Hemoglobinopathies are the most common inherited red
cell disorders worldwide. Among these disorders, sickle cell syndromes
and thalassemias constitute major public health problems. A glutamic
acid to valine substitution at the 6th amino acid of the β-globin chain
of human adult hemoglobin (Hb A) results in formation of sickle
hemoglobin. 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 hemoglobin
C, D, E, or O-Arab. The sickle mutation renders the hemoglobin molecule
insoluble upon deoxygenation; thus red cells containing deoxy Hb
S polymer are rigid and have impaired rheologic properties. The
downstream effects of the sickling process include red cell membrane
changes leading to potassium loss and cellular dehydration, interaction
with vascular endothelium and neutrophils and monocytes, hemolysis,
nitric oxide depletion, activation of inflammatory markers, and
a prothrombotic tendency. These processes lead to 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 sickle cell
disease; the best known modifier of the disease is an elevated level
of hemoglobin F, which exerts a potent antisickling effect. Concomitant α-thalassemia
is also a modifier of sickling, which leads to a decrease in hemolysis.
In recent years, there has been an interest in nonglobin genetic
modifiers of sickle cell disease. Genome-wide association studies
may be expected to shed light on genetic modulation of disease severity.
Over the past three decades, advances in supportive care and implementation
of disease-modifying therapies 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 adult patients with
sickle cell disease. Although its main mechanism of action is to
enhance hemoglobin F production, other effects such as a decrease
in neutrophils, platelets, and decreased expression of adhesion molecules
contribute to its efficacy. Novel agents, most notably, DNA methyltransferase
1 inhibitors (5′-azacytidine and decitabine)
and histone deacetylase inhibitors (butyrate derivates and others),
are now in clinical trials. Evolving therapies include Gardos channel
inhibitors to improve red cell hydration and antiadhesive therapies
to prevent interaction of blood cells with microvascular endothelium.
To date, the only curative therapy is 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. Hb C is associated with
target cells and spherocytes in the blood film and splenomegaly.
Hb D disease is essentially asymptomatic. Hb E is very common in
Southeast Asia, and because of large population movements from this
area, it has also become a prevalent hemoglobinopathy in other regions
of the world. Hb E is a thalassemic variant, and its coinheritance with β-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 hemolytic anemia. ...