Low Dose Iron Chelation as TReatment of Oxidative Damage in Patients With Sickle Cell Disease: the TROS Study

Rationale:

Sickle cell disease (SCD) is an inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crises and organ damage resulting in reduced life expectancy. Oxidative stress is a major pathophysiological factor in SCD playing a significant role in the SCDrelated microvascular dysfunction, vaso-occlusion, inflammation and organ damage. Chronic life-long intravascular hemolysis with the resulting excessive levels of cell-free heme and iron is the major cause of increased production of reactive oxygen species (ROS) in SCD. The cell-free heme rapidly releases its iron which is the main driving force of redox reactions. The hydrophobic heme also rapidly intercalates into the plasma membrane of (endothelial) cells where it releases its iron. This potentiates cell damage by catalyzing non-enzymatic generation of ROS. By inactivating NO, cell-free ferrous hemoglobin reduces nitric oxide (NO) bioavailability, limiting the important vasodilative, anti-thrombotic and anti-inflammatory properties of NO. Since the ongoing and unremitting release of iron is the major cause of oxidative stress in SCD, it is imminent to investigate the role of iron chelators as antioxidative therapy in this disease. Iron chelators have been shown to protect various cells, including red blood cells (RBCs) and endothelial cells, against oxidative toxicity. The investigators recently found that sequestration of free iron by the iron-chelator deferoxamine blocked activation of neutrophils and their release of neutrophil extracellular traps (NETs) by sera of SCD patients (preliminary data). NETs have been demonstrated to be toxic, especially, to endothelial cells. In this study the investigators will test the hypothesis that treating sickle cell patients with low doses of readily available iron chelators might reduce oxidative stress by capturing the excessively released intravascular cell-free iron.

Objective:

To study the safety and efficacy of deferasirox as treatment of oxidative stress in adult subjects with sickle cell disease.

Study design: