Platelet TREM-Like Transcript-1 (TLT-1) regulation in healthy donors and patients at risk of bleeding and thrombosis.

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific α-granule protein, is implicated in haemostasis, but its regulation remains unclear. Platelet dysfunction contributes to trauma-induced coagulopathy (TIC) and thrombotic complications in trauma or mechanical circulatory support (MCS); however, underlying mechanisms remain poorly understood. OBJECTIVES: To investigate the molecular mechanisms underlying sTLT-1 release and its role as a biomarker of platelet dysfunction in patients with severe trauma or receiving MCS. METHODS: TLT-1 dynamics on platelets exposed to GPVI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10-17 kDa fragment was metalloproteinase-dependent and blocked by ADAM10 and ADAM17 inhibition. Unlike GPVI, platelet TLT-1 exposure increased following PAR-1 activation. sTLT-1 was elevated in trauma patients compared with controls and correlated with TIC (p<0.05) and injury severity (p<0.01). ROC analysis demonstrated discriminatory performance for TIC (AUC 0.78, p=0.011), with a Youden cut-off of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilised 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS patients exhibited elevated sTLT-1 levels. CONCLUSION: Unlike GPVI, TLT-1 increased on activated platelets and was regulated by ADAM10 and ADAM17. TLT-1 release is triggered by shear stress, GPVI ligands or FXa. Plasma sTLT-1 was associated with trauma severity and TIC.