1. TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans
- Author
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Washington, A. Valance, Gibot, Sebastien, Acevedo, Ismael, Gattis, James, Quigley, Laura, Feltz, Robert, De La Mota, Alina, Schubert, Rebecca L., Gomez-Rodriguez, Julio, Cheng, Jun, Dutra, Amalia, Pak, Evgenia, Chertov, Oleg, Rivera, Linette, Morales, Jessica, Lubkowski, Jacek, Hunter, Robert, Schwartzberg, Pamela L., and McVicar, Daniel W.
- Subjects
Genes -- Physiological aspects ,Genes -- Research ,Hemorrhage -- Risk factors ,Hemorrhage -- Prevention ,Hemorrhage -- Genetic aspects ,Hemorrhage -- Research ,Blood platelets -- Physiological aspects ,Blood platelets -- Research - Abstract
Triggering receptor expressed on myeloid cells--like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte [alpha]-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1-/- mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1-/- mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1-/- mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation., Introduction Septic shock claims over 200,000 people a year in the United States and is a leading cause of morbidity and mortality. Death from sepsis occurs when the deposition of [...]
- Published
- 2009