Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis.

Abstract

Glycoprotein VI (GPVI), the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen, plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from 15 patients with sepsis were assessed consecutively at day of admission, day 5 to 7, and the day of intensive care unit (ICU) discharge and subjected to comprehensive analyses by flow cytometry, aggregometry, and immunoblotting. Platelet function was markedly reduced in all patients. The defect was most prominent after GPVI stimulation with collagen-related peptide. In 14 of 15 patients, GPVI dysfunction was already present at time of ICU admission, considerably before the critical drop in platelet counts. Sepsis platelets failed to transduce the GPVI-mediated signal to trigger tyrosine phosphorylation of Syk kinase or LAT. GPVI deficiency was partially inducible in platelets of healthy donors through coincubation in whole blood, but not in plasma from patients with sepsis. Platelet aggregation upon GPVI stimulation increased only in those patients whose condition ameliorated. As blunted GPVI signaling occurred early at sepsis onset, this defect could be exploited as an indicator for early sepsis diagnosis, which needs to be confirmed in prospective studies.

• Authors: Lukas J Weiss, Georgi Manukjan, Annerose Pflug, Nadine Winter, Mathis Weigel, Nils Nagler, Markus Kredel, Thiên-Trí Lâm, Bernhard Nieswandt, Dirk Weismann, Harald Schulze
• Journal: Blood (Blood) Vol. 137 Issue 22 Pg. 3105-3115 (06 03 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33827131 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Platelet Membrane Glycoproteins
• platelet membrane glycoprotein VI

Topics

• Adult
• Aged
• Aged, 80 and over
• Blood Platelets (metabolism, pathology)
• Critical Illness
• Female
• Humans
• Male
• Middle Aged
• Pilot Projects
• Platelet Aggregation
• Platelet Membrane Glycoproteins (metabolism)
• Sepsis (metabolism, pathology)
• Signal Transduction