Overview of compound sickle cell syndromes

INTRODUCTION — Compound sickle cell syndromes include any hemoglobinopathy in which the sickle mutation is inherited in combination with another globin gene mutation (affecting alpha globin, beta globin, or gamma globin). These syndromes may have different clinical severity compared with homozygous sickle mutation (Hb SS).

This topic presents an overview of the compound sickle cell syndromes and their clinical features.

Related subjects including the diagnosis of sickle cell syndromes, clinical manifestations, and management, as well as sickle cell trait (generally a benign carrier state) are discussed separately.

●Sickle cell disease

•Prenatal testing – (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

•Diagnosis – (See "Diagnosis of sickle cell disorders".)

•Further details about laboratory methods – (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

•Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

•Management – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

●Sickle cell trait – (See "Sickle cell trait".)

OVERVIEW

Pathophysiology — Vaso-occlusive phenomena and hemolytic anemia are the clinical hallmarks of sickle cell disease (SCD). Vaso-occlusion results in recurrent painful episodes and a variety of serious organ system complications that can lead to life-long disabilities and even death.

Hemoglobin S (Hb S) results from the substitution of a valine for glutamic acid as the seventh amino acid of the beta-globin chain, which produces a hemoglobin tetramer (alpha2/betaS2) that is poorly soluble when deoxygenated [1]. The polymerization of deoxy Hb S is essential to vaso-occlusive phenomena [1]. The polymer assumes the form of an elongated rope-like fiber which usually aligns with other fibers, resulting in distortion of the affected red blood cell into the classic crescent or sickle shape and a marked decrease in red cell deformability. (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

However, polymerization alone does not account for the pathophysiology of SCD. Subsequent changes in red cell membrane structure and function, disordered cell volume control, and increased adherence to vascular endothelium also play an important role [1,2].

The three most common genotypes accounting for SCD are homozygous Hb SS and two compound sickle cell syndromes, sickle–beta thalassemia and hemoglobin SC (Hb SC) disease.

Comparison with sickle cell disease — SCD clinical manifestations are similar in compound heterozygous individuals as in homozygous Hb SS, but they vary in severity (from mild, to as severe as in Hb SS). The clinical heterogeneity in different SCD genotypes is accounted for by the hemoglobin variant that accompanies Hb S, such as Hb D, Hb C, or Hb E, or a variant causing beta thalassemia. While compound heterozygous genotypes generally have a less severe clinical course than Hb SS, there are compound heterozygotes for SCD who have clinical manifestations similar to Hb SS; these include Hb S-beta⁰ thalassemia, Hb SD, and Hb S-O Arab. Any individual with a compound heterozygous SCD genotype may have a more severe clinical course than an individual with Hb SS. (See 'Sickle-beta thalassemia' below and 'Sickle-Hb D disease' below and 'Sickle-Hb O Arab disease' below.)

The implications include extending screening, such as transcranial Doppler screening to identify candidates for stroke prevention, in children with most of the compound sickle cell syndromes, with the exception of Hb SC disease. The American Society of Hematology (ASH) 2020 guidelines for sickle cell disease recommend that transcranial Doppler (TCD) screening should be performed in children who have compound heterozygous SCD other than Hb SC, including Hb S-Lepore disease, Hb SE disease, Hb S-O Arab disease, or Hb SD disease phenotypes, and who have evidence of hemolysis in the same range as those with Hb SS [3]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

In addition, specific complications, such as retinopathy in Hb SC, are more frequent in otherwise mild compound sickle cell syndromes. Viral infections, including Dengue and COVID-19, may be more severe in compound heterozygotes, possibly because of their association with fat embolism syndrome [4-9].

People with Hb SC disease and Hb S beta+ thalassemia tend to have an increased incidence of elevated body mass index (BMI) relative to individuals with SCD. This is likely a factor in pain severity and overall morbidity [10].

Unusual and confusing laboratory presentations for non-sickle cell disorders and suggestive of sickle cell trait

●Occasionally, laboratory testing demonstrates a hemoglobin pattern with Hb S <50 percent, Hb A2 >3.5 percent, and Hb A present. These cases represent sickle cell trait (Hb AS, in which one sickle beta globin gene and one normal beta globin gene are present). The SCD phenotype (based on CBC and hemoglobin analysis) as opposed to the SCD genotype (based on beta globin gene sequence) may be confused with sickle cell-beta thalassemia because of an elevated Hb A2. However, Hb A2 levels are often falsely elevated in the presence of Hb S. Any time the proportion of Hb S is less than 50 percent, the individual has a sickle trait, regardless of the Hb A2 level. Sickle cell trait is discussed separately. (See "Sickle cell trait".)

In a review of newborn screening program results for hemoglobin FSA using protein methods, 30 newborns initially identified as having sickle beta⁺ thalassemia had the diagnosis corrected to sickle cell trait [11]. (See "Diagnosis of sickle cell disorders".)

●Sickle-cell-delta-beta⁺ thalassemia results from heterozygosity for the sickle mutation and heterozygosity for a delta-beta (δβ) fusion gene. This combination is seen in people of Senegalese descent. This is a very mild form of SCD, with patients often asymptomatic. Laboratory testing shows microcytosis, hemoglobin >10 g/dL, elevated Hb S >50 percent, and Hb A and Hb F >12 percent [12].

In contrast to sickle-cell-delta beta⁰ thalassemia (see 'Sickle-delta beta(0) thalassemia' below), sickle-cell-delta–beta⁺ thalassemia produces some normal Hb A. Overall, the population of individuals with this genotype is likely to have milder disease, but any individual may have more severe disease.

SPECIFIC COMPOUND SICKLE CELL SYNDROMES

Hb SC disease

Pathophysiology — The Hb C variant in the beta globin locus (HBB p.Glu7Lys) is approximately one-fourth as common among African Americans as the sickle cell variant [13]. Although oxygenated Hb C forms crystals, Hb C does not participate in polymerization with deoxy Hb S [14,15]. Worldwide, there are at least 55,000 births annually, with the highest frequency in West Africa. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb C'.)

The presence of Hb C within the cell leads to enhanced and sustained potassium and chloride cotransport. The loss of K⁺ produces red cell dehydration and an increase in the intraerythrocytic concentration of Hb S to levels that may support polymerization, sickling, and clinical symptoms [14,16]. In vitro studies have found that, at the same total Hb concentration, a 50:50 Hb S and Hb C mixture undergoes polymerization 15 times more rapidly than a 40:60 Hb S and Hb A mixture; this difference is presumably due to the higher Hb S concentration [14]. The net effect is that compound heterozygosity for Hb S and C results in a disease (Hb SC) that is less severe than sickle cell disease (SCD) but more severe than sickle cell trait [17,18].

Laboratory — Hemoglobin analysis shows approximately equal amounts of Hb S and Hb C (or slightly more Hb S than Hb C), with no Hb A present. If cellulose acetate electrophoresis is used, Hb C may migrate with Hb S E, O-Arab, and C-Harlem. Thus, two independent hemoglobin electrophoresis techniques are necessary in order to distinguish Hb SC from Hb SC Harlem and other compound heterozygotes. The predominant red cell abnormality on the peripheral smear is an abundance of target cells. Sickled cells are relatively uncommon; rare sickled cells may be canoe-shaped (picture 1). Folded (pita bread, clam-shell) cells, irreversibly sickled cells, "billiard ball" cells, and crystal-containing cells also may be seen (picture 1) [19]. (See "Diagnosis of sickle cell disorders".)

Anemia and reticulocytosis are typically mild, with the majority of patients having a milder degree of anemia (hematocrit >28 percent) than is usually seen in SCD. Markers of hemolysis are lower than in Hb SS [20]. This difference is due to the longer survival of Hb SC compared with Hb SS red cells in the circulation (27 versus 17 days) [21,22]. Similarly, markers of inflammation are lower [20]. However, the lipid profiles are higher.

Clinical course — The clinical findings include relatively normal weight, growth, and physical development; splenomegaly is variable. Individuals with Hb SC disease are at risk for the same life-threatening complications as Hb SS but at a decreased frequency [23]. The effects of Hb F and alpha thalassemia on the severity of Hb SC disease are limited [24].

A small subset of individuals with Hb SC have a clinical phenotype similar to Hb SS. Overall, the clinical severity of Hb SC is milder, as indicated from the Cooperative Study of Sickle Cell Disease, which compared Hb SC disease with Hb SS. Data from Ghana reported that at least 10 percent of young adults with Hb SC disease had a severe clinical phenotype [24].

The following have been reported in individuals with Hb SC disease:

●A 50 percent lower rate of acute painful episodes (0.4 versus 0.8 per year) [25].

●A lower risk of silent cerebral infarcts (3 versus 17 percent) [26] and of having a stroke (2 versus 11 percent incidence of a first stroke by age 20) (figure 1) [27].

●A lower rate of focal segmental glomerulosclerosis (2.4 versus 4.2 percent in one study) with a later onset of progressive kidney failure (50 versus 23 years old at diagnosis) [28].

●A lower incidence of fatal bacterial infection in young children [29,30].

●A very low rate of leg ulcers [31].

●Later development of osteonecrosis [32].

●A lesser delay in growth and sexual development [33].

●A two-decade increase in life expectancy (64 versus 45 years) [34]. At two large academic SCD centers, there was no difference in the median survival of individuals with Hb SC compared to individuals with Hb SS.

●In a prospective cohort study, the incidences of severe acute vaso-occlusive pain requiring hospitalization and pain events were no different in pregnant women with Hb SS and Hb SC during the third trimester and early postpartum period, the interval with the highest SCD related morbidity [35,36].

●A higher incidence of peripheral retinopathy, thought to be related to the higher hematocrit in this disorder [37].

●Increased risk for systemic and cerebral fat embolism. The overall incidence is unclear and may be higher than thought [38].

Cohort studies in individuals with Hb SC disease support the observations of the cooperative study above and highlight specific problems and treatments [39-44].

●A clinical diagnosis is often delayed until a serious event during young adulthood because of the mild anemia and relatively benign clinical course in early pediatrics.

●The rates of maternal-fetal morbidity, retinopathy, avascular necrosis of the hip, and chronic kidney disease are increased. While microalbuminuria is lower in Hb SC disease than Hb SS, it still occurs in over 23 percent of adults [40]. In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected.

●Hydroxyurea therapy is beneficial in decreasing vaso-occlusive events and appears safe. Patients may develop reversible cytopenias and are at risk for hyperviscosity syndrome secondary to an increased hemoglobin, which requires therapeutic phlebotomy [45]. This combination is increasingly being used [46]. Pilot data using therapeutic phlebotomy alone suggest this may also lower the rate of vaso-occlusive events [47,48].

Functional asplenia occurs in many patients with Hb SC disease (45 percent in individuals over age 25 in one study) [49]. However, it does not occur prior to age four, and routine administration of prophylactic penicillin may not be necessary in infants and young children. (See "Prevention of infection in patients with impaired splenic function".)

The persistent splenic function means that splenic infarction and splenic sequestration crisis, which primarily occur in young children with SCD, can occur at all ages in Hb SC disease [50].

Treatment — Treatment depends on clinical severity, as discussed separately. (See "Overview of the management and prognosis of sickle cell disease".)

Studies from Ghana have documented that the subgroup of Hb SC patients with severe disease who met criteria for hydroxyurea were rarely treated [24]. Prospective studies of Hb SC disease treatment are needed. (See "Hydroxyurea use in sickle cell disease".)

Sickle-beta thalassemia — Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains. Beta thalassemia is due to impaired production of beta globin chains, which leads to a relative excess of alpha globin chains. These excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. (See "Pathophysiology of thalassemia".)

Incidence and classification — The gene frequency of beta thalassemia among African Americans is 0.004, one-tenth that of the sickle cell gene [13]. As a result, the prevalence of compound heterozygous sickle cell-beta thalassemia is one-tenth that of sickle cell anemia (Hb SS) in this population. In addition to the African American population, people of Hispanic descent are at risk for sickle-beta thalassemia. In California, 12.5 percent of newborns with sickle-beta thalassemia have Hispanic origin [51].

Sickle cell-beta thalassemia is divided into sickle cell-beta⁰ thalassemia and sickle cell-beta⁺ thalassemia, based upon the complete absence beta globin or the presence of reduced amounts of beta globin, respectively, which in turn determines the level of Hb A [52,53]. Most beta thalassemia mutations among African Americans result in beta⁺ thalassemia. The percentage of Hb A produced in individuals with beta⁺ thalassemia varies from 5 to 30 percent, depending upon the molecular defect of the mutation [54-56]. As an example, those with a beta thalassemia mutation of -29(A-->G) have a high Hb A level and a mild clinical course.

Eighty percent of African American beta thalassemia pathogenic variants are due to promoter region mutations that result in a mild phenotype in which Hb A accounts for 18 to 25 percent of total hemoglobin [54,55]. The genotype for sickle-beta thalassemia varies in different regions in the world. Compound heterozygous sickle cell-beta⁰ thalassemia, which results in the production of no normal beta chains and therefore no Hb A, occurs infrequently in the African American population, but more commonly in the Greek, Middle Eastern, and Mediterranean regions. The Brazilian REDS 3 NIH study analyzed 167 sickle-beta thalassemia patients and found that beta⁺ and beta⁰ mutations occurred in approximately equal proportions in people with sickle cell beta thalassemia [57]. However, half the sickle beta⁺ variants were severe and clinically similar to sickle cell beta⁰ thalassemia. Some of the variants in this group included IVS-I-110 (G>A), IVS-I-5 (G>C), and IVS-I-5 (G>A).

Diagnosis and misdiagnosis of Hb S-beta(0) — The clinical and laboratory phenotype of Hb S-beta⁰ thalassemia is similar to that in Hb SS. Nearly all the hemoglobin consists of Hb S, and there is no Hb A present. Microcytosis is a useful indicator of Hb S-beta⁰ thalassemia. However, alpha thalassemia trait is a common finding and may cause microcytosis without a beta thalassemia mutation.

Distinguishing Hb SS from Hb S-beta⁰ thalassemia is challenging, even for hematologists. In a study involving 809 children with a clinical diagnosis of Hb SS or Hb S-beta⁰ thalassemia based on HLPLC or IEF and laboratory values, phenotypic misclassification occurred in 39 of 53 (74 percent) of those with Hb S-beta⁰ thalassemia (they actually had a Hb SS genotype) and 6 of 698 (0.9 percent) of those with Hb SS (they actually had a Hb S-beta⁰ genotype) [58].

Clinical manifestations — The hematologic and clinical severity of sickle cell-beta thalassemia is an inverse function of the quantity of Hb A [56,59].

Patients with sickle cell-beta⁰ thalassemia (no Hb A production) have a clinical course as severe as homozygous sickle cell disease (SCD; ie, Hb SS, sickle cell anemia) [59]. As examples:

●The Cooperative Study of Sickle Cell Disease (over 3000 patients) found that the incidence and severity of painful events and acute chest syndrome were similar between individuals with Hb SS and hemoglobin S-beta⁰ disease [25,60].

●A review of 84 patients suggested that pulmonary hypertension is also comparable between sickle beta⁰ thalassemia and Hb SS [61].

●Individuals with Hb S-beta⁰ thalassemia were found in some studies to have a high rate of ischemic brain injury [27,62]. However, in the absence of genotyping of the beta globin gene, these patients may have been misclassified and may actually have had Hb SS [58]. In neurologically asymptomatic individuals with Hb S-beta⁰ thalassemia, transcranial Doppler and MRI abnormalities are found [63]. In the SIT trial, children with Hb S-beta⁰ thalassemia based on genotyping had significantly lower TCD velocities than children with Hb SS, with the same prevalence of silent cerebral infarcts [64].

●Individuals with Hb S-beta⁰ thalassemia typically develop functional asplenia in early infancy, have an increased rate of sepsis, and have an associated increased risk of pneumococcal sepsis [65]. Depending on the percentage of hemoglobin A, individuals with Hb S-beta⁺ thalassemia do not undergo the rapid splenic infarction seen in Hb SS. Individuals with Hb S-beta⁺ thalassemia may continue to have splenic enlargement, often into adulthood, and they remain at risk for acute splenic sequestration episodes and hypersplenism.

Higher Hb A levels are generally associated with less severe clinical manifestations (individuals with Hb S-beta⁺ thalassemia generally have a more benign clinical course than those with Hb S-beta⁰ thalassemia or Hb SS). Acute painful events do occur, but are less than half those seen in Hb SS [25].

Despite the milder clinical course of individuals with Hb S-beta⁺ thalassemia, an individual with Hb S-beta⁺ thalassemia may have life-threatening episodes of acute chest syndrome, acute chest syndrome following surgery, complications of acute vaso-occlusive pain, or pregnancy related vaso-occlusive complications.

The lesser severity of Hb S-beta⁺ thalassemia was illustrated in the following studies:

●One study compared clinical findings in 27 patients with sickle cell-beta⁺ thalassemia and 28 patients with Hb S-beta⁰ thalassemia [66]. Compared with sickle cell-beta⁰ thalassemia, those with Hb S-beta⁺ thalassemia had the following findings:

•Threefold higher incidence of incidental diagnosis (26 versus 9 percent)

•Later mean age of presentation (8.2 versus 3.2 years)

•Less frequent leg ulcers (8 versus 23 percent)

•Less frequent episodes of acute chest syndrome (14 versus 24 percent); this approximately 50 percent reduction in painful episodes has been noted in other reports [25]

•Less frequent priapism (0 versus 4 patients)

•Less frequent aplastic crises (0 versus 2 patients)

Splenomegaly occurred in approximately one-third of both groups. There was a higher incidence of proliferative retinopathy in individuals with sickle cell-beta⁺ thalassemia (18 versus 10 percent), consistent with an association of higher hematocrits (and blood viscosity) with ocular complications. Both Hb S-beta⁺ thalassemia and Hb S-beta⁰ thalassemia have a decreased incidence of stroke compared with Hb SS (figure 1) [27]. Some individuals with no history of clinical stroke have demonstrated silent infarction on magnetic resonance imaging as well as abnormal transcranial Doppler studies [63].

●Another series evaluated 2115 patients with Hb SS, Hb SC disease, Hb S-beta⁺ thalassemia, or Hb S-beta⁰ thalassemia [33]. The patients with Hb SS or Hb S-beta⁰ thalassemia were consistently smaller and less sexually developed than those with Hb S-beta⁺ thalassemia.

However, the genotype-phenotype correlations in Hb S-beta⁺ thalassemia are variable, and a severe clinical course or life-threatening complications can be seen in patients with a milder beta thalassemic mutation. As an example, those with a beta mutation of IVS1-5(G-->C) have a Hb A level less than 7 percent and manifestations of similar severity to Hb SS [67]. In Brazil, severe Hb S-beta⁺ thalassemia accounted for almost half of this beta⁺ group, and the average hemoglobin A was 4.5 percent, in contrast to 26 percent in mild Hb S-beta⁺ thalassemia [57].

Splenic dysfunction in Hb S-beta⁺ thalassemia is less frequent in childhood but increases with age, resulting in 25 percent of adults having significant functional asplenia [65].

Hb S-beta⁺ thalassemia is associated with anemia, microcytosis, and a Hb A fraction that ranges between 5 and 30 percent (table 1). Neonates with sickle beta⁺ thalassemia may have so little Hb A that the diagnosis of sickle beta⁰ thalassemia is given. Family studies and more definitive testing are often indicated.

Treatment — Treatment depends on disease severity, which is likely to correlate with the beta thalassemia variant (more severe with beta⁰ variants and less severe with beta⁺ variants). (See "Overview of the management and prognosis of sickle cell disease".)

Sickle-alpha thalassemia — Alpha thalassemia results from impaired production of alpha globin chains, which leads to a relative excess of beta globin chains.

A single alpha globin gene deletion, referred to as alpha thalassemia silent carrier, is present in more than 30 percent of SCD patients of African descent, with an even higher prevalence in some SCD populations in the Middle East and India. The peripheral blood smear contains less polychromasia and fewer sickled cells, and more hypochromia and microcytosis, commensurate with the number of alpha globin genes deleted. Hb A2 levels are increased according to the number of alpha globin gene deletions, while Hb F levels are not consistently affected [68-71]. The mean corpuscular volume is reduced and the degree of hemolysis and anemia is lessened [72].

The effect of alpha thalassemia on the clinical course appears to have positive and negative effects:

●Individuals with sickle cell-alpha thalassemia can have milder anemia, with fewer reticulocytes and sickled cells [68-70,73]. The toxicity of excess normal beta globin chains on the red cell membrane skeleton appears to be less than that of the excess partially oxidized alpha globin chains in beta thalassemia. This may be extrapolated to beta S chains to explain why the clinical manifestations are generally less severe in sickle cell-alpha thalassemia compared with sickle cell-beta thalassemia. (See "Pathophysiology of thalassemia", section on 'Globin chain imbalance'.)

●The higher hemoglobin levels in some individuals with sickle-alpha thalassemia may contribute to hyperviscosity, which can increase symptoms. The higher hematocrit is still associated with Hb S-containing red cells, resulting in an overall increase in blood viscosity. This rise in hemoglobin and decreased hemolysis may decrease anemia and hemolysis-related events, while a higher hemoglobin level may increase the risk of some vaso-occlusion complications.

An early report suggested that coinheritance of alpha thalassemia was associated with longevity [74]; this conclusion was controversial [34]. Some studies have shown that the presence of alpha thalassemia and a reduction in intravascular hemolysis is associated with reduced mortality.

In other reports, the simultaneous presence of alpha thalassemia and SCD has been associated with the following effects:

●Reduction in the extent of peripheral retinal vessel closure, without an effect on the frequency of proliferative sickle retinopathy [75]

●Reduction in the incidence of stroke in children [76]

●Protection against high cerebral blood velocities [77,78]

●Reduction in the incidence of leg ulcers [31]

●In some children with high Hb F levels, alpha thalassemia appeared to preserve splenic function [79]

●Lower prevalence of glomerulopathy (macroalbuminuria) [80]

●Reduced prevalence of priapism [81]

●Reduced response to treatment with hydroxyurea [82]

However, not all population studies have shown a clinical benefit from the presence of alpha thalassemia. In a study from Jamaica, the absence of alpha thalassemia gene deletions influenced the clinical phenotype [83]. The best data on life expectancy come from the Cooperative Study of Sickle Cell disease, which found an increased mortality rate associated with higher hemoglobin levels after the age of 20 years [25].

These older studies regarding the clinical history of alpha globin gene deletion and its influence on SCD clinical history are quite limited because they do not reflect the influence of improved clinical management including conjugated vaccines, transcranial Doppler screening, and now four FDA-approved therapies.

Perhaps some of the discrepant results of earlier studies are a result of considering only the vaso-occlusive and viscosity-related complications of disease. Other studies suggest that intravascular hemolysis is closely associated with its own constellation of subphenotypes [84].

Studies of the effects of hemolysis on nitric oxide (NO) bioavailability suggest that alpha thalassemia protects against disease complications related to the intensity of hemolysis (eg, priapism, leg ulcers, stroke, and perhaps pulmonary hypertension) while increasing the risk of complications more directly related to blood viscosity (eg, painful episodes, acute chest syndrome, osteonecrosis) [81]. Patients with hyperhemolysis had higher systolic blood pressure, higher prevalence of leg ulcers, priapism, and pulmonary hypertension, while osteonecrosis and vaso-occlusive pain were less prevalent [85]. Hyperhemolysis was influenced by Hb F levels and the presence of alpha thalassemia, and was a risk factor for earlier death. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Impact of Hb F on sickle cell disease severity' and "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)

Due to the powerful effect of Hb S concentration upon Hb S polymerization, anemia is significantly milder in individuals with SCD and the deletion of either one (-a/aa) or two (-a/-a) alpha globin genes [68-70,86,87]. In one series, for example, the hemoglobin concentration was 9.8 g/dL in patients with Hb SS and the (-a/aa) genotype compared with 7.9 g/dL in those with Hb SS without alpha thalassemia [68]. These individuals have reduced hemolysis that is not demonstrable until approximately seven years of age [86,87].

Despite the improvement in anemia, the clinical effects of the interaction between SCD and alpha thalassemia are variable, due in part to the higher hemoglobin concentration and blood viscosity. While the overall clinical phenotype may be improved, there is not a definitive answer to the question of whether alpha thalassemia increases survival in patients with sickle cell anemia [88,89]. This is particularly true in the era of disease-modifying therapies.

This is illustrated by the following observations:

●The incidence of acute chest syndrome was decreased in one study and unchanged in another [69,70]. In a third report from the Cooperative Study of Sickle Cell disease, concurrent alpha thalassemia had no effect on the incidence of acute painful episodes apart from its association with higher hemoglobin concentrations [25].

●There is a reduced incidence of leg ulcers (more in patients with two versus three alpha globin genes) [31,69]; the incidence of osteonecrosis is increased [32,90].

●The frequency of retinal vessel closure is reduced, but the risk of proliferative retinopathy is increased [91].

Sickle-hereditary persistence of fetal hemoglobin — The physiologic switch from the production of fetal hemoglobin (Hb F: alpha2/gamma2) to adult hemoglobin (Hb A: alpha2/beta2) is usually completed by two years of age, resulting in a normal adult level of Hb F of <1 percent. However, increased levels of Hb F can ameliorate the clinical course of disorders of beta globin gene expression including sickle cell disease (SCD) and beta thalassemia. (See "Pathophysiology of thalassemia", section on 'Combinations of hemoglobin variants'.)

In individuals with Hb SS, a Hb F level of 10 to 20 percent has been suggested as a threshold for diminished clinical severity [92], although some studies have suggested that any increment in Hb F may be clinically important [34]. Hb F in Hb SS usually consists of 4 percent to 10 percent of total hemoglobin.

In a group of disorders called hereditary persistence of fetal hemoglobin (HPFH), expression of the gamma globin gene persists at high levels in almost all of the adult red cells, referred to as pancellular Hb F distribution, with normal red blood cell indices and morphology. The gene frequency of the deletional HPFH locus is 0.0005 among African Americans, resulting in a calculated incidence of compound heterozygous sickle cell-deletional HPFH that is 1 percent that of SCD [93]. Sickle-HPFH may be more frequent than previously estimated [94]. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Hereditary persistence of fetal hemoglobin (HPFH)'.)

Individuals with compound heterozygosity for Hb S and HPFH have high concentrations of Hb S and 20 to 30 percent Hb F evenly distributed among red cells, are not anemic, and do not experience vaso-occlusive complications or other major complications of SCD [95,96].

In individuals with Hb S-HPFH, hemoglobin analysis reveals only Hb S, Hb F, and Hb A2, which resembles sickle cell anemia, sickle cell-beta⁰ thalassemia, and sickle cell-delta beta⁰ thalassemia. Notable differences, however, are the markedly increased percentage of Hb F (10 to 40 percent) and Hb A2 levels <2.5 percent (in contrast to the elevated levels in beta thalassemia) [97,98]. To avoid unnecessary over-treatment of this benign condition, genotypes should be determined in parents and especially in all children with high Hb F levels.

Sickle cell-deletional HPFH provided the first evidence that Hb F was a potent inhibitor of Hb S polymerization. Genetic modulation of the sickle cell anemia phenotype by Hb F as a strategy for cure is discussed separately. (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing' and "Fetal hemoglobin (Hb F) in health and disease", section on 'Sickle cell disease' and "Hematopoietic stem cell transplantation in sickle cell disease".)

In contrast, individuals with Hb SS and heterocellular Hb F distribution may have Hb F levels as high as 25 percent but may still have a clinical course similar to individuals with Hb SS who have lower Hb F levels, particularly as they become older [99,100]. Multiple genetic etiologies for elevated Hb F have been discussed, including beta-globin gene deletions or point mutations in the promoters of the gamma globin gene (HBG1). Unusually high Hb F can also be associated with variants of the major repressors of gamma globin expression, BCL11A and MYB. Perhaps most often, an explanation for very high Hb F levels in SCD is lacking. These conditions are discussed in detail separately. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Hemoglobin switching and downregulation of Hb F expression'.)

Sickle-delta beta(0) thalassemia — The delta-beta (δβ) thalassemia variants usually are large deletions of the delta and beta globin genes. Unlike HPFH, these variants fail to block the switch from fetal to adult hemoglobin production. This allows an attempted switch from the expression of gamma globin to that of the deleted delta and beta genes. The uncommon compound heterozygous condition of Hb S delta-beta⁰ thalassemia results in the presence of Hb S, Hb F, and Hb A2. The 15 to 25 percent Hb F is distributed in a heterocellular fashion. Anemia and reticulocytosis are mild, and clinical complications are infrequent [101]. Compound heterozygosity for delta-beta⁺ thalassemia and the sickle mutation produces an even milder phenotype. (See 'Unusual and confusing laboratory presentations for non-sickle cell disorders and suggestive of sickle cell trait' above.)

Sickle-Hb Lepore disease — The Hb Lepore gene is a crossover fusion product of the delta and beta globin genes, the product of which, in the case of Hb Lepore Boston, has the same alkaline electrophoretic mobility as Hb S [102]. Because of the thalassemic expression of the fusion gene, individuals with simple heterozygosity for Hb Lepore Boston resemble sickle cell trait on hemoglobin electrophoresis, with only 12 percent of the mutant hemoglobin being present. (See "Molecular genetics of the thalassemia syndromes", section on 'Hb Lepore'.)

The doubly heterozygous condition of sickle cell-Hb Lepore (Hb S-Lepore) is rare [103]. The peripheral smear shows microcytosis, hypochromia, and irreversibly sickled cells. Vaso-occlusive complications occur and splenomegaly is common [104].

Patients with this disorder resemble those with Hb SS or sickle cell-beta⁰ thalassemia electrophoretically, but they have less severe anemia, similar to sickle cell-beta⁺ thalassemia. However, a Hb Lepore band can be seen on cellulose acetate electrophoresis and more distinctly on high performance liquid chromatography (HPLC). The combination of predominantly Hb S with microcytosis suggests sickle cell-beta thalassemia, but the diagnosis of Hb S Lepore is suggested by the low to low normal Hb A2 levels that result from the incapacitation of one delta globin gene by the crossover. Hb F levels vary.

Sickle-Hb D disease — The most common hemoglobin D variant, Hb D Los Angeles (HBB p.Glu121Gln, also called Hb D Punjab), is caused by a glutamic acid to glutamine substitution at codon 121 of the beta globin gene [105]. The glutamic acid to glutamine substitution appears to support the polymerization of Hb S [106]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb D'.)

Although asymptomatic in the heterozygous form, inheritance together with an Hb S allele (Hb SD disease) can result in a severe disease with clinical manifestations similar to homozygous SCD [107]. In a study of 42 patients in Iraq, painful events were the most common presentation, occurring in over 90 percent of children [108].

Hb D Los Angeles has an electrophoretic mobility that is similar to Hb S under alkaline conditions. For this reason, Hb SD disease was first reported as an unusual case of sickle cell anemia [109]. Hb D can be distinguished from Hb S by acid electrophoresis or isoelectric focusing. There is moderately severe hemolytic anemia and the peripheral smear shows marked anisocytosis and poikilocytosis, target cells, and irreversibly sickled cells. Some children have severe disease similar to that of sickle cell anemia [110,111]. However, persistent splenomegaly is more common.

Sickle-Hb O Arab disease — Hemoglobin O-Arab is another hemoglobinopathy due to a variant beta globin chain (HBB p.Glu121Lys). It was first described in an Israeli Arab family but its distribution is widespread [112]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb O-Arab'.)

Sickle-Hb O Arab accounts for 5 percent of cases of SCD in Sudan and neighboring regions [113].

Sickle cell-Hb O-Arab resembles Hb SC on alkaline electrophoresis, but Hb O-Arab can be distinguished from Hb C by either acid electrophoresis or isoelectric focusing. Hb O-Arab may be confused with Hb C-Harlem when Hb S is also present. The syndrome is characterized by moderately severe hemolytic anemia, and the peripheral smear shows anisocytosis, poikilocytosis and irreversibly sickled cells [114,115]. Oxygen affinity is reduced in sickle cell-Hb O-Arab compared with sickle cell anemia.

The clinical manifestations are severe and resemble those of homozygous sickle cell anemia. In one study of 13 patients, for example, all patients had significant sickling events including acute chest syndrome (11), recurrent painful episodes (10), nephropathy (four), aplastic crises (two), avascular necrosis (two), leg ulcers (two), and stroke (one) [115].

Sickle-Hb E disease — Hb E (HBB p.glu26Lys) is a beta thalassemic hemoglobinopathy found predominantly in Southeast Asia. The mutant hemoglobin has an electrophoretic mobility similar to Hb C under alkaline conditions but can be resolved by acid electrophoresis or isoelectric focusing [116]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb E'.)

The variant in codon 26 activates a cryptic splice site within the first intron of the beta globin gene, causing alternate splicing and decreased expression of the structural mutant [117]. As a result, Hb E comprises only 30 percent of the total hemoglobin in patients with compound heterozygosity for the Hb S and Hb E variants.

Heterozygotes and homozygotes for Hb E are asymptomatic with minimal anemia and microcytosis [118]. Hb SE disease may cause only mild hemolysis, no vaso-occlusive complications, and no remarkable abnormality of red blood cell morphology in those ≤18 years [119]. However, there are several case reports of more severe manifestations, such as the following:

●Hematuria

●Splenic infarct during air travel [120]

●Acute chest syndrome

●Reversible bone marrow necrosis associated with parvovirus B19 infection [121]

●Exercise-related death syndrome [122]

●Splenomegaly [123]

●Cholelithiasis [123]

In one family, three siblings had moderately severe hemolysis, jaundice, bone pain, splenic infarction, recurrent pneumonia, and irreversibly sickled cells on the blood smear [124]. It has been suggested that patients with Hb SE disease be followed and managed in a similar fashion as those with Hb S beta⁺ thalassemia and treated appropriately when they develop sickling-related symptoms and complications [119].

SICKLE CELL SYNDROMES THAT APPEAR TO BE SICKLE CELL TRAIT ON HEMOGLOBIN ANALYSIS — Depending on the geographic location, the prevalence of sickle cell trait (Hb AS) in newborns can be approximately 0.07 percent in the general United States population and 9 percent of African American births [125]. The prevalence is 30 percent of the births in West Africa [126]. (See "Sickle cell trait", section on 'Genetics'.)

In individuals suspected of having sickle cell trait, the hemoglobin and red blood cell (RBC) parameters are expected to be normal, and these individuals are expected to have a normal life-expectancy, with rare clinical events only seen in extreme physical conditions [125]. There is also a high relative risk (but low absolute risk) of renal cell carcinoma (RCC). (See "Sickle cell trait", section on 'Urologic and kidney disease'.)

However, a very small subset of individuals with a Hb AS pattern will have clinical symptoms typically associated with sickle cell disease (SCD). These individuals should be evaluated for rare syndromes that have a clinical phenotype associated with SCD. At least 14 different clinically relevant sickling Hb variants other than Hb S have been described [127]. Two examples are Hb S-Jamaica Plain and Hb S with pyruvate kinase deficiency. (See 'Hb S-Jamaica plain' below and 'Hb S plus pyruvate kinase deficiency' below.)

These rare SCD syndromes are difficult to diagnosis and are often missed because high-performance liquid chromatography (HPLC) reveals a majority of hemoglobin A. The total hemoglobin levels are low but often not low enough to prompt an extensive evaluation. These compound heterozygotes are heterozygous for both the sickle cell variant and a second beta globin variant. The clinical manifestations can vary considerably, including clinical phenotypes that mimic SCD, such as Hb S-Oman, Hb S-Antilles, Hb S-Jamaica Plain, and Hb S-São Paulo [128].

Hb S-Jamaica plain — In Hb S-Jamaica Plain, the proband has Hb AS on HPLC and is heterozygous for the sickle cell variant. They also have a second, charge-neutral beta globin variant, Leu68Phe. This hemoglobin was studied and noted to have severely reduced oxygen affinity, and structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at normal oxygen pressure [129]. Following splenectomy, laboratory values included a hemoglobin of 8.0 g/dL and a mean corpuscular volume (MCV) of 80.4 fL. HPLC showed Hb A >60 percent, with 25 to 40 percent Hb S, 2.1 to 3.1 percent Hb A2, and 2.7 to 13 percent Hb F.

Hb S plus pyruvate kinase deficiency — The SCD phenotype has also be seen in a compound heterozygote for the sickle cell variant and a variant that causes pyruvate kinase (PK) deficiency. A case report described a female who had recurrent acute vaso-occlusive pain episodes and leg ulcers, clinical features typically associated with SCD [130]. The authors postulated that decreased oxygen affinity associated with PK deficiency caused clinical features of SCD. Her baseline laboratory parameters revealed Hb 9.8 g/dL, and MCV 88.7 fL. Her blood smear revealed a few sickle cells. HPLC showed 62 percent Hb A, 35 percent Hb S, 2 to 3 percent Hb A2, and 0.4 percent Hb F.

Two variants on one beta globin gene — Another example of SCD in heterozygotes occurs when there are two separate variants affecting the same beta globin chain. (See "Sickle cell trait", section on 'Symptoms of sickle cell disease'.)

The two most common types of variants are Hb S-Antilles and Hb S-Oman. Heterozygotes for Hb S-Antilles have a mild hemolytic anemia with sickle cells on the blood smear. These individuals may also develop painful episodes and other symptoms [131]. On hemoglobin electrophoresis, these conditions may appear as sickle trait. Additional molecular and DNA techniques are required to make these diagnoses. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY

●Definitions – There are a variety of sickle cell disease (SCD) syndromes that result from inheritance of the sickle cell variant in compound heterozygosity with other beta globin gene variants (table 1). Sickle cell trait is not a sickle cell disease syndrome. (See 'Overview' above.)

●Hemoglobin SC disease (Hb SC) – Individuals with Hb SC disease are at risk for the same complications as those with Hb SS disease but at a decreased frequency. Anemia is mild, and splenomegaly may be the only finding on physical examination. The blood smear shows target cells, folded cells, occasional irreversibly sickled cells, and occasional cells containing hemoglobin crystals. Hb S and Hb C are seen in equal amounts on electrophoresis. (See 'Hb SC disease' above.)

●Hb S-beta⁰ thalassemia – Individuals with Hb S-beta⁰ thalassemia have severe disease that may be somewhat less severe than Hb SS disease. This variant is more common in the Greek and Mediterranean regions than in the African American population. No Hb A is present on electrophoresis. It is distinguished from Hb SS disease by the presence of hypochromic, microcytic red cells and increased levels of Hb A2. Management is similar to individuals with homozygous SCD (Hb SS). (See 'Sickle-beta thalassemia' above.)

●Hb S-beta⁺ thalassemia – Individuals with Hb S-beta⁺ thalassemia have a form of SCD that is less severe than Hb SS disease. Disease severity is inversely related to the amount of Hb A present, which varies from 5 to 30 percent. The peripheral smear shows the presence of hypochromic, microcytic red cells, and levels of Hb A2 are increased. Management is individualized depending on the patient's clinical course. (See 'Sickle-beta thalassemia' above.)

●Hb SS with alpha thalassemia – The clinical manifestations and degree of anemia in Hb SS with alpha thalassemia are generally less severe than those seen in Hb S-beta⁰ thalassemia. Hb A2 levels are increased according to the number of alpha globin gene deletions. Clinically, a distinction between Hb SS with alpha thalassemia and without alpha thalassemia is not required. (See 'Sickle-alpha thalassemia' above.)

●Sickle hereditary persistence of fetal hemoglobin (sickle HPFH) – Individuals with pancellular sickle HPFH are not anemic, do not experience vaso-occlusive episodes, and may have Hb F levels as high as 35 percent. (See 'Sickle-hereditary persistence of fetal hemoglobin' above.)

●Other variants – Other sickle cell syndrome variants such as sickle-delta beta⁰ thalassemia, Hb S-Lepore, Hb SD, Hb S-O Arab, Hb SE, and variants that cause SCD in heterozygotes are less common and are discussed in the text above. (See 'Sickle-Hb Lepore disease' above and 'Sickle-Hb D disease' above and 'Sickle-Hb O Arab disease' above and 'Sickle-Hb E disease' above and 'Sickle cell syndromes that appear to be sickle cell trait on hemoglobin analysis' above.)

●Diagnosis and management – The diagnosis, clinical manifestations, and management of sickle cell trait and SCD are presented in detail separately. (See "Sickle cell trait" and "Diagnosis of sickle cell disorders" and "Overview of the clinical manifestations of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.