Overview and Risk Factors
Sickle cell disease (SCD) is an autosomal recessive condition, in which red blood cells become sickle shaped and fragile. This results in hemolytic anemia and recurrent vaso-occlusion in the microvasculature due to increased red blood cell adhesion and retention. Sickle cell crises, caused by acute vaso-occlusion, are characterized by severe pain in the musculoskeletal system, abdomen, and other areas. Other acute vaso-occlusive complications include splenic sequestration and/or infarct and the acute chest syndrome associated with pulmonary infarcts. Large vessel stroke occurs in the setting of stenotic blood vessels due to chronic vessel wall injury.
Hemoglobin S (HbS) is characterized by a single change in the amino acid sequence of the α²-globin chain and is responsible for creating the abnormal red cell morphology. Individuals who are heterozygous for the HbS gene generally have no symptoms or sequelae of SCD, but they and are said to have sickle cell trait; ie, they are carriers of the HbS gene. Their offspring could be affected if the other parent is heterozygous or homozygous for the gene, or carries another abnormal hemoglobin gene.
Other SCD variants include hemoglobin SC, a heterozygous combination of HbS and hemoglobin C, and hemoglobin S and α²-thalassemia (hemoglobin Sα²+- thalassemia or Sα²o-thalassemia). These conditions cause SCD, although the symptoms and complications may be less severe than those in the homozygous condition. The remainder of this chapter will focus on SCD that results from homozygous HbS.
Acute signs and symptoms may include pain in the hands and feet, fever, immunocompromise due to splenic sequestration/infarction, priapism, chest pain, shortness of breath, fatigue, pallor, tachycardia, jaundice, and urinary symptoms. Chronic complications include delayed growth/puberty, retinopathy, chronic lung and kidney disease, avascular necrosis of the hips and shoulders, bone infarcts, and leg ulcers.
The disease occurs most often among people whose ancestry can be linked to sub-Saharan Africa, South and Central America, the Caribbean, India, and the Middle East and Mediterranean regions. A Texas study showed the disease to be about 300 times more common in African Americans (approximately 3 per 1,000) than in whites, and 3 times more common in individuals of Hispanic ethnicity than in non-Hispanic whites.1 Approximately 1 in 12 African Americans carry sickle cell trait.
Prenatal screening is possible through chorionic villous sampling if the fetus is at risk for SCD. Other tests may be routinely available in the near future.
Universal newborn screening by electrophoresis (or other diagnostic testing) is performed in all states. Sickle cell anemia is indicated by the presence of fetal hemoglobin (hemoglobin F) and hemoglobin S, and an absence of hemoglobin A.
Electrophoretic findings for sickle cell anemia are:
- Hemoglobin S at 85% to 98% (normally 0%).
- Hemoglobin A at 0% (normally 95%-98%).
- Hemoglobin F at 5% to 15% (normally 0.8%-2.0%).
Additional findings are likely to include a normochromic, normocytic anemia, reticulocytosis, and sickle cells (and other abnormal findings including polychromasia) visible on peripheral blood smear. Other findings consistent with hemolysis may also be present.
Subsequent to diagnosis, patients should undergo periodic testing, which includes complete blood count (CBC), iron studies, liver function tests, and tests of renal function, such as urinalysis, blood urea nitrogen (BUN), and creatinine. These data can be compared with those assessed during exacerbations to guide medical management.
In the acute pain setting, analgesics, warm compresses, and oral and intravenous fluids are appropriate interventions. Complementary therapies, such as hypnosis, relaxation techniques, and biofeedback, may also be helpful.
Comprehensive and multidisciplinary care is essential. Education of both patient and family may help prevent complications of the disease.
Influenza and pneumococcus vaccines should routinely be used. Pneumococcal prophylaxis (oral penicillin V 125-250 mg twice daily) should be taken continuously by children with SCD until age 5. Children with a history of splenectomy or severe pneumonia may need further prophylaxis.
Folic acid should be taken in doses of 1 mg daily.
Transcranial Doppler may identify children at risk for stroke. Those at higher risk should receive blood exchange transfusions.2
Routine eye exams should monitor for proliferative retinopathy.
Assessment for chronic complications, including chronic lung and kidney disease, should be performed periodically, especially in older children and adults.
Narcotics are often required for pain relief. Initial boluses with patient-controlled anesthesia for later pain control are appropriate strategies.
Morphine sulfate and hydromorphone are first-line agents. Hydromorphone is more concentrated, and therefore beneficial in fluid-restricted patients. Morphine synthetics, such as fentanyl, can also be used. Meperidine is not recommended.
Nonnarcotic analgesia may also be helpful. Ketorolac is especially helpful for bone pain and is as effective as meperidine.3 Note: Ulcer prophylaxis is needed. Tramadol can be used for outpatient management and is less likely than narcotics to lead to dependence.
Lesser-potency analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are likely important adjuncts to the above narcotic agents, but they have not been well-studied in this context.
Infections cause nearly 50% of SCD-induced mortality. Patients with febrile episodes, without other symptoms, need broad-spectrum antibiotic coverage (eg, ceftriaxone). Depending on the severity of the fever and prophylactic penicillin status (in children), antibiotics can be administered intravenously or intramuscularly, and on an inpatient or outpatient basis.
Meningitis, bacteremia, osteomyelitis, urinary tract infections, and acute chest syndrome require specific antibiotic regimens.
Transfusions may be of the simple or exchange type. It is important that patients are not transfused acutely above a hemoglobin of 10 g/dL, which can lead to increased blood viscosity. Strategies and formulas have been devised to help calculate appropriate volumes to be transfused in both children and adults.
Simple transfusions restore blood volume and oxygen-carrying capacity in individuals with SCD.
Partial-exchange transfusions may be required during a severe acute complication (eg, acute chest syndrome) to prevent increased blood viscosity. As mentioned previously, exchange therapy lowers the risk of stroke2 and may also prevent other end-organ damage and reduce iron loading, as compared with simple transfusion.
Transfusion therapy is not indicated for uncomplicated SCD pain events.
Alloimmunization, antibody formation after blood transfusion, is approximately 6 times more common in persons with SCD compared with other anemias, and the cost to ensure more strictly matched blood can be high. A racially and ethnically diverse blood supply can help reduce the likelihood of alloimmunization.
Hydroxyurea stimulates the production of hemoglobin F. In addition, hydroxyurea may reduce the number of acute pain episodes and acute chest syndrome attacks.
Erythropoietin's ability to stimulate production of hemoglobin F is less clear, but if hydroxyurea produces a less than adequate stimulus, substitution or addition of erythropoietin may be tried empirically.4
Hematopoietic cell transplantation and gene therapy are potentially curative treatment strategies, but remain experimental.
Magnesium supplementation may reduce the number of acute pain episodes, though more thorough study of its role is underway. Inhaled nitric oxide may have a role in treatment of SCD, and poloxamer 188 is promising for relief of acute pain episodes,5 but both of these treatments need further study.
Patients with sickle cell anemia have greater than average requirements for both calories and micronutrients. During sickle cell crises, energy intake can be especially poor. Children frequently hospitalized for sickle cell disease (SCD) commonly show poor linear growth, lean body mass, and reduced fat-free mass. For reasons that are poorly understood, many patients are deficient in essential micronutrients. A diet emphasizing fruits, vegetables, whole grains, and legumes will provide a greater proportion of essential nutrients than a typical Western diet, and appropriate supplementation (1-3 times the recommended intakes for most essential nutrients) can prevent deficiency and may decrease the likelihood of disease exacerbation.
High-calorie, nutrient-dense diet. The average energy intake of sickle cell patients is typically below the suggested allowance for calories during the quiescent phase of the disease, and it drops to roughly half the recommended levels during times of illness requiring hospitalization.6 As a result, children with SCD have impaired growth and significantly lower fat and fat-free mass, compared with unaffected individuals.7 Standard nutritional assessment methods used to calculate energy needs typically underestimate resting energy expenditure in persons with SCD.8,9 A careful nutritional assessment and the addition of energy supplements are indicated.
Adequate fluid consumption to maintain hydration. Sickling of erythrocytes increases in patients with SCD who exercise in the heat without consuming fluids, compared with those who maintain well-hydrated status.10
Micronutrient status may need correction. Blood levels of several vitamins and minerals are often low in individuals with SCD, including vitamin A and carotenoids,11,12 vitamin B6,13 vitamin C,14 vitamin E,15 magnesium,16 and zinc.17,18 These deficiencies cause a significant depreciation in blood-antioxidant status in these patients,19, and the resulting oxidative stress may precipitate vaso-occlusion-related acute chest syndrome.20 Studies indicate that vitamin-mineral supplements of certain nutrients (vitamins C and E, zinc, magnesium) or treatment with a combination of high-dose antioxidants can reduce the percentage of irreversibly sickled cells.15,21-24
Omega-3 fatty acid supplements. The serum phospholipids of children with SCD contain reduced proportions of both the parent (alpha-linolenic acid) and the long-chain omega-3 polyunsaturated fatty acids (eicosapentanoic acid, EPA, and docosahexanoic acid, DHA), compared with healthy controls.25,26 Long-chain omega-3 fatty acids (EPA/DHA) increase the fluidity of red blood cell membranes,27 whose lack characterizes sickle cell crisis.28 A small preliminary study indicated that the antithrombotic effect of fish oil (0.1 g/kg/day) reduced the number of painful episodes requiring hospitalization, compared with olive oil treatment.27 However this finding has not yet been confirmed in controlled trials.
High-potency multiple vitamin with minerals, 1 tablet by mouth daily.
Nutrition consultation for assessment, to advise patient regarding specific dietary recommendations, and to arrange follow-up as needed.
Protein-calorie supplements per nutrition consultant.
What to Tell the Family
Good nutrition can help safeguard healthy growth in children with sickle cell disease and may reduce the risk of complications. A registered dietitian can advise the patient and family on how to meet macronutrient and micronutrient needs. Supplemental nutrients may be required and ordered by the physician.
1. Strahan JE, Canfield MA, Drummond-Borg LM, Neill SU. Ethnic and gender patterns for the five congenital disorders in Texas from 1992 through 1998. Tex Med. 2002;98:80-86.
2. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11.
3. Grisham JE, Vichinsky EP. Ketorolac versus meperidine in vaso-occlusive crisis: A study of safety and efficacy. Int J Pediatr Hematol Oncol. 1996;3:239.
4. Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of fetal hemoglobin response to hydroxyurea in sickle cell patients. N Engl J Med. 1993;328:73-80.
5. Gibbs WJ, Hagemann TM. Purified poloxamer 188 for sickle cell vaso-occlusive crisis. Ann Pharmacother. 2004;38:320-324.
19. Blann AD, Marwah S, Serjeant G, et al. Platelet activation and endothelial cell dysfunction in sickle cell disease is unrelated to reduced antioxidant capacity. Blood Coagul Fibrinolysis. 2003;14:255-259.
21. Jaja SI, Ikotun AR, Gbenebitse S, et al. Blood pressure, hematologic and erythrocyte fragility changes in children suffering from sickle cell anemia following ascorbic acid supplementation. J Trop Pediatr. 2002;48:366-370.
24. Muskiet FA, Muskiet FD, Meiborg G, et al. Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. Am J Clin Nutr. 1991;54:736-744.
25. Glew RH, Casados JK, Huang YS, et al. The fatty acid composition of the serum phospholipids of children with sickle cell disease in Nigeria. Prostaglandins Leukot Essent Fatty Acids. 2002;67:217-222.
26. VanderJagt DJ, Trujillo MR, Bode-Thomas F, Huang YS, Chuang LT, Glew RH. Phase angle and n-3 polyunsaturated fatty acids in sickle cell disease. Arch Dis Child. 2002;87:252-254.