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.
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.
Hemoglobin SS disease. (Peripheral blood, 100 ×.) Sickled red blood cells and target cells in a patient with hemoglobin SS disease and sickle hepatopathy. In addition, the red blood cell in the lower central area of the field contains a hard peripheral inclusion called a Howell-Jolly body. This represents nuclear remnants and is the consequence of hyposplenism. (Used, with permission, from L Damon.)
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.
Table 13–9.Hemoglobin distribution in sickle cell syndromes. ||Download (.pdf) Table 13–9. Hemoglobin distribution in sickle cell syndromes.
|Genotype ||Clinical Diagnosis ||Hb A ||Hb S ||Hb A2 ||Hb F |
|AA ||Normal ||97–99% ||0% ||1–2% ||< 1% |
|AS ||Sickle trait ||60% ||40% ||1–2% ||< 1% |
|AS, alpha-thalassemia ||Sickle trait, alpha-thalassemia ||70–75% ||25–30% ||1–2% ||< 1% |
|SS ||Sickle cell anemia ||0% ||86–98% ||1–3% ||5–15% |
|SS, alpha-thalassemia (3 genes) ||SS alpha-thalassemia, silent ||0% ||90% ||3% ||7–9% |
|SS, alpha-thalassemia (2 genes) ||SS alpha-thalassemia, trait ||0% ||80% ||3% ||11–21% |
|S, beta0-thalassemia ||Sickle beta0-thalassemia ||0% ||70–80% ||3–5% ||10–20% |
|S, beta+-thalassemia ||Sickle beta+-thalassemia ||10–20% ||60–75% ||3–5% ||10–20% |