Circulating Markers of Endoplasmic Reticulum Stress and Apoptosis in Acute Pulmonary Embolism: A Prospective Case-Control Study

Acute pulmonary embolism (PE) may promote endoplasmic reticulum (ER) stress through hypoxia, hemodynamic stress, and thromboinflammation; however, its circulating unfolded protein response (UPR) profile remains poorly characterized. This study evaluated UPR-related and cell-death markers in controls and patients with provoked or unprovoked acute PE.

This prospective case-control study included 60 patients with CT pulmonary angiography-confirmed acute PE (30 provoked and 30 unprovoked) and 30 controls. Pretreatment serum levels of IRE1, PERK, ATF6, cleaved ATF6-p50, GRP78, CHOP, CK18-M30, and CK18-M65 were measured by ELISA. Analyses included Kruskal-Wallis testing with Bonferroni-adjusted Dunn comparisons, Jonckheere-Terpstra trend testing, ROC analysis, and logistic regression.

All eight biomarkers differed significantly among groups and increased sequentially from controls to unprovoked and provoked PE (all p < 0.001). Seven biomarkers, excluding GRP78, were higher in provoked than unprovoked PE. Cleaved ATF6-p50 showed the largest effect size (ε² = 0.817) and the highest discriminatory performance for PE versus controls (AUC = 0.991) and provoked versus unprovoked PE (AUC = 0.934). D-dimer and CRP did not significantly discriminate between the two PE groups. CK18-M65 was associated with more proximal thrombus location (ρ = 0.347; p = 0.007).

Acute PE is associated with coordinated changes in circulating UPR-related markers and increased epithelial cell-death signaling. Cleaved ATF6-p50 may represent a candidate biomarker warranting independent validation.