Clinical characteristics.

Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a "splenic sequestration." The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections, primarily encapsulated organisms. Acute chest syndrome (ACS) is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation as well as activating pathways that contribute to the pathophysiology directly. Individuals with the highest rates of hemolysis are at higher risk for pulmonary artery hypertension, priapism, and leg ulcers and may be relatively protected from vaso-occlusive pain.

Diagnosis/testing.

SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for the majority of SCD. Other forms of SCD result from compound heterozygosity for HbS with other specific pathogenic beta globin chain variants (e.g., sickle-hemoglobin C disease [Hb S/C], sickle beta-thalassemia [Hb S/β⁺-thalassemia and Hb S/β⁰-thalassemia], Hb S/D, Hb S/O_Arab, Hb S/E).

The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal beta globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants including at least one p.Glu6Val allele (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing.

Newborn screening for SCD began in the United States in 1975 in New York and expanded to include all 50 states by 2006. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. Some newborn screening programs confirm results with molecular testing.

Management.

Targeted therapies: Disease-modulating pharmacotherapies (hydroxyurea, L-glutamine, voxelotor, and crizanlizumab); hematopoietic stem cell transplantation; gene therapy.

Supportive care: Education of parents, caregivers, and affected individuals on avoidance of potential triggers of vaso-occlusion (dehydration, climate extremes, overexertion, and, when possible, trauma and infection), health maintenance, prophylactic medications, early interventions, warning signs of acute illness, pain management options, and urgent care plan; antibiotic prophylaxis for Streptococcus pneumoniæ; immunizations including those for asplenic individuals; folic acid supplementation; red blood cell (RBC) transfusion therapy and treatment for iron overload. Management of pain episodes includes reversal of inciting triggers, hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodal approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). RBC transfusion as needed for splenic sequestration; splenectomy may be necessary. Fever and suspected infection are treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe ACS, stroke, aplastic crisis, chronic kidney failure) are often treated with RBC transfusion or RBC exchange. Treatment of pulmonary hypertension generally includes treating inciting factors and optimizing SCD therapy to stop progression; severe priapism may require aspiration and irrigation. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for those with kidney disease with kidney transplant for end-stage kidney disease; mental health therapy and community resources.

Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual complete blood count with differential and reticulocyte count; annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β⁰-thalassemia; annual developmental assessment throughout childhood; neurocognitive assessment prior to school entry and as needed; brain MRI in childhood when examination can be tolerated without anesthesia and repeated as needed; annual assessment of vitamin D level and renal function (blood urea nitrogen, serum creatinine, urinalysis, and urine microalbumin or urine protein-to-creatinine ratio); ophthalmologic evaluation annually beginning at age ten years. Because of the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, six-minute walk test, N-terminal pro-brain natriuretic peptide (NT-proBNP), and sleep study in individuals of any age with cardiac or pulmonary concerns; EKG in those on medications that may alter corrected QT interval; growth assessments throughout childhood; annual assessment of iron status and liver function; MRI as needed to evaluate for iron overload; assessment of mental health and social needs at least annually.

Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, trauma, infection, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine.

Evaluation of relatives at risk: Early diagnosis of at-risk family members allows for genetic counseling as well as education and intervention before symptoms or end-organ damage are present.

Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician. Increased risk for preterm labor, thrombosis, preeclampsia, infectious complications, ACS, and acute painful episodes have been reported during pregnancy. Hydroxyurea should be discontinued during pregnancy.

Genetic counseling.

SCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic beta globin chain variants and being affected, a 50% chance of inheriting one beta globin chain variant and being heterozygous, and a 25% chance of inheriting neither of the familial beta globin chain variants. If the SCD-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are heterozygous; if only one (or neither) SCD-related HBB pathogenic variant in a family is known, HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when both HBB pathogenic variants have been identified in an affected family member and the genetic status of the parents is known.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of SCD is established in a proband by identification of significant quantities of HbS with or without an additional abnormal and pathogenic beta globin chain variant by hemoglobin assay, and/or by identification of biallelic HBB pathogenic variants including at least one p.Glu6Val allele (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing.

Clinical Description

The clinical manifestations of sickle cell disease (SCD) result from intermittent episodes of microvascular occlusion leading to tissue ischemia/reperfusion injury and chronic hemolysis, both of which contribute to multiorgan dysfunction. The severity of disease manifestations varies, even in individuals with the same HBB pathogenic variants.

Vaso-occlusive events are associated with ischemia/reperfusion damage to tissues that lead to pain and acute or chronic injury affecting any organ system. The bones/marrow, spleen, liver, brain, lungs, kidneys, eyes, and joints are often affected. The biologic markers associated with the "vaso-occlusive phenotype" include the following [Darbari et al 2012, Wood et al 2012, Kato et al 2018]:

• A higher white blood cell count
• A lower fetal hemoglobin level
• Coexisting alpha-thalassemia trait
• Vessel flow resistance related to deoxygenation

Chronic hemolysis is associated with chronic anemia as well as vascular dysfunction [Sundd et al 2019]. Individuals with the highest rates of hemolysis are at increased risk of developing pulmonary artery hypertension, priapism, gallstones, leg ulcers, and nephropathy [Kato et al 2018]. Biologic markers for the "hemolytic phenotype" include the following:

• Elevated plasma levels of lactate dehydrogenase (LDH)
• A low hemoglobin level
• A high reticulocyte count

Conversely, coexisting alpha-thalassemia trait is protective against this phenotype [Romana et al 2021].

Complications related to vaso-occlusive events

• Vaso-occlusive pain episodes are the most frequent cause of recurrent morbidity in individuals with SCD and account for most SCD-related hospital admissions as well as school and work absences [Bou-Maroun et al 2018, Fingar et al 2019]. Pain can be acute, recurrent, or chronic, and is complicated by coexisting chronic disease [Martinez at al 2020]. Racial prejudice and suspicion of drug seeking frequently prevent sufficient treatment for excruciating pain in individuals with SCD. Vaso-occlusion results from multicellular aggregates that block blood flow in small blood vessels, depriving downstream tissues of nutrients and oxygen, followed by re-perfusion injury resulting in tissue ischemia, inflammation, and tissue death in the affected vascular beds. Vaso-occlusion and ischemic tissue damage cause excruciating pain. Young children more often report pain in their extremities, whereas older individuals more commonly experience pain in the head, chest, abdomen, and back [Brandow & DeBaun 2018]. Recurrent episodes of acute pain ultimately contribute to the development of chronic pain, likely driven by nervous system sensitization. Diagnostic criteria for chronic pain syndrome in individuals with SCD have been established [Dampier et al 2017]. It is imperative for providers to recognize the complex role of various psychosocial factors in an individual's experience of pain [Brandow & DeBaun 2018].
• Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD and occurs in infants and children. The dorsa of the extremities are most often involved; one or all four extremities can be involved. Although immediate sequelæ are rare, dactylitis has been implicated as a risk factor for severe disease [Silva et al 2015].
• Splenic sequestration and infarction. Splenic sequestration occurs in 10%-30% of children with SCD, most commonly between age six months and three years, and may follow a febrile illness. Splenic sequestration is characterized by an acutely enlarging spleen with hemoglobin more than 2 g/dL below the affected individual's baseline value. Mild-to-moderate thrombocytopenia may also be present. Children with splenic sequestration may experience abdominal pain, nausea, vomiting, lethargy, or irritability. Blood transfusion may be required, as severe splenic sequestration may progress rapidly to shock and death. Recurrent episodes (or difficult-to-manage acute episodes) may require splenectomy. Historically most children with sickle cell disease due to Hb S/S or Hb S/β⁰-thalassemia have a dysfunctional spleen within the first year of life and complete auto-infarction and atrophy resulting from ischemia of the spleen by age five years, although this natural history may be altered by hydroxyurea and chronic transfusion therapy [Gale et al 2016, Pereda et al 2019]. Splenic dysfunction contributes to the increased risk of sepsis and infection.
• Infection. Young children with SCD and splenic dysfunction are at high risk for septicemia and meningitis caused by encapsulated bacteria including Streptococcus pneumoniæ, Neisseria meningiditis, and Hæmophilus influenzæ. Vaccination programs and prophylactic penicillin have significantly decreased the incidence of these infections [Adamkiewicz et al 2003, Oligbu et al 2019].
  Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by Staphylococcus aureus or other organisms such as Salmonella species. Infectious agents implicated in acute chest syndrome include Mycoplasma pneumoniæ, Chlamydia pneumoniæ, and Streptococcus pneumoniæ, as well as viruses. Parvovirus remains an important cause of aplastic crisis. Indwelling central venous catheters confer a high risk of bacteremia in individuals with SCD [Chulamokha et al 2006, Zarrouk et al 2006, Ordóñez et al 2021].
• Acute chest syndrome (ACS) is a complex process that can arise from multiple diverse etiologies. ACS is a major cause of mortality [Klings & Steinberg 2022]. While the definition of ACS varies in the literature, the diagnosis is typically established by identification of a new pulmonary infiltrate on chest radiograph in a person with SCD, often in the presence of respiratory tract symptoms, chest pain, hypoxemia, and/or fever. ACS often develops in the setting of a vaso-occlusive episode or with other acute manifestations of SCD, frequently after two to three days of severe vaso-occlusive pain. ACS can progress rapidly (over several hours to days) to requiring intubation and mechanical ventilatory support. A high index of suspicion is indicated; the presenting signs and symptoms of ACS can be highly variable, and affected individuals may initially have a normal physical examination [Morris et al 1999]. Multiple etiologies, often occurring simultaneously, can contribute to ACS (e.g., fat emboli from bone marrow infarcts, pneumonia, pulmonary infarction, pulmonary embolus, asthma) [Mekontso Dessap et al 2011, Klings & Steinberg 2022].

Neurologic complications in SCD include stroke, silent cerebral infarcts, cerebral hemorrhage, cerebral blood flow abnormalities including moyamoya disease, and cerebral microvascular disease. Up to 50% of individuals with SCD will manifest some degree of cerebrovascular disease by age 14 years [Bernaudin et al 2011].

• Ischemic strokes, most often seen in children and older adults, are among the most catastrophic manifestations of SCD. Common presenting signs and symptoms include hemiparesis, monoparesis, seizures, aphasia or dysphasia, cranial nerve palsies, and mental status changes. Prior to routine screening with transcranial Doppler (TCD), overt strokes occurred in as many as 11% of children with SCD in the United States, with the peak occurrence between ages two and nine years. Without therapy, strokes recur in 50%-70% of affected individuals within three years after the first event. Transfusion therapy instituted after an initial stroke has significantly reduced this risk [Serjeant 2013]. Narrowing of cerebral vessels is a risk factor for stroke, and elevated flow velocity on TCD identifies most children at high risk [Adams et al 1998], allowing intervention prior to the development of stroke [DeBaun & Kirkham 2016]. A proportion of children with normal velocities on initial TCD convert to higher-risk velocities over time.
• Silent cerebral infarcts (SCI) occur in approximately 39% of children with SCD by age 18 years [Bernaudin et al 2015] and greater than 50% of adults with SCD by age 30 years [Kassim et al 2016]. SCI are lesions identified on cerebral imaging studies without known focal neurologic symptoms; however, such lesions are associated with neurocognitive deficits [Prussien et al 2019] and an increased risk for overt stroke [Miller et al 2001, Jordan et al 2018]. Thus, despite a normal physical exam, SCI should not be considered clinically insignificant. Cerebral arterial stenosis is noted to be a risk factor for SCI but is not always reflected by increased TCD velocities. Thus, TCDs are used to screen for intracranial stenosis and risk of overt stroke, while MRI/MRA are used to identify SCI [DeBaun et al 2020].

Complications related to hemolysis. A hemolysis syndrome marked by an elevated LDH, low hemoglobin level, and high reticulocyte count is associated with leg ulcers, priapism, pulmonary artery hypertension, systemic hypertension, and platelet activation [Hebbel 2011]. Other consequences of hemolysis include chronic anemia, jaundice, predisposition to aplastic crisis, and cholelithiasis. While those with the highest rates of hemolysis may experience fewer pain episodes, the overall mortality rate for this group of individuals may be higher [Hebbel 2011, Kato et al 2017].

Aplastic crisis is the temporary interruption of red blood cell (RBC) production, typically caused by human parvovirus B19 infection in children, resulting in an acute and potentially life-threatening anemia. Sickle RBCs survive for about seven to 12 days, compared to 100-120 days for normal RBCs. Thus, infection with parvovirus B19, which has tropism to erythroid precursors, can interrupt RBC production for eight to ten days, resulting in a drop in hemoglobin level of 1 g/dL per day, leading to life-threatening anemia in individuals with SCD that may require RBC transfusion. Other infections such as Streptococcus pneumoniæ, Salmonella, and Epstein-Barr virus (EBV) have also been associated with transient RBC aplasia.

Pulmonary artery hypertension (PAH) affects approximately 6%-35% of adults with SCD and can have profound consequences [Parent et al 2011]. Although a similar proportion of children with SCD have PAH as diagnosed by echocardiography, PAH in children does not appear to be associated with the same dire outcomes as in adults [Lee et al 2009, Liem et al 2009, Hebson et al 2015].

While many have defined PAH in SCD based on elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), subsequent studies using direct measurement of pulmonary arterial pressure (PAP) by right heart catheterization indicate that this may overdiagnose PAH [Parent et al 2011]. PAH in adults is associated with markedly increased mortality [De Castro et al 2008] and significant morbidity, including exercise intolerance [Sachdev et al 2011]. Risk factors for PAH include markers of increased hemolysis such as elevated LDH [Kato et al 2006], markers of cardiac strain such as elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) [Machado et al 2006], and the presence of obstructive sleep apnea [Hebson et al 2015]. Some individuals are relatively asymptomatic in the early stages of PAH. The relevance of these factors in children is less clear.

Priapism is very common among males with SCD. Upward of 35% of adult males with SCD have experienced this complication, with a mean age of onset of 15 years [Adeyoju et al 2002]. These painful, unwanted erections occur spontaneously, with nocturnal erections, or with fever and dehydration. Males may have episodes of stuttering (intermittent) priapism lasting less than two to four hours that are often recurrent and may precede a more severe and persistent episode. Severe priapism episodes are persistent; those lasting more than two to four hours need rapid intervention because prolonged priapism may result in permanent erectile tissue damage and impotence [Rogers 2005].

Kidney disease. Various renal manifestations are seen in SCD. The term sickle nephropathy is used to describe the accumulation of multiple renal insults. The acidity, hypoxia, and hypertonicity characteristic of the renal medulla, in combination with slow capillary transit, makes this location particularly inciting of HbS polymerization and RBC sickling. The vasculopathy associated with both occlusion and hemolysis leads to glomerular and tubular dysfunction correlating to the clinical manifestations of volume depletion, nocturia, and polyuria. Although work is ongoing [Lemes et al 2021, Ataga et al 2022], there are no widely accepted early biomarkers of kidney damage; elevated creatinine is evident only in later stages of disease progression. Hyperfiltration, however, begins early and leads to microalbuminuria and proteinuria, which should be monitored. Greater than 50% of infants with SCD (ages 9-12 months) were shown to have elevated glomerular filtration rates [Ware et al 2010]. Improvement can be seen with hydroxyurea therapy [Aygun et al 2013].

Other renal complications include acute kidney injury, hematuria, urinary tract infection and pyelonephritis, renal medullary carcinoma, and blood pressure abnormalities [Ataga et al 2022].

Other complications of SCD include avascular necrosis (most commonly involving the femoral head or humerus), restrictive lung disease, cholelithiasis, retinopathy, cardiomyopathy, and delayed growth and sexual maturation. Individuals with sickle-hemoglobin C disease (Hb S/C) are at particularly high risk for retinopathy and avascular necrosis [Powars et al 2002]. Cardiopulmonary complications represent a major mortality risk in adults [Fitzhugh et al 2010].

Individuals who receive frequent RBC transfusion can have complications of iron overload resulting from tissue iron deposition damaging the liver, lungs, and heart [Kushner et al 2001], and alloimmunization that may interfere with the ability to obtain fully matched units of blood for transfusion [Vichinsky et al 1990].

Mental health manifestations. Both children and adults with SCD are at increased risk for mental health disorders including depression, anxiety, social withdrawal, and suicidal ideations [Levenson et al 2008, Connolly et al 2019].

Life expectancy and quality of life. While there has been a significant decrease in childhood death rates to as low as 0.47 in 100,000 between 2015 and 2017 [Payne et al 2020], overall survival has not varied much, and quality of life is greatly diminished [Kato et al 2018]. The median survival in the US for those with SCD is difficult to determine but was estimated at age 43 years as of 2017 [Payne et al 2020]. The main causes of death are infection, ACS, PAH, and cerebrovascular events [Bakanay et al 2005]. Causes of death in children tend to differ from those in adults. Children have higher rates of death from infection and sequestration crises, whereas adult mortality is secondary to chronic end-organ dysfunction, thrombotic disease, and treatment-related complications [Manci et al 2003].

Systemic and institutional racism are major contributors to decreased quality of life and increased mortality in those with SCD [Power-Hays & McGann 2020]. Individuals with SCD are often stigmatized and marginalized. Access to quality, respectful care is decreased, and research and funding are significantly lower for SCD than other less common conditions in the US.

Heterozygotes for HbS (i.e., Hb A/S or sickle cell trait) have hemoglobins A (adult) and S (sickle). Heterozygous individuals are not anemic and have normal RBC indices, with HbS percentages typically near 40%. Hb A/S confers a survival advantage in children who contract malaria; this is thought to be a major selective pressure for persistence of the HbS pathogenic variant (p.Glu6Val) in regions of the world where malaria is endemic.

The amount of HbS present in heterozygotes is insufficient to produce sickling manifestations under most circumstances and, thus, these individuals are usually asymptomatic. However, they are at risk for several complications [Key & Derebail 2010]:

• Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [Mitchell 2007]. Individuals with Hb A/S should maintain aggressive hydration during extreme physical exertion, with no formal activity restrictions recommended. There is increased awareness of the low but significant risks for pulmonary emboli, exertional rhabdomyolysis, and sudden death with extreme exertion in individuals with Hb A/S. This has led to the mandatory offering of testing to all NCAA Division I college athletes [Bonham et al 2010]. The full implications of this policy are unclear, and the role of genetic counseling in this setting is complex, as there is debate about the impact and consequences of testing [Tarini et al 2012, Thompson 2013, Buchanan et al 2020].
• Splenic infarct at high altitudes can occur in some individuals with Hb A/S.
• Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with Hb A/S [Goldsmith et al 2012]; investigation for renal medullary carcinoma should be considered in individuals with Hb A/S who present with hematuria. Recent population studies have identified an increased incidence of renal manifestations in individuals with Hb A/S including rhabdomyolysis, end-stage kidney disease, chronic kidney disease, and renal papillary necrosis [Hulsizer et al 2022].
• HB A/S may be associated with an increased risk for venous thromboembolism [Kato 2019, Hulsizer et al 2022].
• Individuals with Hb A/S are at increased risk for serious complications following traumatic hyphema [Gharaibeh et al 2019].
• Hb A/S has not been associated with avascular necrosis, stroke, leg ulcers, or cholelithiasis [Goldsmith et al 2012, Naik et al 2017].

Genotype-Phenotype Correlations

Although a tremendous amount of individual variability occurs, individuals with Hb S/S and S/β⁰-thalassemia are generally more severely affected than individuals with Hb S/C or S/β⁺-thalassemia. Genetic factors that are responsible for this variability are being investigated [Steinberg & Adewoye 2006].

Individuals with Hb S/C have longer RBC life span and higher hemoglobin concentration associated with fewer vaso-occlusive pain episodes. Splenomegaly and the associated risk for splenic sequestration can persist well beyond early childhood. Proliferative retinopathy and avascular necrosis are more likely to develop than in those with other sickle hemoglobinopathies.

The presence of alpha-thalassemia may modify SCD severity (see Differential Diagnosis). In general, alpha-thalassemia improves RBC survival and decreases hemolysis in SCD. However, the clinical effect on SCD is unclear and can be variable, including possible decreased complications arising from hemolysis and potentially increased complications from vaso-occlusive events [Steinberg 2005].

Nomenclature

Historically in the US the term sickle cell anemia has been used to describe persons homozygous for p.Glu6Val (i.e., Hb S/S) or, at times, persons with Hb S/β⁰-thalassemia. With increased awareness of the broad spectrum of clinically significant sickle hemoglobinopathies with varying degrees of anemia, the trend has been to use the umbrella term "sickle cell disease" (SCD). The term SCD should be followed by a detailed genotypic description for the individual (e.g., Hb S/S, Hb S/C, Hb S/β⁰-thalassemia). It is important to avoid dehumanizing terms such as "sickler" when referring to individuals with SCD.

Prevalence

The HbS allele is common in persons of African, Mediterranean, Middle Eastern, and Indian ancestry and in persons from the Caribbean and parts of Central and South America but can be present in individuals of any ethnic background.

Among African Americans, the prevalence of sickle cell trait (Hb A/S) is about 10%, resulting in the birth of approximately 1,100 infants with SCD (Hb S/S) annually in the US. Approximately one in 300-500 African Americans born in the US has SCD; more than 100,000 individuals are estimated to have SCD (Hb S/S) [Hassell 2010].

The prevalence of HBB alleles associated with SCD is higher in other parts of the world. In many regions of Africa, the prevalence of the HbS pathogenic variant (p.Glu6Val) is as high as 25%-35%, with an estimated 15 million Africans affected by SCD and 300,000-400,000 affected births per year worldwide [Kato et al 2018]. SCD accounts for as many as 16% of deaths of children younger than age five years in western Africa [Neville & Panepinto 2011].

Evaluations Following Initial Diagnosis

To establish the extent of end-organ damage and needs in an individual diagnosed with SCD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Affected individuals should be seen routinely for evaluation of SCD-related comorbidities. Surveillance should be tailored to an individual's specific genotype and clinical history. Routine age-dependent screening allows for early detection and treatment of end-organ damage. While the National Heart, Lung, and Blood Institute in the US released guidelines for surveillance, the recommendations are not complete, and some have been modified since publication. The American Society of Hematology has been developing multiple sets of guidelines, but gaps remain, especially for genotypes other than Hb S/S and Hb S/β⁰-thalassemia. The following are general guidelines compiled from several sources (see also Published Guidelines / Consensus Statements).

Agents/Circumstances to Avoid

Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:

• Dehydration
• Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
• Physical exhaustion
• Extremely high altitude without oxygen supplementation
• Trauma
• Infection
• Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
• The analgesic meperidine, which should be avoided as first-line therapy because of potential central nervous system toxicity

Evaluation of Relatives at Risk

Early diagnosis of at-risk family members may allow for intervention before symptoms are present.

If born in the US, sibs with SCD are diagnosed by universal newborn screening soon after birth (at which time referral to a pediatric hematologist is appropriate). Many states also identify sickle cell trait on newborn screening.

If newborn screening data are not available for at-risk sibs, several diagnostic approaches can be considered:

• If the HBB pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, the gold standard is a combination of high-performance liquid chromatography or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy complications in SCD can be minimized with close follow up and collaboration between hematologic and obstetric teams [Asare et al 2017]. Pregnancy in women with SCD involves increased risk for thrombosis, infectious complications, acute painful episodes, acute chest syndrome, preeclampsia, and maternal death [Oteng-Ntim et al 2015a, Kuo & Caughey 2016, Lewis et al 2021]. For the fetus, there is increased risk of preterm birth, intrauterine growth restriction, stillbirth, and perinatal mortality [Oteng-Ntim et al 2015b, Boafor et al 2016, Kuo & Caughey 2016]. The risk of pregnancy complications increases when access to prenatal care is limited, reinforcing the importance of close hematologic and obstetric follow up [Asare et al 2017]. The benefits of a chronic transfusion program versus the use of "as-needed" transfusions has not been established [Okusanya & Oladapo 2016], but expert consensus has identified individuals for whom prophylactic transfusions at regular intervals should be considered at the onset of pregnancy. These include women with a history of severe SCD-related complications before the current pregnancy, additional features of high-risk pregnancy (e.g., additional comorbidities including nephropathy) [Chou et al 2020], and those who develop SCD-related complications during the current pregnancy.

Current guidelines recommend discontinuing hydroxyurea treatment during pregnancy. While reports of human infants exposed prenatally to hydroxyurea have not identified an increased risk of malformations, hydroxyurea has been noted to increase congenital anomalies in experimental animal models.

The role of chronic transfusions in lieu of hydroxyurea needs to be addressed. Chelation during pregnancy remains controversial and is generally not advised; both deferasirox and deferoxamine are category C medications in pregnancy, while deferiprone is category D. However, given the deleterious long-term effects of discontinuing iron chelation for nine months, many providers recommend resuming chelation therapy in the second and third trimesters, specifically with deferoxamine due to its larger molecular size, prohibiting it from crossing the placenta [Diamantidis et al 2016, Sorrentino et al 2020, Taher et al 2020].

More than 99% of births to women with SCD occurring after 28 weeks' gestation are live births of infants with normal Apgar scores [Smith et al 1996]. Attention to postnatal opiate withdrawal in infants of mothers treated with high-dose opiates during pregnancy is warranted.

Therapies Under Investigation

Increased understanding of SCD pathophysiology has led to the development of drugs that target different pathways as well as attempts to improve medications currently in use. While not comprehensive, several promising agents targeting different pathways are presented here, with emphasis on those that are in Phase II/III clinical trials [Kato et al 2018, Carden & Little 2019, Osunkwo et al 2020, Rai & Ataga 2020].

Allosteric changes in hemoglobin to decrease HbS polymerization. HbS polymerizes in the T (tense) conformation associated with deoxygenation, but not the R (relaxed) conformation associated with oxygenation. The FDA-approved drug voxelotor binds a subpopulation of hemoglobin leading to a conformational change stabilizing the R state, decreasing polymerization, increasing hemoglobin, and decreasing hemolysis. However, a more efficacious version is in trials. Erythrocyte pyruvate kinase activators lower 2,3-DPG, increasing oxygen affinity homogeneously, thus decreasing crystallization, while also increasing RBC ATP, which may provide additional benefits. Multiple versions are in trials with promising results.

Decreasing the consequences of hemolysis. Hemolysis leads to multiple consequences, including both decreased synthesis and increased destruction of nitric oxide (NO). Arginine, the precursor of NO, has been studied in several contexts in the US and Africa and has shown benefit in hospitalized people with SCD pain as well as with other complications. Notably, the FDA-approved amino acid L-glutamine is a precursor to arginine. In addition, multiple agents such as soluble guanylate cycle stimulators and phosphodiesterase inhibitors are in trials to improve NO metabolism. Free heme leads to multiple negative downstream events, thus hemopexin and other agents to "detoxify" heme are being investigated.

Decreasing adhesion to the endothelium. Adhesion of WBC to the endothelium of the microcirculation slows blood flow through the microcirculation, increasing HbS polymerization and worsening SCD. While the FDA-approved chimeric anti-P-selectin antibody crizanlizumab decreases pain and acute events, multiple trials with fully humanized antibodies and antibodies to other adherence receptors are yielding promising results.

Induction of fetal hemoglobin. Though induction of fetal hemoglobin (HbF) is the oldest approach to drug therapy for SCD, hydroxyurea remains the only FDA-approved HbF inducer. Multiple pathways and factors associated with the high-level expression of the HbF genes (HBG1 and HBG2) have been identified and continue to be investigated. Multiple agents aimed at inhibiting epigenetic modifications known to repress gamma globin production are being investigated with the goal of "reactivating" expression and inducing HbF (e.g., DNA methyltransferase [DNMT1], histone deacetylase and lysine-specific demethylase [LSD-1] inhibitors). While progress on these agents has been slow, there has been explosive progress in activating HbF by inhibiting Bcl11a activity, a natural inhibitor of gamma gene expression. While pharmaceutical agents are being sought, multiple gene therapy trials designed to disrupt Bcl11a expression using a variety of approaches are ongoing. (One gene therapy approach to disrupt Bcl11a expression was recently approved by the FDA; see Targeted Therapies.)

Anti-inflammatory pathways. Multiple approaches are being pursued, including the use of omega-3 fatty acids and adenosine A2A receptor agonists.

Anticoagulants and antiplatelet agents. Hypercoagulability and platelet activation are major contributors to vaso-occlusion. While many agents have been investigated, one promising agent is tinzaparin, which may act both through anticoagulation activity and by decreasing platelet adherence and activation.

Due to the rapid development of therapies for SCD, it is important to search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe to access information on clinical studies and to discuss available studies with an expert in SCD.

Mode of Inheritance

Sickle cell disease (SCD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an individual with SCD are typically heterozygous for one HBB pathogenic variant; that is, one parent is heterozygous for hemoglobin S (HbS; HBB variant p.Glu6Val) and one parent is heterozygous for HbS or a different beta globin chain variant (e.g., HbC, HbD, HbO, or HbE).
  Alternatively, it is possible that one or both parents have biallelic beta globin chain variants (e.g., Hb S/S or compound heterozygous HBB pathogenic variants [e.g., Hb S/β⁰-thalassemia]) and are affected.
  Typical parental alleles are described in Table 6.
• Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment.
  • If both SCD-related HBB pathogenic variants have been identified in the proband, molecular genetic testing can be used to determine the genetic status of the parents.
  • If only one (or neither) SCD-related HBB pathogenic variant has been identified in the proband, high-performance liquid chromatography (HPLC) can be used to detect common abnormal hemoglobins.
    Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β⁰-thalassemia from Hb S/S (this differentiation requires molecular genetic testing or integration with other laboratory studies).
• If one parent is found to have an HbS allele, a beta globin chain variant is not identified in the other parent, and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the beta globin chain variants identified in the proband occurred as the result of a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband has Hb S/S (i.e., two HbS alleles), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the HbS allele that resulted in homozygosity for the p.Glu6Val pathogenic variant in the proband [Swensen et al 2010].
• Heterozygotes for HbS have hemoglobins A and S (i.e., Hb A/S or sickle cell trait). The amount of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, such individuals are usually asymptomatic, but are at risk for several complications (see Clinical Description, Heterozygotes for HbS).

Sibs of a proband

• If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic beta globin chain variants and being affected, a 50% chance of inheriting one beta globin chain variant and being heterozygous, and a 25% chance of inheriting neither of the familial beta globin chain variants.
• If one parent is known to be heterozygous for a beta globin chain variant and the other parent is affected with SCD, each sib of an affected individual has a 50% chance of inheriting biallelic beta globin chain variants and being affected and a 50% chance of inheriting one beta globin chain variant and being heterozygous.
• If both parents have biallelic beta globin chain variants (i.e., both parents have homozygous or compound heterozygous HBB pathogenic variants), all sibs of an affected individual will inherit biallelic beta globin chain variants and be affected.
• Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in a sib who inherits biallelic beta globin chain variants cannot be predicted on the basis of the clinical course observed in the proband (see Genotype-Phenotype Correlations).
• Heterozygotes for HbS have hemoglobins A (adult) and S (sickle) (i.e., Hb A/S or sickle cell trait). The concentration of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, these individuals are usually asymptomatic but are at risk for several complications (see Clinical Description, Heterozygotes for HbS).

Offspring of a proband. If the reproductive partner of an individual with SCD:

• Does not have a beta globin chain variant (or variants), offspring will be heterozygous for a beta globin chain variant (i.e., heterozygous for an HBB pathogenic variant);
• Is heterozygous for a beta globin chain variant, offspring will have a 50% chance of having SCD and a 50% chance of being heterozygous for a beta globin chain variant;
• Is also affected with SCD, all offspring will have biallelic beta globin chain variants (i.e., biallelic HBB pathogenic variants) and be affected.

Note: Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in offspring who inherit biallelic beta chain variants cannot be predicted on the basis of the clinical course observed in other affected family members (see Genotype-Phenotype Correlations).

Other family members. Each sib of the proband's parents is at a 50% or greater risk of being heterozygous for a beta globin chain variant (i.e., an HBB pathogenic variant).

Heterozygote Detection

Molecular genetic testing. If the SCD-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are heterozygous.

HPLC. If only one (or neither) SCD-related HBB pathogenic variant in a family is known, HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). Note that HPLC may not always detect quantitative abnormalities such as thalassemias, which, when inherited with an HbS allele, result in a significant hemoglobinopathy; see Beta-Thalassemia for information on how to diagnose a coexisting thalassemia.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• It must be kept in mind that non-sickle hemoglobin disorders (e.g., beta-thalassemia) can interact with the SCD-causing variant to cause clinically significant disease. As a result, family members without HbS can still have a child with a significant sickle hemoglobinopathy, which makes counseling difficult and leads to misconceptions in the community and, on occasion, allegations of infidelity. For example, if one parent has sickle cell trait and the other is a carrier of beta-thalassemia, it would be correct to state that, although one parent is not a SCD carrier, there is still a 25% chance that each pregnancy would have a significant hemoglobinopathy. Therefore, partners of individuals who are known to be heterozygous for HbS should be offered a thalassemia screening panel that includes hemoglobin electrophoresis, complete blood count and reticulocyte count, and a measure of iron status (e.g., zinc protoporphyrin, ferritin, and total iron-binding capacity) to screen for carrier status for sickle cell trait and other beta globin disorders.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Early testing. Increasing community awareness of SCD in populations at high risk (see Prevalence) is important in facilitating genetic counseling and early testing.

Cord blood banking. Given the increasing safety and availability of stem cell transplantation in SCD and the limited number of immunologically matched donors available for individuals with SCD, it is appropriate to discuss sib cord blood banking with the parents of an affected individual.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when:

• Both HBB pathogenic variants have been identified in an affected family member; and
• The genetic status of the parents is known. Because one parent may have a non-HbS HBB pathogenic variant (or biallelic HBB pathogenic variants) that can interact with HbS to cause a sickle hemoglobinopathy (e.g., sickle-hemoglobin C disease or sickle beta-thalassemia), the genetic status of the parents must be defined before prenatal testing can be performed.

Because of the extreme variation in clinical course, it is not currently possible to accurately predict the severity of SCD based on the prenatal finding of biallelic SCD-related HBB pathogenic variants.

When the mother is known to be heterozygous and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

HBB encodes the hemoglobin beta chain. The normal heterotetrameric protein hemoglobin A (HbA) comprises two hemoglobin alpha chains, two hemoglobin beta chains, and four heme moieties. Sickle hemoglobin (HbS) results specifically from the p.Glu6Val variant. In deoxygenated sickle hemoglobin, an interaction between p.Val6 and the complementary regions on adjacent molecules results in the formation of highly ordered, insoluble molecular polymers that aggregate and distort the shape of red blood cells (RBCs), making them brittle and poorly deformable, increasing adherence to the endothelium. This can lead to veno-occlusion, decreased tissue perfusion, and ischemia. While this is thought to be the proximate defect leading to several aspects of clinical disease, multiple pathophysiologic pathways are involved in SCD [Zhang et al 2016, Kato et al 2017].

Polymerized hemoglobin is also injurious to the RBC membrane, resulting in cellular dehydration, oxidative damage, and increased adherence to endothelial cells [Gladwin & Rodgers 2000, Hebbel 2000, Nagel 2001] and chronic hemolysis. Other factors contributing to the pathophysiology of SCD include leukocytosis (resulting in increased production of injurious cytokines and altered blood flow), coagulation abnormalities, and abnormal vascular regulation. The net result of these abnormalities is shortened RBC life span or hemolysis and intermittent vascular occlusion and a state of chronic inflammation.

Mechanism of disease causation. The variant p.Glu6Val leads to a gain of function due to a change in protein conformation that exposes a hydrophobic patch allowing for polymerization under certain conditions [Valastyan & Lindquist 2014, Kato et al 2018].

HBB-specific laboratory technical considerations. The variant p.Glu6Val is detectable by targeted molecular genetic testing or sequence analysis. If sickle beta-thalassemia disease is suspected, consider HBB sequence analysis and deletion analysis as deletions, frameshift, nonsense, and missense variants have been reported, including in the 5'UTR, 3'UTR, and deep intronic regions.

Author Notes

Dr Bender formally ran the Odessa Brown Children's Clinic Sickle Cell Program associated Seattle Children's and the University of Washington, and a basic science lab at the Fred Hutchinson Cancer Research Center focused on the regulation of the chromatin structure and gene expression using the beta globin locus as a model, gene therapy, and novel agents to treat sickle cell disease and thalassemia. Clinically, Dr Bender has a long-standing commitment to hemoglobinopathies with particular interest in patient and provider education, immigrant populations, community outreach, and optimizing access to health care, and he has a special admiration of and interest in understanding the diverse array of cultural beliefs about sickle cell disease and how to use this to optimize care. He has a special interest in newborn screening; he consults for the Washington Newborn Screening Program, works with the Association of Public Health Laboratories Hemoglobinopathy group, and contributes to the ACMG ACT sheets. Dr Bender has received the American Society of Hematology's Champion for Advocacy award, was a member of the NIH Sickle Cell Disease Advisory Committee, and worked with the Puget Sound Blood Center's Rare Blood Groups Task Force. He is honored to have the ability to work with patients and families affected by sickle cell disease. Email: gro.hctuhderf@rednebm

Dr Carlberg is a pediatric hematologist with a clinical focus on patients affected by hemoglobinopathies and other red blood cell disorders. She has a particular interest in simplifying and demystifying the process of transitioning from the pediatric to adult heath care system for those with chronic health care needs. Her research during fellowship focused on the development of a noninvasive prenatal test for hemoglobinopathies. Email: gro.snerdlihcelttaes@greblrac.eitak

Acknowledgments

The authors would like to acknowledge Katie Bergstrom, MS, CGC, for expert review and comments.

We are indebted to the patients and families with sickle cell disease who continuously inspire and teach us.

Author History

MA Bender, MD, PhD (2006-present)
Katie Carlberg, MD (2022-present)
Gabrielle Douthitt Seibel, MN, MPH, ARNP; Seattle Children's Hospital (2014-2017)
William Hobbs, MD, PhD; Puget Sound Blood Center (2009-2014)
Krysta Schlis, MD; Children's Hospital Oakland (2003-2006)
Elliott Vichinsky, MD; Children's Hospital Oakland (2003-2006)

Revision History

• 28 December 2023 (mb/aa) Revision: Exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) added to Targeted Therapies after FDA approval
• 17 November 2022 (sw) Comprehensive update posted live
• 17 August 2017 (sw) Comprehensive update posted live
• 23 October 2014 (me) Comprehensive update posted live
• 9 February 2012 (me) Comprehensive update posted live
• 6 August 2009 (me) Comprehensive update posted live
• 7 March 2006 (me) Comprehensive update posted live
• 15 September 2003 (me) Review posted live
• 21 April 2003 (ev) Original submission

Published Guidelines / Consensus Statements

• American College of Emergency Physicians. Managing sickle cell disease in the ED. Available online. Accessed 7-13-23.
• Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-701. [PubMed]
• Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR, Thein SL, Westhoff CM, Wong TE, Akl EA. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4:327-55. [PubMed]
• DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4:1554-88. [PubMed]
• Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-89. [PubMed]
• Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3:3867-97. [PubMed]
• National Health Service. Sickle cell and thalassaemia screening programme: standards. 2019. Available online. Accessed 7-13-23.
• National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report. 2014. Available online. Accessed 7-13-23.
• Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, Roper D, Rees DC, de la Salle B, Streetly A; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010;149:35-49. [PubMed]
• Sickle Cell Society. Standards for clinical care of adults with sickle cell disease in the UK. 2nd ed. 2018. Available online. Accessed 7-13-23.
• Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-48. [PubMed]

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