Platelet triggering receptor expressed on myeloid cells-like transcript 1 regulation in healthy donors and patients at risk of bleeding and thrombosis.

Abstract

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific &#x3b1;-granule protein, is implicated in hemostasis, 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: This study investigated the molecular mechanisms underlying soluble TLT (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 glycoprotein (GP)VI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS-treated patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10- to 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 < .05) and injury severity (P < .01). Receiver-operating characteristic analysis demonstrated discriminatory performance for TIC (area under the curve, 0.78; P = .011), with a Youden cutoff of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilized 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS-treated 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 activated factor X. Plasma sTLT-1 was associated with trauma severity and TIC.