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Sickle Cell Disease

(Hb S Disease)

By Evan M. Braunstein, MD, PhD, Assistant Professor of Medicine, Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine

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Sickle cell disease (a hemoglobinopathy—see Hemoglobinopathies) causes a chronic hemolytic anemia occurring almost exclusively in blacks. It is caused by homozygous inheritance of Hb S. Sickle-shaped RBCs cause vaso-occlusion and are prone to hemolysis, leading to severe pain crises, organ ischemia, and other systemic complications. Acute exacerbations (crises) may develop frequently. Infection, bone marrow aplasia, or lung involvement (acute chest syndrome) can develop acutely and be fatal. Anemia is present, and sickle cells are usually evident on the peripheral smear. Diagnosis requires Hb electrophoresis. Painful crises are treated with analgesics and other supportive measures. Transfusions are occasionally required. Vaccines against bacterial infections, prophylactic antibiotics, and aggressive treatment of infections prolong survival. Hydroxyurea may decrease the frequency of crises and the acute chest syndrome.

Homozygotes (about 0.3% of blacks in the US) have sickle cell anemia; heterozygotes (8 to 13% of blacks) are typically not anemic but have an increased risk of other complications.

Pathophysiology

In Hb S, valine is substituted for glutamic acid in the 6th amino acid of the beta chain. Oxygenated Hb S is much less soluble than oxygenated Hb A; it forms a semisolid gel that causes RBCs to deform into a sickle shape at sites of low PO2. Distorted, inflexible RBCs adhere to vascular endothelium and plug small arterioles and capillaries, which leads to infarction. Vaso-occlusion also causes endothelial injury, which results in inflammation and can lead to thromboses. Because sickled RBCs are fragile, the mechanical trauma of circulation causes hemolysis. Chronic compensatory marrow hyperactivity deforms the bones.

Acute exacerbations

Acute exacerbations (crises) occur intermittently, often for no known reason. In some cases, crisis appears to be precipitated by

  • Fever

  • Viral infection

  • Local trauma

Vaso-occlusive crisis (pain crisis) is the most common type; it is caused by ischemia, tissue hypoxia and infarction, typically of the bones, but also of the spleen, lungs, or kidneys.

Aplastic crisis occurs when marrow erythropoiesis slows during acute infection due to human parvovirus, during which an acute erythroblastopenia may occur.

Acute chest syndrome results from pulmonary microvascular occlusion and is a common cause of death, with mortality rates of up to 10%. It occurs in all age groups but is most common in childhood. Repeated episodes predispose to chronic pulmonary hypertension.

In children, acute sequestration of sickled cells in the spleen may occur, exacerbating anemia.

Priapism, a serious complication that can cause erectile dysfunction, is most common in young men.

Hepatic sequestration with rapid enlargement of the liver can occur.

Complications

Chronic spleen damage can lead to autoinfarction and increases susceptibility to infection, particularly pneumococcal and Salmonella infections (including Salmonella osteomyelitis). These infections are especially common in early childhood and can be fatal.

Recurrent ischemia and infarction can cause chronic dysfunction of multiple different organ systems. Complications include ischemic stroke, seizures, avascular necrosis of the hips, renal concentrating defects, renal failure, heart failure, pulmonary hypertension and fibrosis, and retinopathy.

Heterozygotes

Patients who are heterozygous (Hb AS) do not experience hemolysis or painful crises. However, they do have an increased risk of chronic kidney disease and pulmonary embolism. In addition, rhabdomyolysis and sudden death may occur during sustained, exhausting exercise. Impaired ability to concentrate urine (hyposthenuria) is common. Unilateral hematuria (by unknown mechanisms and usually from the left kidney) can occur but is self-limited. Typical renal papillary necrosis can occur but is less common than among homozygous patients, and there is an association with the extremely rare medullary carcinoma of the kidney.

Symptoms and Signs

Most symptoms occur only in patients who are homozygous and result from

  • Anemia

  • Vaso-occlusive events resulting in tissue ischemia and infarction

Anemia is usually severe but varies among patients and is usually compensated; mild jaundice and pallor are common.

Hepatosplenomegaly is common in children, but because of repeated infarctions and subsequent fibrosis (autosplenectomy), the spleen in adults is commonly atrophied. Cardiomegaly and systolic ejection (flow) murmurs are common. Cholelithiasis and chronic punched-out ulcers around the ankles are common.

Painful crisis causes severe pain in long bones, the hands and feet , back, and joints. Hip pain may result from avascular necrosis of the femoral head. Severe abdominal pain may develop with or without vomiting and is usually accompanied by back and joint pain.

Acute chest syndrome is characterized by sudden onset of fever, chest pain, and pulmonary infiltrates. It may follow bacterial pneumonia. Hypoxemia may develop rapidly, causing dyspnea.

Diagnosis

  • DNA testing (prenatal diagnosis)

  • Peripheral smear

  • Solubility testing

  • Hb electrophoresis (or thin-layer isoelectric focusing)

The type of testing done depends on the age of the patient. DNA testing can be used for prenatal diagnosis or to confirm a diagnosis of the sickle cell genotype. Screening of neonates is available in most US states and involves Hb electrophoresis. Screening and diagnosis in children and adults involve examination of the peripheral smear, Hb solubility testing, and Hb electrophoresis.

Prenatal screening

The sensitivity of prenatal diagnosis has been greatly improved with the availability of the PCR technique. It is recommended for families at risk for sickle cell (eg, couples with medical or family histories of anemia or of suggestive ethnic background). DNA samples can be obtained by chorionic villus sampling at 8 to 10 wk gestation. Amniotic fluid can also be tested at 14 to 16 wk. Diagnosis is important for genetic counseling.

Newborn screening

Universal testing is currently recommended and is frequently one of a battery of newborn screening tests. To distinguish between Hbs F, S, A, and C, the recommended tests are Hb electrophoresis using cellulose acetate or acid citrate agar, thin-layer isoelectric focusing, or Hb fractionation by high performance liquid chromatography (HPLC). Repeat testing at age 3 to 6 mo may be necessary for confirmation. Solubility testing for Hb S is unreliable during the first few months of life.

Screening and diagnosis of children and adults

Patients with a family history of sickle cell disease or trait should be screened with peripheral smear, Hb solubility testing, and Hb electrophoresis.

Patients with symptoms or signs suggesting the disorder or its complications (eg, poor growth, acute and unexplained bone pain, aseptic necrosis of the femoral head, unexplained hematuria), and black patients with normocytic anemia (particularly if hemolysis is present) require laboratory tests for hemolytic anemia, Hb electrophoresis, and examination of RBCs for sickling. If sickle cell disease is present, RBC count is usually between 2 and 3 million/μL with Hb reduced proportionately; cells are normocytic (microcytosis suggests a concomitant alpha-thalassemia). Nucleated RBCs frequently appear in the peripheral blood, and reticulocytosis 10% is common. Dry-stained smears may show sickled RBCs (crescent-shaped, often with elongated or pointed ends).

The homozygous state is differentiated from other sickle hemoglobinopathies by electrophoresis showing only Hb S with a variable amount of Hb F. The heterozygote is differentiated by the presence of more Hb A than Hb S on electrophoresis. Hb S must be distinguished from other Hb with a similar electrophoretic pattern by showing the pathognomonic RBC morphology.

Bone marrow examination is not used for diagnosis. If it is done to differentiate other anemias, it shows hyperplasia, with normoblasts predominating; bone marrow may become aplastic during sickling or severe infections. ESR, if done to exclude other disorders (eg, juvenile RA causing hand and foot pain), is low.

Incidental findings on skeletal x-rays may include widening of the diploic spaces of the skull and a sun-ray appearance of the diploic trabeculations. The long bones often show cortical thinning, irregular densities, and new bone formation within the medullary canal.

Unexplained hematuria, even among patients not suspected of having sickle cell disease, should prompt consideration of sickle cell trait.

Evaluation of exacerbations

If patients with known sickle cell disease have acute exacerbations, including pain, fever, or other symptoms of infection, aplastic crisis is considered and CBC and reticulocyte count are done. Reticulocyte count < 1% suggests aplastic crisis, particularly when Hb decreases below the patient’s usual level. In a painful crisis without aplasia, WBC count rises, often with a shift to the left, particularly during bacterial infection. Platelet count usually increases. If measured, serum bilirubin is usually elevated (eg, 2 to 4 mg/dL [34 to 68 μmol/L]), and urine may contain urobilinogen.

In patients with chest pain or difficulty breathing, acute chest syndrome and pulmonary embolism are considered; chest x-ray and pulse oximetry are necessary. Because acute chest syndrome is the leading cause of death in sickle cell disease, early recognition and treatment are critical. Hypoxemia or pulmonary parenchymal infiltrates on chest x-ray suggest acute chest syndrome or pneumonia. Hypoxemia without pulmonary infiltrates suggests pulmonary embolism.

In patients with fever, infection and acute chest syndrome are considered; cultures, chest x-ray, and other appropriate diagnostic tests are done.

Prognosis

The life span of homozygous patients has steadily increased to > 50 yr. Common causes of death are acute chest syndrome, intercurrent infections, pulmonary emboli, infarction of a vital organ, and renal failure.

Treatment

  • Broad-spectrum antibiotics (for infection)

  • Analgesics and IV hydration (for vaso-occlusive pain crisis)

  • Sometimes transfusions

  • Immunizations, folate supplementation, and hydroxyurea (for health maintenance)

Treatment includes regular health maintenance measures as well as specific treatment of the complications as they arise. Complications are treated supportively. No effective in vivo anti-sickling drug is available. Splenectomy is valueless.

Hematopoietic stem cell transplantation remains the only curative treatment for sickle cell disease. Given the risks associated with this therapy, it is generally restricted to patients with advanced disease complications. However, this field is rapidly evolving and use of stem cell therapy may expand in the near future.

Gene therapy offers hope for a cure, but it is still under study.

Indications for hospitalization include suspected serious (including systemic) infection, aplastic crisis, acute chest syndrome, and, often, intractable pain or the need for transfusion. Fever alone may not be a reason to hospitalize. However, patients who appear acutely ill and have a temperature > 38° C should be admitted so that cultures can be obtained from multiple areas and IV antibiotics can be given.

Antibiotics

Patients with suspected serious bacterial infections or acute chest syndrome require broad-spectrum antibiotics immediately.

Analgesics

Painful crises are managed with liberal administration of analgesics, usually opioids. IV morphine (continuous or bolus) is effective and safe; meperidine is avoided. During crises, pain and fever may persist for as long as 5 days. Nonsteroidal anti-inflammatory drugs (NSAIDS) are often useful in reducing opioid requirements; however, they must be used cautiously in patients with renal disease.

Intravenous hydration

Although dehydration contributes to sickling and may precipitate crises, it is unclear whether vigorous hydration is helpful during crises. Nevertheless, maintaining normal intravascular volume has been a mainstay of therapy.

Transfusion

Transfusion is given in many situations in which its efficacy has not been demonstrated. However, chronic transfusion therapy is indicated for prevention of recurrent cerebral thrombosis, especially in children, in an effort to maintain the Hb S percentage less than 30%.

In the acute setting, specific indications include acute splenic sequestration, aplastic crises, cardiopulmonary symptoms or signs (eg, high-output heart failure, hypoxemia with PO2 < 65 mm Hg), preoperative use, priapism, and life-threatening events that would benefit from improved oxygen delivery (eg, sepsis, severe infection, acute chest syndrome, stroke, acute organ ischemia). Transfusion is not helpful during an uncomplicated painful crisis. Transfusion may be needed during pregnancy.

Simple transfusion can be done when the goal is to correct anemia, such as during aplastic crisis or splenic sequestration. Exchange transfusion is done during other acute events in order to decrease the Hb S percent and prevent ischemia. It can be done with modern apheresis machines. If the initial Hb is low (< 7 g/dL), this process cannot be initiated before first transfusing red cells. Partial exchange transfusion minimizes iron accumulation and hyperviscosity.

Health maintenance

For long-term management the following interventions have reduced mortality, particularly during childhood:

  • Pneumococcal, Haemophilus influenzae, influenza (inactivated, not live), and meningococcal vaccines

  • Early identification and treatment of serious bacterial infections

  • Prophylactic antibiotics, including continuous prophylaxis with oral penicillin from age 4 mo to 6 yr

  • Use of hydroxyurea and folate supplementation

Supplemental folate, 1 mg po once/day, is usually prescribed.

Hydroxyurea, by increasing Hb F and thereby reducing sickling, decreases painful crises (by 50%) and decreases acute chest syndrome and transfusion requirements. It is indicated in patients with recurrent pain crises or other complications. The dose of hydroxyurea is variable and is adjusted based on blood counts and adverse effects. Hydroxyurea is a leukemogen and causes neutropenia and thrombocytopenia. It is also a teratogen and should not be given to females of child-bearing age.

Transcranial Doppler flow studies in children can help predict risk of stroke, and many experts recommend annual screening for children from age 2 to 16 yr. Children at high risk appear to benefit from prophylactic, chronic exchange transfusions to keep HbS at < 30% of total Hb; iron overload is common and must be screened for and treated.

Key Points

  • Patients homozygous for Hb S have an abnormal beta chain, resulting in fragile, relatively inflexible RBCs that can plug capillaries, causing tissue infarction and that are prone to hemolysis, causing anemia.

  • Patients have various acute exacerbations including painful crisis, sequestration crisis, aplastic crisis, and acute chest syndrome.

  • Long term consequences include pulmonary hypertension, chronic kidney disease, stroke, aseptic necrosis, and increased risk of infection.

  • Diagnose using Hb electrophoresis.

  • For acute crises, give opioid analgesics for pain, check for worsening anemia (suggesting aplastic or sequestration crisis) and signs of acute chest syndrome or infection, restore normal intravascular volume using 0.9% saline and then give maintenance fluids.

  • Prevent infection by using vaccinations and prophylactic antibiotics; limit painful crises and risk of acute chest syndrome by giving hydroxyurea.

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