General Discussion

Anemia is a frequent laboratory abnormality in children, affecting as many as 20% of children in the United States and as many as 80% of children in developing countries. Anemia is defined as a decreased concentration of hemoglobin and red blood cell (RBC) mass compared with age-matched controls. Age-specific blood cell indices are outlined below in Table 4-1.

The physiologic anemia of infancy is often confused with a pathologic condition. During the first weeks of life, erythropoietin synthesis abruptly decreases, resulting in a relative anemia. In the ensuing 6 to 8 weeks, the hemoglobin reaches a low point of 9 to 11 g/dL in term infants. The hemoglobin may reach a low point of 7 to 9 g/dL in premature infants. Erythropoietin production is then stimulated, and the hemoglobin level returns to normal. This physiologic anemia does not require work-up unless it is lower than the expected range.

Anemia varies with sex as well as race. African-American children have a lower normal value than their Caucasian counterparts, and glucose-6-phosphate dehydrogenase (G6PD) deficiency is far more common in male than in female children.

Most children with anemia are asymptomatic and have an abnormal hemoglobin level detected at routine screening. A child may present with pallor, fatigue, or jaundice if the anemia is severe or acute.

Anemia usually results from decreased production of RBCs, increased destruction of RBCs, or blood loss. Erythropoietin is the main hormonal regulator of RBC production. In the fetus, it comes from the monocyte/macrophage system of the liver, and postnatally is produced in the peritubular cells of the kidneys.

Medications Associated with Anemia

Causes of Anemia

Key Historical Features

Key Physical Findings

Suggested Work-Up

Complete blood cell count (CBC) evaluation of the mean corpuscular volume (MCV)	When a low hemoglobin level is detected, evaluation of the MCV may be used to classify the anemia further as microcytic, normocytic, or macrocytic. The differential diagnosis of each is presented in Table 4-2
Peripheral smear	Pathologic findings on the smear can indicate the cause of the anemia based on RBC morphology. For example, basophilic stippling is seen in thalassemia, whereas Howell-Jolly bodies are seen in asplenia, pernicious anemia, and severe iron deficiency anemia
Reticulocyte count	The reticulocyte count helps distinguish a hypoproductive anemia (decreased RBC production) versus a destructive process (increased RBC destruction). A low reticulocyte count may indicate bone marrow disorders or aplastic crisis, whereas a high count generally indicates a hemolytic process or active blood loss
	There usually is a natural increase in RBC production in response to anemia. The corrected reticulocyte count is the reticulocyte count × (hematocrit [Hct]/normal Hct). This corrected reticulocyte count is generally >2%. A low count is suggestive of chronic anemia/hemolysis or a marrow problem

Additional Work-Up

If the MCV, peripheral smear, and reticulocyte count do not elucidate the diagnosis, other, more specific lab tests can be performed:

Iron studies (ferritin, iron, total iron-binding capacity [TIBC])	If iron deficiency is suspected, a trial of treatment with iron supplementation followed by a repeat CBC is also reasonable. An increase in hemoglobin levels of greater than 1.0 g/dL by 4 weeks is diagnostic of iron deficiency
Coombs’ test	To evaluate for autoimmune hemolytic anemia
G6PD assay	If G6PD deficiency is suspected
Hemoglobin electrophoresis	If a hemoglobinopathy is suspected
LDH, total bilirubin, indirect bilirubin, haptoglobin, and reticulocyte count.	If hemolytic anemia is suspected. LDH indirect bilirubin levels will increase when there is increased RBC destruction. Haptoglobin is reduced with intravascular and extravascular hemolysis. Reticulocyte count will be high

Direct Coombs’ test If hemolytic anemia is suspected. Tests for the presence of antibody on patient’s RBCs Indirect Coombs test If hemolytic anemia is suspected. Tests for free autoantibody in the patient’s serum after RBC antibody binding sites are saturated Vitamin B₁₂ level If B₁₂ deficiency is suspected Folic acid level If folic acid deficiency is suspected Thyroid stimulating hormone (TSH) If hypothyroidism is suspected Osmotic fragility tests If hereditary spherocytosis is suspected Bone marrow biopsy If bone marrow failure or malignancy is suspected or if the diagnosis remains in doubt after thorough evaluation Red cell enzyme studies If G6PD deficiency or pyruvate kinase deficiency is suspected Blood typing and cross-matching If isoimmune anemia is suspected Specific viral titers If Epstein-Barr, cytomegalovirus, or parvovirus B19 infection is suspected Chest radiograph If leukemia or congestive heart failure is suspected Computed tomography (CT) scan If trauma is suspected in the setting of acute anemia Esophagogastroduodenscopy and/or colonoscopy If a GI source of blood loss is suspected Tagged RBC scan If cryptogenic bleeding is suspected