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Blood. 2018 Dec 6;132(23):2495-2505. doi: 10.1182/blood-2018-03-841593. Epub 2018 Oct 3.

Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model.

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Department of Biology, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
Division of Natural Sciences, Maryville College, Maryville, TN.
Retroviral Research Center, Universidad Central del Caribe, Bayamón, Puerto Rico.
Department of Computer Science, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
Department of Pediatrics/Neonatology and Molecular Medicine Program and.
Department of Internal Medicine and Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT.
Bloodworks Northwest Research Institute, Seattle, WA; and.
Geriatric Research, Education and Clinical Center, Department of Medicine, George E. Wahlen VA Medical Center, Salt Lake City, UT.


Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (P < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor (P < .0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition, and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73 ± 24.75% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (P ≤ .001) and tissue damage by 25% (P ≤ .001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS.

[Available on 2019-12-06]

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