Work

Prothrombotic profiles in myelofibrosis: Fibrinogen oxidation and the beneficial effects of ruxolitinib

Year: 2025

Type: article

Abstract: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, extramedullary hematopoiesis and aberrant inflammation. About 90 % of MF patients carry mutations in JAK2, CALR, or MPL, with JAK2 mutations promoting cytokine independence, STAT proteins activation and enhances reactive oxygen species (ROS) production. Inflammation and oxidative stress are key contributors to thrombotic risk, a major cause of morbidity and mortality in MF. Fibrinogen, a key factor in coagulation and inflammation, may play a central role due to its susceptibility to oxidative modifications. In particular, in MPN patients, impaired fibrinolysis associated with endothelial cell dysfunction, increased ROS and proinflammatory cytokines production have been reported. This study investigates the role of oxidation-induced structural and functional changes in fibrinogen in MF patients compared to healthy controls, also analyzing the effects of ruxolitinib, a first-in-class JAK inhibitor. Plasma samples from 15 untreated MF patients, 39 ruxolitinib-treated MF patients, and 40 matched healthy controls were analyzed for redox status and fibrinogen properties. MF patients showed elevated plasma lipid peroxidation and nitrate/nitrite levels, reduced antioxidant capacity, and lower free thiol content. These changes were associated with significant fibrinogen oxidation, leading to structural alterations and impaired function, including reduced fibrin polymerization and decreased plasmin-mediated fibrinolysis. Strong correlations were observed between oxidative stress markers and fibrinogen dysfunction. Treatment with ruxolitinib improved redox balance and restored fibrinogen structure and function. These findings provide the first evidence of a prothrombotic profile in MF patients, driven by structural and functional fibrinogen modifications.

Source: Thrombosis Research

DOI: 10.1016/j.thromres.2025.109517