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INTRODUCTION

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SUMMARY

Hemoglobinopathies are the most common inherited red cell disorders worldwide. Among these disorders, sickle cell syndromes and thalassemias constitute a major public health problem. A glutamic acid to valine substitution at the sixth amino acid of the β-globin chain of human hemoglobin (HbA) results in formation of sickle hemoglobin (HbS). Sickle cell disease results from homozygosity for this mutation, or from a compound heterozygosity for sickle hemoglobin and β-thalassemia or another β-globin variant such as HbC, HbD, HbE, or HbOArab. The sickle mutation renders the hemoglobin molecule insoluble upon deoxygenation; thus red blood cells containing deoxy HbS polymer are rigid and have impaired rheologic properties. The downstream effects of the sickling process include: membrane changes leading to potassium loss and cellular dehydration, interaction of sickle hemoglobin with microvascular endothelium, neutrophils, and monocytes, hemolysis, nitric oxide depletion, release of inflammatory proteins and activation of coagulation. These processes lead to a hemolytic anemia, an inflammatory state, painful vasoocclusive episodes, and damage to multiple organ systems with a resultant shortened life expectancy. There is considerable heterogeneity in the severity of the disease; the best known modifier of the disease is an elevated level of fetal hemoglobin (HbF), which exerts a potent antisickling effect. Concomitant α-thalassemia is also a modifier, which leads to a decrease in hemolysis. There is an interest in nonglobin genetic modifiers of sickle cell disease. Over the past 3 decades, advances in supportive care and implementation of disease-modifying therapies, such as anti–γ to β-globin switching therapies, which result in increased HbF and less HbS synthesis, and have led to an increase in life expectancy. Hydroxyurea has emerged as an effective disease-modifying agent that has been approved by the FDA for use in adults with sickle cell disease. Although its main mechanism of action is to enhance HbF production, other effects such as a decrease in neutrophils, platelets, and decreased expression of adhesion molecules contribute to its efficacy. Novel antiswitching agents, most notably, DNA methyltransferase 1 inhibitors (5′-azacytidine and decitabine) and histone deacetylase inhibitors (butyrate derivatives and others) are now in clinical trials. Evolving therapies include antiadhesive therapies to prevent interaction of sickle cells with microvascular endothelium, antiinflammatory approaches, and modulation of hemoglobin–oxygen affinity to prevent sickling. To date, the only curative therapy remains allogeneic hematopoietic stem cell transplantation.

Sickle trait, the heterozygous state for sickle hemoglobin, affects approximately 8 percent of Americans of African descent, and with rare exceptions is asymptomatic. HbC is associated with target cells and spherocytes in the blood film and splenomegaly. HbD disease is essentially asymptomatic. HbE is very common in Southeast Asia, and because of large population movements from this area, it has become a prevalent hemoglobinopathy in other regions of the world. HbE is a thalassemic variant and its coinheritance with β0-thalassemia mutations can result in severe transfusion-dependent thalassemia major. Unstable hemoglobin variants appear as rare, sporadic cases and are characterized by a Heinz body ...

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