Although normocytic anemia is less common than microcytic anemia, the differential diagnosis in childhood is extensive (Table 103-4). The primary determinant in establishing a differential is whether the anemia is owing to decreased production, increased destruction, or blood loss. Most diagnosis may be made based on history, reticulocyte count, and review of RBC morphology.4
TABLE 103-4Differential Diagnosis for Normocytic Anemia |Favorite Table|Download (.pdf) TABLE 103-4 Differential Diagnosis for Normocytic Anemia
Blood loss (high reticulocyte count)
Hemolytic anemia (high reticulocyte count)
Artificial cardiac valve
Nonhemolytic anemia (low or normal reticulocyte count)
Abnormality isolated to red cell line
Transient erythroblastopenia of childhood (TEC)
Abnormality affecting other cell lines
Bone marrow infiltration
Acquired aplastic anemia
Normocytic Anemia With High Reticulocyte Count
If the reticulocyte count is high in the presence of a normocytic anemia, blood loss must be considered. If there is no evidence of blood loss, a hemolytic anemia is likely. The workup for a patient with hemolytic anemia includes a Coombs or direct antiglobulin test (DAT) to determine whether the hemolytic anemia is immunologic in nature. Immune hemolytic anemia may be the result of a drug reaction, infection, collagen vascular disorder, or malignancy, but commonly no etiology is determined.
Patients often present acutely with severe anemia, pallor, jaundice, and hemoglobinuria. Transfusions may be necessary with severe symptomatic anemia but may be difficult owing to the circulating antibody causing “incompatibility” in vitro and rapid destruction of transfused RBCs in vivo. Immunosuppression with corticosteroid is frequently adequate to diminish RBC destruction, so that the patient's brisk reticulocytosis can repair the anemia. In severe or refractory cases, plasmapheresis or IVIG may be necessary.
The differential diagnosis for nonimmune hemolytic anemia includes micro and macroangiopathic destruction, membrane disorders, metabolic abnormalities, and hemoglobinopathies. Sickle cell anemia is discussed in detail in Chapter 104.
Microangiopathic RBC destruction can occur with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome. The peripheral smear will demonstrate schistocytes, burr cells, and other RBC fragments.
Hereditary spherocytosis (HS)5 and elliptocytosis (HE) result from inherited mutations in a variety of proteins making up the red cell membrane. The incidence of HS is estimated at 1 in 5000 in the United States. Most cases are inherited in an autosomal dominant pattern, making family history important in the diagnosis. However, up to 25% of cases may arise in patients with no family history.4,5 Hemolytic anemia occurs due to splenic destruction of abnormally shaped RBCs. The disease often presents as jaundice and anemia in infancy. The degree of anemia varies widelyt is often consistent within affected family members. Laboratory studies reveal anemia, reticulocytosis, and hyperbilirubinemia. The diagnosis is made by reviewing the peripheral smear and possibly family history; osmotic fragility studies are confirmatory. The major hematologic crisis is aplastic anemia, which is usually secondary to a parvovirus infection. Patients may also have an increased rate of hemolysis with stress or infection. Splenectomy is curative and is considered in patients with severe hemolysis leading to frequent transfusion or hospitalization. Spherocytes may be seen in the peripheral smear of conditions other than HS, including neonates with ABO incompatibility, patients with clostridial sepsis, severe burns, and spider, bee, or snake bites.
Inherited metabolic disorders, such as pyruvate kinase and glucose-6-phosphate dehydrogenase (G6PD) deficiencies, also cause chronic hemolysis. There are multiple variants of G6PD deficiency, with varying degrees of severity. The A-variant is seen in approximately 10% of African American males and becomes symptomatic only after a significant challenge from a drug or infection. Enzyme levels are higher in young cells, so normal levels of G6PD may be obtained when assayed from G6PD-deficient patients during periods of brisk reticulocytosis. The assay may have to be repeated when the acute hemolysis has passed. Treatment involves blood transfusion with severe anemia and counseling regarding avoidance of oxidant stressors.
Normocytic Anemia With Low Reticulocyte Counts
A low reticulocyte count in the face of significant anemia indicates bone marrow underproduction. If the abnormality is isolated to the RBC line, the primary considerations are TEC and an aplastic crisis complicating an underlying hemolytic anemia.
TEC is an acquired pure RBC aplasia; WBC and platelet counts are normal. It typically affects children between 1 and 4 years of age. There is seasonal clustering and an associated history of preceding viral illness, but no causative viral agent has been identified. Supportive therapy is usually sufficient as patients are typically hemodynamically stable and recover spontaneously over several weeks. Transfusion may be necessary in symptomatic patients. Steroids have not been shown to speed recovery.
Other entities in the differential of normocytic anemia with low-to-normal reticulocyte counts and no abnormalities of other cell lines include anemia of chronic disease, inflammatory processes, and decreased erythropoietin from renal insufficiency. Anemia of chronic disease (ACOD) occurs in patients with acute or chronic immune activation, resulting in disorder of iron hemostasis and blunted erythropoietin response.6 ACOD is usually a mild normocytic, normochromic anemia, but may be microcytic in long-standing cases, making it difficult to differentiate from iron deficiency (see Table 103-1). Diamond–Blackfan anemia is a congenital RBC aplasia that usually presents in the first year of life with severe anemia. The age of onset of anemia may help to differentiate Diamond–Blackfan from TEC. Occasionally, other congenital abnormalities are associated, such as cleft palate, skeletal anomalies, and congenital heart disease.
Thrombocytopenia or WBC abnormalities associated with normocytic anemia and poor reticulocyte response suggests marrow infiltration or acquired aplastic anemia. Marrow infiltration is most commonly due to leukemia. Leukemic blasts may be apparent in the peripheral blood. Atypical lymphocytes from Epstein–Barr virus or other viral infections can appear similar to lymphoblasts. Lymphoma and other tumors with potential to metastasize to the bone marrow may also cause failure of production, with resultant decreases in multiple cell lines.
Acquired aplastic anemia in the absence of an underlying hemolytic anemia has been associated with drugs and infections. Often no etiology is determined. The prognosis is quite poor and bone marrow transplantation is often required. Blood transfusion is performed judiciously for patients who are candidates for bone marrow transplantation because of the risk of sensitization.