13-13: Sickle Cell Anemia & Related Syndromes

Sickle cell anemia is an autosomal recessive disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences. A single DNA base change leads to an amino acid substitution of valine for glutamate in the sixth position on the beta-globin chain. The abnormal beta chain is designated beta^s and the tetramer of alpha-2beta^s-2 is designated hemoglobin S (eFigure 13–13). Hemoglobin S is unstable and polymerizes in the setting of various stressors, including hypoxemia and acidosis, leading to the formation of sickled red blood cells. Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. Adenosine binds to its receptor (A2B), resulting in the production of 2,3-biphosphoglycerate and the induction of more sickling, and to its receptor (A2A) on natural killer cells, resulting in pulmonary inflammation. The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction, vascular injury, and pulmonary hypertension.

The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. Hemoglobin F cannot participate in polymer formation, and its presence markedly retards sickling. Factors that increase sickling are red blood cell dehydration and factors that lead to formation of deoxyhemoglobin S (eg, acidosis and hypoxemia) either systemic or local in tissues. Hemolytic crises may be related to splenic sequestration of sickled cells (primarily in childhood before the spleen has been infarcted as a result of repeated sickling) or with coexistent disorders such as G6PD deficiency.

The beta^S gene is carried in 8% of American blacks, and 1 of 400 American black children will be born with sickle cell anemia; prenatal diagnosis is available when sickle cell anemia is suspected. Genetic counseling should be made available to patients.

A. Symptoms and Signs

The disorder has its onset during the first year of life, when hemoglobin F levels fall as a signal is sent to switch from production of gamma-globin to beta-globin. Chronic hemolytic anemia produces jaundice, pigment (calcium bilirubinate) gallstones, splenomegaly (early in life), and poorly healing skin ulcers over the lower tibia. Life-threatening severe anemia can occur during hemolytic or aplastic crises, the latter generally associated with viral or other infection caused by immunoincompetence from hyposplenism or by folic acid deficiency causing reduced erythropoiesis.

Acute painful episodes due to acute vaso-occlusion from clusters of sickled red cells may occur spontaneously or be provoked by infection, dehydration, or hypoxia. Common sites of acute painful episodes include the spine and long appendicular bones. These episodes last hours to days and may produce low-grade fever. Acute vaso-occlusion may cause strokes due to sagittal sinus venous thrombosis or to bland or hemorrhagic central nervous system arterial ischemia and may also cause priapism. Vaso-occlusive episodes are not associated with increased hemolysis.

Repeated episodes of vascular occlusion especially affect the heart, lungs, and liver. The acute chest syndrome is characterized by acute chest pain, hypoxemia, and pulmonary infiltrates on a chest radiograph and must be distinguished from an infectious pneumonia. Ischemic necrosis of bones may occur, rendering the bone susceptible to osteomyelitis due to salmonellae and (somewhat less commonly) staphylococci. Infarction of the papillae of the renal medulla causes renal tubular concentrating defects and gross hematuria, more often encountered in sickle cell trait than in sickle cell anemia. Retinopathy similar to that noted in diabetes mellitus is often present and may lead to visual impairment. Pulmonary hypertension may develop and is associated with a poor prognosis. These patients are prone to delayed puberty. An increased incidence of infection is related to hyposplenism as well as to defects in the alternate complement pathway.

On examination, patients are often chronically ill and jaundiced. There is often hepatomegaly, but the spleen is not palpable in adult life. The heart may be enlarged with a hyperdynamic precordium and systolic murmurs and, in some cases, a pronounced increase in P2. Nonhealing cutaneous ulcers of the lower leg and retinopathy may be present.

B. Laboratory Findings

Chronic hemolytic anemia is present. The hematocrit is usually 20–30%. The peripheral blood smear is characteristically abnormal, with sickled cells comprising 5–50% of red cells. Other findings include reticulocytosis (10–25%), nucleated red blood cells, and hallmarks of hyposplenism such as Howell-Jolly bodies and target cells (eFigure 13–14). The white blood cell count is characteristically elevated to 12,000–15,000/mcL, and reactive thrombocytosis may occur. Indirect bilirubin levels are high.

The diagnosis of sickle cell anemia is confirmed by hemoglobin electrophoresis (Table 13–9). Hemoglobin S will usually comprise 85–98% of hemoglobin. In homozygous S disease, no hemoglobin A will be present. Hemoglobin F levels are sometimes increased, and high hemoglobin F levels (15–20%) are associated with a more benign clinical course. Patients with S-beta⁺-thalassemia and SS alpha-thalassemia also have a more benign clinical course than straight sickle cell anemia (SS) patients.

When allogeneic hematopoietic stem cell transplantation is performed before the onset of significant end-organ damage, it can cure more than 80% of children with sickle cell anemia who have suitable HLA-matched donors, with a reasonably good quality of life. Transplantation remains investigational in adults. Other therapies modulate disease severity: hydroxyurea increases hemoglobin F levels epigenetically. Hydroxyurea (500–750 mg orally daily) reduces the frequency of painful crises in patients whose quality of life is disrupted by frequent vaso-occlusive pain episodes (three or more per year). Long-term follow-up of patients taking hydroxyurea demonstrates it improves overall survival and quality of life with little evidence for secondary malignancy. The use of omega-3 (n-3) fatty acid supplementation may also reduce vaso-occlusive episodes and reduce transfusion needs in patients with sickle cell anemia. L-glutamine has been shown to favorably modulate sickle pain crises and acute chest syndrome. Finally, a monoclonal antibody (crizanlizumab-tmca) reduces vaso-occlusive episodes by 50%. It blocks P-selectin on activated endothelial cells and thus disrupts the adverse interactions of platelets, red blood cells, and leukocytes with the endothelial wall.

Supportive care is the mainstay of treatment for sickle cell anemia. Patients are maintained on folic acid supplementation (1 mg orally daily) and given transfusions for aplastic or hemolytic crises. When acute painful episodes occur, precipitating factors should be identified and infections treated if present. The patient should be kept well hydrated, given generous analgesics, and supplied oxygen if hypoxic. Pneumococcal vaccination reduces the incidence of infections with this pathogen while hydroxyurea and L-glutamine reduce hospitalizations for acute pain. Angiotensin-converting enzyme inhibitors are recommended in patients with microalbuminuria.

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. It has been recommended that children with SS who are aged 2–16 years have annual transcranial ultrasounds and, if the Doppler velocity is abnormal (200 cm/s or greater), the clinician should strongly consider beginning transfusions to prevent stroke. Iron chelation is needed for those on chronic transfusion therapy.

Sickle cell anemia becomes a chronic multisystem disease, leading to organ failure that may result in death. With improved supportive care, average life expectancy is now between 40 and 50 years of age.

Patients with sickle cell anemia should have their care coordinated with a hematologist and should be referred to a Comprehensive Sickle Cell Center, if one is available.

Patients should be admitted for management of acute chest syndrome, for aplastic crisis, or for painful episodes that do not respond to outpatient interventions.