Transcriptomic analysis identifies immune-related clusters and PPP2R1A as a candidate gene associated with venous thromboembolism recurrence.

Venous thromboembolic disease (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is associated with substantial morbidity, mortality, and recurrence risk. However, immune-related transcriptomic heterogeneity and recurrence-associated molecular features in VTE remain incompletely defined. This study aimed to explore immune-related transcriptomic clusters associated with VTE recurrence and to prioritize recurrence-associated candidate genes. Public GEO datasets were analyzed, with GSE19151 used as the discovery cohort and GSE48000 used for external validation. Consensus clustering, WGCNA, differential expression analysis, GO/KEGG enrichment, and random forest-based exploratory gene prioritization were performed. The functional relevance of PPP2R1A was further evaluated using a mouse inferior vena cava thrombosis model and endothelial cell experiments, including western blotting, qRT-PCR, CCK-8, Transwell, flow-cytometry, and endothelial-immune co-culture assays. Two exploratory immune-related clusters were identified among VTE patients. Compared with subtype I, subtype II showed stronger IFN-gamma, monocyte, and IL-6 enrichment and a higher recurrence proportion (61.4% vs. 41.7%). Random forest analysis prioritized 23 recurrence-associated candidate genes, including PPP2R1A, although external validation showed modest discriminatory performance (AUC = 0.615). In experimental systems, PPP2R1A expression was associated with thrombus burden, endothelial cell proliferation, migration, apoptosis, inflammatory activation, and altered p-MEK/p-ERK signaling. These findings identify exploratory immune-related clusters in VTE and support PPP2R1A as a recurrence-associated candidate gene linked to endothelial MEK/ERK signaling. Larger prospective cohorts and cell-specific mechanistic studies are needed before these findings can be translated into clinical biomarkers or therapeutic targets.