Hemoglobinopathies are the most common inherited red blood cell disorders worldwide. Among these disorders, sickle cell disease (SCD) and thalassemias constitute a major public health problem. SCD is caused by a glutamic acid to valine substitution at the sixth amino acid of the β-globin chain. Individuals with SCD may be homozygous for the sickle mutation (HbSS), or be compound heterozygotes, inheriting HbS and β-thalassemia or another β-globin variant such as HbC, HbD, HbE, or HbOArab. The sickle mutation makes the hemoglobin molecule stack and form a polymer when deoxygenated, which makes the red blood cells rigid and have abnormal hemorrheologic properties. The downstream effects of the sickling process include (a) red blood cell membrane changes leading to potassium loss and cellular dehydration; (b) interaction of the red blood cell with neutrophils, monocytes, and the microvascular endothelium; (c) hemolysis and nitric oxide depletion; (d) release of inflammatory proteins from activated immune cells; and (e) activation of coagulation. These processes lead to hemolytic anemia, inflammation, painful vasoocclusive episodes, damage to multiple organ systems, and shortened life expectancy in individuals with SCD.
There is considerable heterogeneity in the severity of SCD; even individuals with the same genotype may have different clinical courses. The best-known modifier of SCD is the level of fetal hemoglobin (HbF), which exerts a potent antisickling effect when present in sufficient amounts in the red blood cell. Coinheritance of α-thalassemia also modifies the disease, reducing hemolysis and ameliorating anemia. Non-globin genetic modifiers of SCD also contribute to clinical variability.
Since the 1980s, advances in supportive care and implementation of disease-modifying therapies, such as hydroxyurea and chronic blood transfusion, have led to an increase in life expectancy, although the average life expectancy is still less than 5 decades for individuals with HbSS. Hydroxyurea is an established and effective disease-modifying agent that has been approved by the FDA for use in children and adults with SCD. Although its main mechanism of action is HbF induction, hydroxyurea also decreases neutrophils, platelets, and adhesion molecule expression, contributing to its efficacy. Newly FDA-approved agents for SCD include L-glutamine, which reduces painful events, crizanlizumab, an anti-adhesive monoclonal antibody that reduces painful events, and voxelotor, which covalently binds to HbS, keeping it in its oxygenated state, and prevents sickling, reduces hemolysis, and increases Hb concentration. Gene-based therapies, which either insert a functional Hb gene similar to HbA or increase HbF via various strategies, are in clinical trials that show early encouraging results. As of this writing, the only curative therapies are allogeneic hematopoietic stem cell transplantation and gene-modification approaches.
Sickle cell trait, the heterozygous state for sickle Hb, affects approximately 8% 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, has also become a prevalent hemoglobinopathy in ...