Sickle Cell Anemia

Essentials of Diagnosis

• Irreversibly sickled cells on peripheral blood smear

• Positive family history and lifelong personal history of hemolytic anemia

• Recurrent pain episodes

• Hemoglobin S is the major hemoglobin seen on electrophoresis

General Considerations

• Autosomal recessive disorder in which abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences

• Single DNA base change leads to amino acid substitution of valine for glutamate in the sixth position on beta-globin chain

• Sickling is caused by increased red blood cell (RBC) hemoglobin S concentration, RBC dehydration, acidosis, and hypoxemia

• Acute painful episodes as a result of vaso-occlusion by sickled RBCs occur spontaneously or they are provoked by infection, dehydration, or hypoxia

• Sickling is retarded markedly by hemoglobin F; high hemoglobin F levels are associated with more benign course

• Patients with S-beta⁺-thalassemia and SS alpha-thalassemia also have a benign clinical course

• Patients with heterozygous genotype (hemoglobin AS) have sickle cell trait

Demographics

• Beta^S gene is carried in 8% of American blacks

• Sickle cell anemia occurs in 1 birth in 400 in American blacks

• Onset during first year of life, when hemoglobin F levels fall

Symptoms and Signs

• Chronic hemolytic anemia produces

  • Jaundice

  • Pigment (calcium bilirubinate) gallstones

  • Splenomegaly (early in life)

  • Poorly healing skin ulcers over the lower tibia

• Anemia may be life-threatening during

  • Hemolytic or aplastic crises

  • Aplastic crises are generally associated with viral or other infection caused by

    • Immunoincompetence from hyposplenism or

    • Folic acid deficiency causing reduced erythropoiesis

• Hemolytic crises result from splenic sequestration of sickled cells (primarily in childhood, before spleen has infarcted) or with coexistent disorders such as glucose-6-phosphate dehydrogenase deficiency

• Aplastic crises occur when bone marrow compensation is reduced by infection or folate deficiency

• Acute painful episodes

  • Include spine long appendicular bones

  • Can last hours to days and produce low-grade fever

• Acute vaso-occlusion may cause priapism and strokes

• Repeated vaso-occlusion affects

  • Heart (cardiomegaly, hyperdynamic precordium, systolic murmurs)

  • Lungs

  • Liver

  • Bone (ischemic necrosis, staphylococcal or salmonella osteomyelitis)

  • Spleen (infarction, asplenia)

  • Kidney (infarction of renal medullary papillae, renal tubular concentrating defects, and gross hematuria)

• Acute chest syndrome

  • Characterized by acute chest pain, hypoxemia and pulmonary infiltrates on a chest radiograph

  • Must be distinguished from an infectious pneumonia

• Pulmonary hypertension is associated with decreased survival

• Increased susceptibility to infection occurs as a result of hyposplenism and complement defects

• Sickle cell trait

  • Asymptomatic most often

  • Acute vaso-occlusion occurs only under extreme conditions

  • Gross hematuria or renal tubular defect causing inability to concentrate urine may occur

Differential Diagnosis

• Other sickle cell syndromes

  • Sickle cell trait

  • Sickle thalassemia

  • Hemoglobin SC disease

• Osteomyelitis

• Hematuria from other cause

• Acute rheumatic fever

Laboratory Tests

• Hematocrit usually 20–30%

• Peripheral blood smear: sickled cells comprise 5–50% of RBCs; reticulocytosis (10–25%); nucleated RBCs; Howell-Jolly bodies and target cells

• White blood cell count characteristically elevated to 12,000–15,000/mcL; reactive thrombocytosis may occur

• Elevated serum indirect bilirubin

• Screening test for sickle hemoglobin positive

• Hemoglobin electrophoresis confirms diagnosis

• Sickle cell anemia (homozygous S)

  • Hemoglobin S usually comprises 85–98% of hemoglobin and no hemoglobin A is present

  • Hemoglobin F levels sometimes increased

• Sickle cell trait

  • Complete blood count and peripheral blood smear normal

  • Hemoglobin electrophoresis shows that hemoglobin S comprises ~40% of hemoglobin

General Measures

• Supportive care is mainstay of treatment

• Prenatal diagnosis and genetic counseling should be made available to those with personal or family history

• Omega-3 (n-3) fatty acid supplementation may reduce vaso-occlusive episodes and transfusion needs

• L-glutamine has been shown to favorably modulate sickle pain crises and acute chest syndrome

• Sickle cell trait

  • No treatment necessary

  • Genetic counseling appropriate

• Acute painful episodes

  • Identify precipitating factors

  • Treat infections if present

  • Maintain good hydration

  • Provide adequate analgesics

  • Administer oxygen if hypoxic

Medications

• Folic acid, 1 mg orally once daily

• Hydroxyurea, 500–750 mg orally once daily

  • Increases hemoglobin F levels

  • Reduces frequency of painful crises in patients whose quality of life is disrupted by frequent vaso-occlusive pain crises (3 or more per year)

  • Concern exists about potential for secondary malignancies

  • Long-term follow-up demonstrates improved overall survival with little evidence for secondary malignancy

• Crizanlizumab-tmca (a monoclonal antibody)

  • Reduces vaso-occlusive episodes by one-half

  • Blocks P-selectin on activated endothelial cells

  • Disrupts the adverse interactions of platelets, red blood cells, and leukocytes with the endothelial wall

• Angiotensin-converting enzyme inhibitors are recommended in those with microalbuminuria

Therapeutic Procedures

• Exchange transfusions are indicated for the treatment of severe or intractable acute vaso-occlusive crises, acute chest syndrome, priapism, and stroke

• Long-term transfusion therapy has been shown to be effective in reducing the risk of recurrent stroke in children

• Phenotypically-matched transfused red blood cells are recommended to reduce the risk of red blood cell alloimmunization

• Iron chelation is needed for those on chronic transfusion therapy

• Transfusions given for aplastic or hemolytic crises

• Exchange transfusion primarily indicated for treatment of severe acute vaso-occlusive crises, intractable pain crises, acute chest syndrome, priapism, and stroke

• Long-term transfusion therapy shown to reduce risk of recurrent stroke in children

• Iron chelation is needed for those patients receiving long-term transfusion therapy

• When allogeneic hematopoietic stem cell transplantation is performed before onset of significant end-organ damage, it can cure more than 80% of children with sickle cell anemia who have suitable HLA-matched donors

Follow-Up

• Annual transcranial ultrasound

  • Indicated for children with SS who are aged 2–16 years

  • If the Doppler velocity is abnormal (200 cm/s or greater), the clinician should strongly consider beginning transfusions to prevent stroke

Prevention

• Pneumococcal vaccination reduces incidence of infections

Complications

• Sickle cell anemia becomes a chronic multisystem disease, with death from organ failure

• Acute chest syndrome

Prognosis

• With improved supportive care, average life expectancy is between ages 40 and 50

When to Refer

• Patients should have their care coordinated with a hematologist and should be referred to a Comprehensive Sickle Cell Center if one is available

When to Admit

• Patients should be admitted for management of acute chest syndrome or for painful episodes that do not respond to outpatient intervention