional in the blood circulation.

• Authors: Shuchi Gupta, Deya Cherpokova, Markus Spindler, Martina Morowski, Markus Bender, Bernhard Nieswandt
• Journal: Blood (Blood) Vol. 131 Issue 10 Pg. 1106-1110 (03 08 2018) ISSN: 1528-0020 [Electronic] United States
• PMID: 29295843 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Platelet Membrane Glycoproteins
• platelet membrane glycoprotein VI
• Syk Kinase
• Syk protein, mouse
• Phospholipase C gamma

Topics

• Acute Disease
• Animals
• Blood Platelets (metabolism, pathology)
• Cellular Microenvironment
• Male
• Megakaryocytes (metabolism, pathology)
• Mice
• Phospholipase C gamma (metabolism)
• Platelet Membrane Glycoproteins (metabolism)
• Signal Transduction
• Syk Kinase (metabolism)
• Thrombocytopenia (metabolism, pathology)