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TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans.

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.

Pubmed ID: 19436112

Authors

  • Washington AV
  • Gibot S
  • Acevedo I
  • Gattis J
  • Quigley L
  • Feltz R
  • De La Mota A
  • Schubert RL
  • Gomez-Rodriguez J
  • Cheng J
  • Dutra A
  • Pak E
  • Chertov O
  • Rivera L
  • Morales J
  • Lubkowski J
  • Hunter R
  • Schwartzberg PL
  • McVicar DW

Journal

The Journal of clinical investigation

Publication Data

June 2, 2009

Associated Grants

  • Agency: NCRR NIH HHS, Id: 2G12RR3035
  • Agency: NCI NIH HHS, Id: N01-CO-12400
  • Agency: NIGMS NIH HHS, Id: SC2GM081237
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Animals
  • Fibrinogen
  • Hemorrhage
  • Humans
  • Inflammation
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Aggregation
  • Protein Binding
  • Receptors, Immunologic
  • Recombinant Proteins
  • Sepsis
  • Solubility