Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

In recent years there have been major advances in our knowledge of the regulation of iron metabolism that have had implications for understanding the pathophysiology of some human disorders like beta-thalassemia and other iron overload diseases. However, little is known about the relationship among ineffective erythropoiesis, the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. The principal aim of this paper is an update about the role of Ferroportin during human normal and pathological erythroid differentiation. Particular attention will be given to beta-thalassemia and other diseases with iron overload. Recent discoveries indicate that there is a potential for therapeutic intervention in beta-thalassemia by means of manipulating iron metabolism.

In β-thalassemia, the erythropoietic process is markedly altered, and the lack or reduced synthesis of β-globin chains induces an excess of free α-globin chains within the erythroid cells. Aggregation, denaturation, and degradation of these chains lead to the formation of insoluble precipitates causing damage to the red blood cell membrane. One of the major consequences in this genetic disorder is iron overload due to ineffective erythropoiesis and premature hemolysis in the plasma and in major organs such as heart, liver, and endocrine glands. The chapter describes the etiology of iron accumulation, the role of hepcidin in regulating increased iron absorption, and the pathophysiology resulting from excess of “free iron” and discusses new ways to decrease the iron overload and to neutralize its deleterious effects in the tissues other than iron chelation.