Sickle Cell Disease

One of the most challenging aspects of sickle cell disease is its clinical variability. While in general, HbSS and HbSβ⁰ are the most severe genotypes, there are patients with HbSC and HbSb⁺ who have significant sickle-cell–related complications, and may have a more severe clinical course than a HbSS patient.²¹ A great deal of this clinical variability cannot be explained, but some can be attributed to endogenous fetal hemoglobin (HbF) levels.^22–24 The importance of HbF levels in sickle cell disease was first noted by a pediatrician in the 1940s.²⁵ She observed that sickle cell disease complications in children under the age of 1 were rare, and attributed it to the presence of HbF.²⁵ HbF levels decline more slowly in individuals with hemoglobinopathies, reaching their nadir after the age of 5 rather than within 6 months of birth in individuals without hemoglobinopathies.²⁶ HbF levels remain elevated lifelong in most sickle cell disease patients, especially those with the HbSS and HbSβ⁰ genotypes. Levels of HbF vary widely between individuals, from zero to 20% to 30%, with a median of 10%.^26–28 Individuals who produce more HbF have a milder course, in general.²⁴ An association between the 4 β-globin haplotypes and HbF levels has been reported in the past,^27,29 but more sophisticated next-generation sequencing has revealed causal variants in BCL11A and HBS1L-MYB that contribute approximately 50% of the observed variability in HbF levels.^30–33

Co-inheritance of α-thalassemia also modifies disease course; less available α-globin chains results in a lower hemoglobin concentration within the cell. Paradoxically, this results in a higher overall hemoglobin level, as there is a reduction in polymerization, and therefore sickling due to lower HbS concentrations in the cell. Patients therefore are less anemic, reducing the risk of stroke in childhood,^34,35 but blood viscosity may be higher, resulting in more frequent pain crises and increased risk³⁶ of avascular necrosis.^34,35,37 It is often helpful to think of sickle cell patients as falling into 1 of 2 groups: high hemolysis/low hemoglobin and high viscosity/high hemoglobin. Individuals with high rates of hemolysis are at greater risk for stroke, pulmonary hypertension, and acute chest syndrome (ACS). Higher rates of hemolysis result in higher levels of free hemoglobin, which scavenges nitric oxide. This leads to the vascular damage and dysfunction that contributes to the associated clinical complications. This phenotype is most commonly seen in HbSS and HbSβ⁰.³⁸ High hemoglobin/high viscosity phenotypes are most often found in HbSC patients and in sickle cell anemia with α-thalassemia coinheritance.^39–42

TREATMENT OPTIONS

In high-resource countries with newborn screening, the initiation of penicillin prophylaxis has dramatically altered the natural history of the disease, allowing the majority of patients to reach adulthood.⁴³ Penicillin prophylaxis is usually discontinued at age 5 years; however, individuals who have undergone surgical splenectomy or have had pneumococcal sepsis on penicillin prophylaxis may remain on penicillin to age 18 or beyond.²⁰

Another advance in sickle cell care is screening for stroke risk through transcranial Doppler ultrasound (TCD).^44–47 This screening tool has reduced the incidence of childhood stroke from 10% by age 11 to 1%. TCDs typically cannot be performed after the age of 16 due to changes in the skull. Individuals found to have abnormal (elevated) TCD velocities are placed on chronic transfusion therapy for primary stroke prevention. They may remain on monthly chronic transfusions, with the goal of suppressing the percentage of HbS to 30% to 50% indefinitely. A clinical trial (STOPII) designed to determine if pediatric sickle cell disease patients on chronic transfusion therapy for primary stroke prevention could be safely taken off transfusion therapy was discontinued early due to an excess of strokes and conversion to abnormal TCD velocities in the untransfused arm.⁴⁴ Individuals who have experienced an ischemic stroke have a 70% risk of another stroke, and must remain on chronic transfusion therapy indefinitely. Chronic transfusion reduces their stroke risk to 13%.