Ruxolitinib mitigates oxidative stress and ROS-induced structural and functional fibrinogen alterations in primary myelofibrosis.

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal myeloproliferation, bone marrow fibrosis, extramedullary hematopoiesis, and abnormal inflammation. About 90% of MF patients carry mutations in the JAK2, CALR, or MPL genes. Among these, JAK2 mutations promote cytokine independence, constitutive activation of STAT proteins, and increased reactive oxygen species (ROS) production within hematopoietic stem cells. Excessive ROS and inflammation are potential triggers for thrombotic events, a leading cause of morbidity and mortality in myeloproliferative neoplasm patients.

To explore the mechanisms of inflammation-induced thrombosis in MF, we analyzed oxidation-induced fibrinogen alterations in MF patients compared to healthy controls and the effects of treatment with Ruxolitinib, a first-in-class JAK inhibitor.

Methods: This study included 20 primary MF patients and 20 age- and sex-matched healthy controls. Plasma redox status and structural and functional fibrinogen alterations were assessed in both primary MF patients (before and after Ruxolitinib treatment) and controls.

Results: MF patients displayed a significant increase in plasma lipid peroxidation and nitrate/nitrite levels, associated with a reduced total antioxidant capacity and free thiol plasma content. Oxidative imbalance was associated with fibrinogen oxidation, resulting in structural and functional alterations. Structural changes impaired fibrinogen polymerization into fibrin and reduced fibrin susceptibility to plasmin-induced lysis. A positive correlation between fibrin resistance to plasmin digestion and plasma oxidative stress was observed. Patients treated with Ruxolitinib exhibited significant improvements in redox status, as well as in fibrinogen structure and function.

Conclusions: MF patients exhibit a prothrombotic profile sustained by oxidative modifications of fibrinogen. Preliminary findings suggest that Ruxolitinib may improve redox balance and provide cardiovascular protection in these patients.