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 α-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

Icenticaftor, a CFTR Potentiator, in COPD:A Multicenter, Parallel-Group, Double-Blind Clinical Trial

CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25?mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV after 12?weeks. Secondary endpoints included change from baseline in trough FEV and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24?weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24?weeks were assessed in exploratory and analyses, respectively. Nine hundred seventy-four patients were randomized. After 12?weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24?weeks for trough FEV , E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300?mg b.i.d. was consistently the most effective. Improvements for 300?mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. The primary endpoint was negative, as icenticaftor did not improve trough FEV over 12?weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV ; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24?weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887)

Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial

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