Pantothenate metabolic alterations in PROS1 mutation carriers and the antithrombotic effects of pantethine

Background Patients carrying PROS1 mutations are at increased risk of venous thromboembolism (VTE). However, metabolic alterations linked to PROS1 mutations and their thrombotic contribution remain unclear. Objectives This study aimed to identify metabolic changes in PROS1‑mutation patients through integrated multi‑omics analyses, and to investigate the role of pantothenate derivatives in thrombosis using in vivo and in vitro models. Methods Serum metabolomics, siRNA‑mediated PROS1 knockdown in THLE‑2 cells, murine thrombosis models, and endothelial cell functional assays were employed. Results Patients with PROS1 mutations exhibited significantly reduced serum levels of pantothenate derivatives, particularly pantetheine. siRNA‑mediated PROS1 knockdown in THLE‑2 cells recapitulated this metabolic disturbance. In vivo, pantethine supplementation attenuated thrombus formation and platelet activation in murine models, accompanied by reduced serum levels of vWF and ICAM‑1, and increased TFPI. In vitro, pantethine pretreatment suppressed NF‑κB phosphorylation and reduced endothelial reactive oxygen species, counteracting IL‑1β‑induced procoagulant phenotype, leading to downregulation of vWF and ICAM‑1 and upregulation of TFPI and THBD. Furthermore, pantethine‑conditioned endothelial cells reduced responsiveness of co‑incubated platelets, including attenuated spreading, aggregation, and activation. These findings associate PROS1 mutation‑driven metabolic alterations with thrombotic risk, and suggest a metabolic‑endothelial‑platelet mode of interaction. Conclusions This study demonstrates that patients with PROS1 mutations exhibit reduced circulating pantothenate derivatives, and that pantethine attenuates murine thrombosis and modulates endothelial and platelet function in vitro. These findings identify a metabolic‑endothelial‑platelet association in Protein S deficiency. Whether PROS1 mutations directly cause pantothenate metabolic disturbance, and whether this disturbance mediates thrombosis, require testing in PROS1‑deficient in vivo models.