• Sickle cell disease (SCD) is a hemoglobin synthesis disorder in which the substitution of valine for glutamic acid at position six of the beta-globin chain yields a variant molecule, hemoglobin S. In its deoxygenated form, hemoglobin S (deoxy HgbS) polymerizes into long strands, deforming red blood cells (RBCs) into a characteristic sickle shape. Chronic RBC membrane damage from this process locks cells into an abnormal sickle shape; along with abnormal adherence to vascular endothelium, this leads to obstruction in the microcirculation and causes painful crises-the hallmark of sickle cell disease.

SCD patients include those who are homozygous sickle cell hemoglobin (HbS) and those with one sickle hemoglobin gene inherited with other hemoglobin abnormalities, notably beta thalassemia (Hgb S/β^o or Hgb S/β⁺ thalassemia) and hemoglobin C (HbSC). A comparison of sickle cell syndromes is summarized in Table 1.

Sickle cell anemia

SCD

Hemoglobin S disease

• SCD is an autosomal-recessive disorder. Sickle cell disease affects approximately 100,000 Americans. One in 13 children born to African Americans has sickle cell trait, and approximately 1 in 365 black children born in the U.S. has sickle cell anemia. Among children born to Hispanic Americans, the incidence of SCD is 1 in 16,300 live births.
• Sickle cell trait occurs in approximately 300 million people worldwide, with the highest prevalence of approximately 30% to 40% in sub-Saharan Africa, but also in the southern Mediterranean region (usually as Hgb S/β^o or Hgb S/β⁺), parts of the Middle East, and India. In the U.S., it is found in nearly 10% of African Americans.
• An estimated 2000 babies are born with sickle cell disease in the U.S. each year, and worldwide 275,000 infants are born with the disease annually.
• There is no predominant sex.

• Physical examination is variable depending on the degree of anemia and presence of acute vasoocclusive syndromes, as well as acute pulmonary, neurologic, cardiovascular, genitourinary, and musculoskeletal complications. Clinical manifestations of sickle cell disease are described in Table 2. Table 3 summarizes organ damage seen in sickle cell disease. Table 4 summarizes acute problems in sickle cell disease.
• A study of the prevalence of pain in sickle cell patients found that they complained of pain on 55% of days surveyed; another study showed 40% to 80% complained. Chronic pain may be due to avascular necrosis of joints and is sometimes poorly explained.
• There is no clinical laboratory finding that is pathognomonic of an episode of painful SCD crisis. The diagnosis is made solely on the basis of the medical history and physical examination. Elevated total bilirubin, reticulocytosis, and lactate dehydrogenase (LDH) are sometimes seen with crisis due to increased hemolysis. However, hemolytic anemia is typical for sickle cell disease at baseline. “Aplastic crisis” refers to crisis presenting with severe anemia and low reticulocyte count, usually caused by B19 parvovirus infection.
• Bones are the most common site of pain. Dactylitis, or hand-foot syndrome (acute, painful swelling of the hands and feet), is the first manifestation of sickle cell disease in many infants. Irritability and refusal to walk are other common symptoms. After infancy, musculoskeletal pain can be symmetric, asymmetric, or migratory, and it may or may not be associated with swelling, low-grade fever, redness, or warmth.
• In both children and adults, sickle vasoocclusive episodes are difficult to distinguish from osteomyelitis, septic arthritis, synovitis, rheumatic fever, or gout.
• Cholecystitis presents with abdominal pain commonly in patients with chronic hemolysis. In general, localizing symptoms for infections should be evaluated because these can trigger sickle crisis. Adult patients with severe SCD have splenic atrophy, whereas patients with milder disease (e.g., Hgb S/C) may have splenic infarct-related pain.
• Acute chest syndrome is a potentially life-threatening complication that manifests with chest pain, fever, wheezing, tachypnea, and cough and pulmonary infiltrates on imaging. Causes include infection (Mycoplasma, Chlamydia, viruses), infarction, and fat embolism; Fig. E1 illustrates the pathogenesis of the acute chest syndrome.
• Musculoskeletal and skin abnormalities include leg ulcers (particularly on the malleoli) and limb-girdle deformities caused by avascular necrosis of the femoral and humeral heads. Osteonecrosis of the heads of the femur and humerus is found in nearly 50% of adults with Hgb S/S disease.
• Endocrine abnormalities include delayed sexual maturation and late physical maturation, especially evident in boys.
• Neurologic abnormalities on examination may include seizures and altered mental status. Strokes occur in about 10% of children and adults with sickle cell anemia and approximately 35% of children with sickle cell anemia have cerebrovascular disease.
• Infections, particularly involving Salmonella, Staphylococcus aureus, Mycoplasma, and Streptococcus, are relatively common. Catheter-associated bacteremia should be considered if a vascular access device is present; these may present without fever.
• Severe splenomegaly as a result of sequestration often occurs in children before splenic atrophy.

• Thalassemia
• Other hemolytic anemias
• The differential diagnosis of patients presenting with a painful crisis is discussed in “Physical Findings”

• Screening of all newborns regardless of racial background is performed in the U.S. Screening can be performed with sodium metabisulfite reduction test (Sickledex test).
• Hemoglobin electrophoresis will also confirm the diagnosis and is useful to identify hemoglobin variants such as fetal hemoglobin and hemoglobin C.
• Patients will have evidence of hemolysis (elevated reticulocyte count, low haptoglobin, variable elevation of LDH and total bilirubin).
• Chest x-ray often reveals typical vertebral body changes (“fish mouth” vertebrae) caused by chronic vasoocclusive injury to vertebral bodies.
• For prenatal diagnosis, initial step is identification of parenteral globin gene mutation by DNA-based testing. If positive, then DNA-based testing of chorionic villus sampling or amniotic fluid cells is performed.

• Anemia (from chronic hemolysis), reticulocytosis, leukocytosis, and thrombocytosis are common. Hgb S/β⁰ and Hgb S/β⁺ thalassemia will have microcytosis; Hgb S/C is also typically microcytic. Hgb S/C may have normal or near-normal hematocrit but will have characteristic changes on peripheral smear (target cells).
• Elevations of bilirubin, lactate dehydrogenase, and low haptoglobin are consistent with chronic hemolysis.
• Peripheral blood smear may reveal sickle cells, target cells, poikilocytosis, and hypochromia (Fig. 2).
• Elevated blood urea nitrogen and creatinine may be present in patients presenting acutely with dehydration or chronically with progressive renal insufficiency.
• Urinalysis may reveal hematuria and proteinuria. Patients with SCD should be screened for microalbuminuria and proteinuria with spot urine testing by 10 yr of age.

• Chest x-ray or noncontrast chest CT scan to evaluate acute and chronic lung changes is helpful.
• Routine skeletal imaging is rarely helpful in acute crisis and should usually be reserved for pain that is not consistent with transient acute crisis.
• MRI or bone scan is useful to address chronic avascular necrosis or, in the acute setting, osteomyelitis.
• CT or MRI scan of brain is not indicated in asymptomatic adults and children with SCD but is often needed in patients with neurologic complications, such as transient ischemic attack, cerebrovascular accident, seizures, or altered mental status.
• Transcranial Doppler ultrasonography (TCD) is used to identify children with sickle cell anemia who are at risk for stroke. There should be an annual screening starting at age 2 until age 16. Patients determined to be at risk (transcranial Doppler velocity ≥200 cm/s) should be enrolled in long-term transfusion programs. These transfusions are effective in reducing risk of stroke by >90%. In adults, magnetic resonance angiography (MRA) can be used instead of TCD to identify those at risk for stroke.
• Doppler echocardiography should be performed in patients with unexplained respiratory symptoms to evaluate for pulmonary hypertension (Fig. E5), with right heart catheterization performed if abnormal. Screening for vasculopathy is done by estimating the tricuspid regurgitant jet velocity (TRV). Elevated values are predictive of early mortality. The prevalence of pulmonary hypertension when right heart catheterization is performed is approximately 6% in adults with sickle cell disease.

• Patients should be instructed to avoid conditions that may precipitate sickling crisis, such as extremes of cold and heat and dehydration.
• Maintain adequate hydration (PO or IV).
• Correct hypoxia when present.

• Initiate aggressive IV and oral hydration; most patients in crisis have evidence of dehydration. Use hypo-osmolar fluids, such as LR or 0.45 normal saline, for intravenous hydration during acute crisis in the hospitalized patient. Normal saline has adverse biochemical effects on sickled cells and may lead to increase pain.
• L-arginine 1000 mg/kg TID, decreases narcotic use by approximately 54% in the hospitalized patient during a vaso-occlusive crisis.
• Aggressively diagnose and treat suspected infections such as urinary infection, respiratory infections, or catheter-associated line infections. Table 6 summarizes bacteria and viruses that most frequently cause serious infection in patients with sickle cell disease.
• Provide pain relief during the vaso-occlusive crisis (Table 7). Most patients will have a treatment history that can guide dosing. Opiate management is complicated by high levels of tolerance in patients often treated over many years. Patient-controlled analgesic pumps are often helpful; caution should be used when employing continuous infusions, which are usually not necessary or helpful. Morphine and hydromorphone are most commonly used. Meperidine is rarely used now and generally discouraged because of neurologic side effects, although some patients state a preference for it.
• Oral diphenhydramine is used to control pruritus, which is commonly associated with opiate analgesics; preferred to IV therapy in guidelines.
• Tables 8 and 9 summarize overall strategies for the management of acute chest syndrome.
• Follow oxygenation in patients presenting with chest pain or respiratory symptoms; assess for evolving acute chest syndrome if oxygenation deteriorates.
• Urology evaluation for priapism.

• Hydroxyurea increases hemoglobin F levels, reduces the incidence of vasoocclusive complications, and improves survival. It is helpful in patients with Hgb S/S and S/β^o thalassemia; its value in other variants is less certain. There is strong evidence to support use of hydroxyurea therapy in children ages 9 mo and older to decrease the frequency of vasoocclusive crises and acute chest syndrome. Hydroxyurea is also strongly recommended for adults with three or more crises during any 12-mo period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. It should be stopped in pregnancy, and contraception counseling should be given to all patients.
• Recommended starting doses for hydroxyurea are 15 mg/kg/day in adults and 5 to 10 mg/kg/day in patients with renal disease. A recent randomized study has shown markedly superior efficacy with a dose escalation strategy of up to 30 mg/kg/day compared with traditional dosing of 20 mg/kg/day.
• Pharmaceutical grade L-glutamine is approved for use to decrease crisis symptoms in patients with Hgb S/S and Hgb S/β^o thalassemia; benefits include decrease in acute crisis episodes, reduced hospitalization, and decrease in episodes of acute chest syndrome. Dosing is 5 to 15 g tid, taken with food or 8 oz of cold or room-temperature fluid. Constipation, nausea, headache, and abdominal discomfort were common side effects, occurring in approximately 15% to 20% of patients. It may work with or without concomitant use of hydroxyurea. Caution may be warranted in prescribing L-glutamine to patients with clinically significant renal or hepatic dysfunction.
• Replace folic acid (1 mg PO daily) to replace increased utilization of folic acid stores from chronic hemolysis. Patients also have mineral and vitamin deficiencies (calcium; zinc; and vitamins A, C, D, and E) and may need oral supplementation.
• Chronic pain management represents an enduring challenge, made more difficult by the current opiate addiction and overdose epidemic. In one study, patients reported pain in 55% of days. Review of guidelines for safe opiate prescribing is strongly recommended and management with pain management specialists is also strongly recommended.
• Indications for PRBC transfusion in SCD are described in Table 10. Urgent exchange transfusion for acute chest syndrome with progressive hypoxia (arterial oxygen saturation <90%) or multiorgan failure may be lifesaving. Simple transfusion may be adequate in milder cases with a target Hgb of 10 g/dl. Transfusion therapy is appropriate for patients with stroke or at high risk by transcranial Doppler study (see earlier) if possible. Transfusion has shown to be beneficial in children with silent infarcts by MRI in preventing progression. Transfusion to Hgb 10 g/dl is recommended in anemic patients undergoing general anesthesia to reduce crisis and respiratory complications after surgery. Patients on chronic transfusion therapy should receive RBC matched at C, E, and K antigens to avoid alloimmunization. Transfusion is not recommended for asymptomatic anemia. Serum ferritin level should be monitored quarterly. Iron overload due to blood transfusions (transfusional hemosiderosis) can be treated with chelating agents (deferoxamine [SC infusion], deferasirox [PO], and deferiprone [PO]).
• Annual screening for proteinuria is recommended. ACE inhibitor therapy should be started for microalbuminuria in adults with SCD to prevent progression of renal injury. Progressive renal injury may cause worsening anemia and responds to erythropoietin.
• Annual retinopathy screening should be performed beginning at age 10, especially for patients with Hgb S/C variant, in whom proliferative retinopathy occurs in about 30% to 50%. It is less common in Hgb S/S and other variants.
• Gene therapy for SCD patients represents a novel approach. Clinical trials with lentiviral vector-mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells are ongoing with encouraging early results in terms of reduction of sickle cell crises and correction of the biologic hallmarks of the disease. A level of erythrocyte fetal hemoglobin (HbF) comprising alpha and gamma globins may ameliorate the hemolytic anemia of sickle cell disease by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of gamma-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. Gene therapy trials with the use of LentiGlobin have shown sustained production of HbA^T87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events.¹
• Allogeneic stem cell transplantation can be curative in young patients with symptomatic SCD.
• Crizanlizumab, an antibody against the adhesion molecule p-selectin, revealed a significantly lower rate of sickle cell-related pain crisis than placebo and was associated with a low incidence of adverse events in a recent study. It has been approved for the prevention of vasoocclusive crises in adults and pediatric patients ages 16 yr and older.
• Voxelotor, an inhibitor of sickle hemoglobin (HbS) polymerization, significantly increases hemoglobin levels and reduces markers of hemolysis and is approved for the therapy of adults and children over age 12 yr.
• Penicillin V 125 mg PO bid should be administered by age 2 mo and increased to 250 mg bid by age 3 yr. Penicillin prophylaxis can be discontinued after age 5 yr, except in children who have had splenectomy.
• Table 11 summarizes disease-modifying treatments to consider.

• Hospitalization for pain crisis unresponsive to oral analgesics, or involving fever, respiratory symptoms, or vomiting and diarrhea.
• Optimal management requires coordination with hematology, blood banking, pain management, and psychosocial counseling and support.
• Referral for patients with organ-specific complications, notably pulmonary hypertension, acute/chronic kidney disease, and ophthalmologic complications.
• Referral to an ophthalmologist for an annual dilated retinal examination beginning at 10 yr of age.

• The average life span of individuals with sickle cell trait is similar to that of the general population. It may be associated with hematuria, often painless, and rhabdomyolysis under extreme conditions. Chronic pain and acute pain are not typical of sickle cell trait. It is also associated with a higher incidence of renal medullary cancer. Chronic problems in sickle cell disease are summarized in Table 12.
• Regular immunizations, especially pneumococcal vaccination, are recommended. The prophylactic administration of penicillin soon after birth and the timely administration of pneumococcal and Haemophilus influenzae type b vaccines have resulted in a significant decline in the incidence of these infections. The heptavalent conjugated pneumococcal vaccine (Prevnar) should be administered from 2 mo of age. The 23-valent unconjugated pneumococcal vaccine (Pneumovax) is given from age 2 yr and can be boosted once 3 yr later. Influenza vaccination can be given after 6 mo of age.
• In patients with SCD presenting with acute crisis, intravenous hydration with hypotonic saline is favored over normal saline. Normal saline can have adverse biochemical effects on sickle cell and possibly lead to increased pain.
• Pulmonary hypertension is a complication of chronic hemolysis and is associated with a high risk of death. It can be detected by Doppler echocardiography in more than 30% of adult patients with sickle cell disease. Cardiac catheterization will confirm the diagnosis. It is resistant to hydroxyurea therapy.
• Malnutrition can lead to poor clinical outcomes in patients with SCD. Identifying patients at risk might improve outcomes.
• Vitamin D deficiency is common and should be treated to prevent adverse skeletal outcomes.
• Metformin increases fetal hemoglobin (HbF) levels in patients with SCD. A recent study revealed that metformin use in SCD patients with diabetes is associated with fewer episodes of consequential SCD complications and with lower health care utilization.
• Exposure to systemic corticosteroids is associated with a fourfold excess risk for hospitalization for a vaso-occlusive episode (VOE).²

Sickle Cell Anemia (Patient Information)