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C H A P T E R 42

SICKLE CELL DISEASE: CLINICAL FEATURES AND MANAGEMENT

Yogen Saunthararajah and Elliott P. Vichinsky

Hemoglobinopathies are the most common genetic diseases in approximately 3% to 15%. Additional laboratory features of hemo-
humans. In sickle cell disease (SCD), a mutated β-globin gene pro- lysis are unconjugated hyperbilirubinemia, elevated lactate dehydro-
duces sickle hemoglobin (Hb S). This mutation has been positively genase (LDH), and low haptoglobin levels. The reticulocytosis
selected during human evolution because one copy of the sickle gene accounts for high or high-normal mean corpuscular volume (MCV).
and one normal β-globin gene (sickle cell trait) confers a survival If the age-adjusted MCV is not elevated, the possibility of sickle
advantage in malaria-endemic regions. With two copies of the sickle cell–β-thalassemia, coincident α-thalassemia, or iron deficiency must
gene (Hb SS or sickle cell anemia) or the sickle mutation and another be considered.
mutated β-globin gene, for example, sickle cell–β°-thalassemia (Hb In the peripheral smear (Fig. 42.1), there may be sickled forms,
S–β thal) or Hb SC disease (Hb SC) (mixed hemoglobinopathies), target cells, polychromasia indicative of reticulocytosis, and Howell-
the less soluble Hb S can polymerize in deoxygenated regions of the Jolly bodies demonstrating hyposplenia. The RBCs are normochromic
circulation, resulting in red blood cell (RBC) rigidity, RBC adhesion unless there is coexistent thalassemia or iron deficiency. Sickled forms
to endothelium, and hemolysis. In addition to hemolytic anemia, (irreversibly sickled cells [ISCs]) occur in the peripheral smear only
these events activate inflammation and coagulation pathways and in the SCDs and not in sickle cell trait. In Hb SS disease, ISCs
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cause vasoocclusion. Thus the clinical manifestations are chronic predominate, and target cells may be few; in sickle cell–β-thalassemia,
hemolytic anemia, recurrent painful episodes, and chronic organ ISCs, target cells, and hypochromic microcytic discocytes are promi-
damage from vasoocclusion. This chapter presents the diagnosis and nent; in Hb SC disease, target cells predominate, and ISCs are rare.
natural history, and describes overall clinical management as well as White blood cell (WBC) counts are higher than normal in Hb SS
specific management by organ complications. Clinical interventions disease, particularly in patients under age 10 years. Mean WBC
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are founded on an understanding of underlying pathophysiologic counts tend not to be elevated in Hb SC disease or sickle cell–β -
processes. The exigency of living with a painful, life-threatening thalassemia. Mean platelet counts are elevated in Hb SS disease,
chronic disease in an ethnically diverse society adds complexity to the particularly in patients younger than age 18 years, but are usually
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psychosocial aspects of this illness. A comprehensive management normal in those with Hb SC disease and sickle cell–β -thalassemia.
approach directed at preventing pain crises, chronic organ damage,
and early mortality while effectively managing acute complications is
recommended. For a full discussion of the fascinating history and Solubility Tests and Hemoglobin Electrophoresis
molecular pathology of this disease, please see Chapter 42. Normal
Hb synthesis, structure, and function are described in Chapter 33, Solubility test results (e.g., Sickledex) are positive in both SCD and
and the thalassemias are considered in Chapter 40. sickle cell trait. All patients require definitive diagnosis with Hb
electrophoresis (which separates Hb species according to amino acid
composition) (Fig. 42.2) or high performance liquid chromatography
PREVALENCE (HPLC). Cellulose acetate electrophoresis at a pH of 8.4 is a standard
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method of separating Hb S from other variants. However, Hb S, G,
The distribution and frequency of the sickle cell gene in different and D have the same electrophoretic mobility with this method.
areas of the world have been influenced by natural selection and gene Using citrate agar electrophoresis at pH 6.2, Hb S has a different
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transmission via trade routes including the slave trade. Among mobility than Hb D and G, which comigrate with Hb A in this
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African Americans, the prevalence of sickle cell trait is 8% to 10% system.
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among newborns, and in this population, the frequencies of the Results from electrophoresis or thin-layer isoelectric focusing are
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sickle cell (0.045), Hb C (0.015), and β-thalassemia (0.004) genes similar in Hb SS disease and sickle cell–β°-thalassemia: nearly all of
indicate that there are 4000–5000 pregnancies a year at risk for SCD. the Hb consists of Hb S. Although differences in the fetal hemoglobin
The burden of this disease in the United States is dwarfed by that in (Hb F) (see Variant Sickle Cell Syndromes) and Hb A 2 levels may be
the rest of the world, as evidenced by a prevalence of the sickle cell useful in distinguishing these syndromes, the presence of microcytosis
gene as high as 25% to 30% in western Africa and an estimated or of one parent without sickle cell trait is a more useful indicator of
annual birth of 120,000 babies with SCD in Africa. 5 sickle cell–β°-thalassemia. The diagnosis of Hb SC disease is straight-
forward; nearly equal amounts of Hb S and Hb C are detected.
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Sickle cell–β -thalassemia and sickle cell trait both have substantial
DIAGNOSIS amounts of Hb A and Hb S. This superficial electrophoretic similarity
does not provide an obstacle to diagnosis: whereas sickle cell trait is
The diagnosis of a sickle cell syndrome is suggested by characteristic associated with neither anemia nor microcytosis and has an Hb A
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findings on the complete blood count (CBC) and peripheral smear fraction more than 50%, sickle cell–β -thalassemia is associated with
that prompt Hb electrophoresis. If a diagnosis of SCD is confirmed, anemia, microcytosis, and an Hb A fraction that ranges from 5%
evaluation of the various organ systems at risk is required. These to 30%.
evaluations are discussed in the section on clinical management. The Hb F level is usually slightly to moderately elevated; the
degree varies among patients. The amount of Hb F present is a
function of the number of reticulocytes that contain Hb F, the extent
Complete Blood Count and Peripheral Blood Smear of selective survival of Hb F–containing reticulocytes that become
mature Hb F–containing erythrocytes (F cells), and the amount of
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The chronic hemolytic anemia of SCD presents with mild to mod- Hb F per F cell. The Arab–Indian and Senegal haplotypes are associ-
erately low hematocrit and Hb levels and a reticulocytosis of ated with higher levels of Hb F than the others. 9
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