History and Physical Examination

As with any medical condition, a detailed history and thorough physical exam are essential when evaluating an anemic child. Important historical facts should include age, sex, race and ethnicity, diet, medications, chronic diseases, infections, travel, and exposures. A family history of anemia and/or associated difficulties such as splenomegaly, jaundice, or early-age onset of gallstones is also of consequence. There often are few physical symptoms or signs that result solely from a low hemoglobin, particularly when the anemia develops slowly. Clinical findings generally do not become apparent until the hemoglobin level falls to <7-8 g/dL. Clinical features can include pallor, sleepiness, irritability, and decreased exercise tolerance. Pallor can involve the tongue, nail beds, palms, or palmar creases. A flow murmur is often present. Ultimately, weakness, tachypnea, shortness of breath on exertion, tachycardia, cardiac dilatation, and high-output heart failure will result from increasingly severe anemia, regardless of its cause. Unusual physical findings linked to particular underlying disease etiologies are discussed in detail in sections describing the associated disorders.

Laboratory Studies

Initial laboratory testing should include hemoglobin, hematocrit, and red cell indices as well as a white blood cell count and differential, platelet count, reticulocyte count, and examination of the peripheral blood smear. The need for additional laboratory studies is dictated by the history, the physical, and the results of this initial testing.

Differential Diagnosis

Anemia is not a specific entity but rather can result from any of number of underlying pathologic processes. In order to narrow the diagnostic possibilities, anemias may be classified on the basis of their morphology and/or physiology (Fig. 441-1).

Figure 441-1 Use of the mean corpuscular volume (MCV) and reticulocyte count in the diagnosis of anemia.

(Adapted from From Brunetti M, Cohen J: The Harriet Lane handbook, ed 17, Philadelphia, 2005, Elsevier Mosby, p 338.)

Anemias may be morphologically categorized on the basis of RBC size (mean corpuscular volume [MCV]), and microscopic appearance. They can be classified as microcytic, normocytic, or macrocytic based on whether the MCV is low, normal, or high, respectively. RBC size also changes with age, and normal developmental changes in MCV should be recognized before a designation is made (see Table 441-1). Examination of a peripheral blood smear often reveals changes in RBC appearance that will help to further narrow the diagnostic categories (Fig. 441-2). Details regarding morphologic changes associated with particular disorders are described in subsequent sections.

Figure 441-2 Morphologic abnormalities of the red blood cell. A, Normal. B, Macrocytes (folic acid or vitamin B₁₂ deficiency). C, Hypochromic microcytes (iron deficiency). D, Target cells (HbCC disease). E, Schizocytes (hemolytic-uremic syndrome).

(Courtesy of Dr. E. Schwartz.)

Anemias may also be further divided on the basis of underlying physiology. The two major categories are decreased production and increased destruction or loss. The two groups are not always mutually exclusive. Decreased RBC production may be a consequence of ineffective erythropoiesis or a complete or relative failure of erythropoiesis. Increased destruction or loss may be secondary to hemolysis, sequestration, or bleeding. The peripheral blood reticulocyte percentage or absolute number will help to make a distinction between the two physiologic categories. The normal reticulocyte percentage of total RBCs during most of childhood is about 1.0%, with an absolute reticulocyte count of 25,000-75,000/mm³. In the presence of anemia, EPO production and the absolute number of reticulocytes should rise. Low or normal numbers of reticulocytes generally represent an inadequate response to anemia that is associated with relative bone marrow failure or ineffective erythropoiesis. Increased numbers of reticulocytes represent a normal bone marrow response to ongoing RBC destruction (hemolysis), sequestration, or loss (bleeding).

Figure 441-1 presents a useful approach to assessing the common causes of anemia in the pediatric age group. Children with microcytic anemia and low or normal reticulocyte counts most often have defects in erythroid maturation or ineffective erythropoiesis. Iron deficiency (Chapter 449) is the most common cause. Thalassemia trait (Chapter 456) constitutes the primary differential diagnosis when iron deficiency is suspected. Distinctions between these entities are presented in Table 449-1 (Chapter 449). Chronic disease or inflammation (more often normocytic), lead poisoning, and sideroblastic anemias should also be considered and are discussed in other chapters. Microcytosis and elevated reticulocyte counts are associated with thalassemia syndromes and hemoglobin C and E (Chapter 456). Notably, thalassemias and hemoglobinopathies are most commonly seen in patients of Mediterranean, Middle Eastern, African, or Asian background.

Normocytic anemia and low reticulocyte count characterize a large number of anemias. The anemia of chronic disease/inflammation (Chapter 445) is usually normocytic. The anemia associated with renal failure, caused by reduced erythropoietin production, will invariably be associated with clinical and laboratory evidence of significant kidney disease. Decreased or absent red cell production secondary to transient erythroblastopenia of childhood (TEC), infection, drugs, or endocrinopathy usually results in a normocytic anemia, as does bone marrow infiltration by malignancy. In the case of invading leukemia or malignancy, abnormal leukocytes or tumor cells in association with thrombocytopenia or reduced or elevated white cell counts may be seen. Acute bleeding, hypersplenism, and congenital dyserythropoietic anemia (CDA) type II (Chapter 446) are also normocytic.

In children with normocytic anemia and an appropriate (high) reticulocyte response, the anemia is usually a consequence of bleeding, hypersplenism, or ongoing hemolysis. In hemolytic conditions, reticulocytosis, indirect hyperbilirubinemia, and increased serum lactate dehydrogenase are indicators of accelerated erythrocyte destruction. There are many causes of hemolysis, resulting from conditions that are extrinsic (usually acquired) or intrinsic (usually congenital) to the red cell. Abnormal RBC morphology (e.g., spherocytes, sickle forms, microangiopathy) identified on the peripheral smear is often helpful in ascertaining the cause.

The anemia seen in children with macrocytic blood cells is sometimes megaloblastic (Chapter 448), resulting from impaired DNA synthesis and nuclear development. The peripheral blood smear in megaloblastic anemias contains large macrovalocytes, and the neutrophils often show nuclear hypersegmentation. The major causes of megaloblastic anemia include folate deficiency, vitamin B₁₂ deficiency, and rare inborn errors of metabolism. Other macrocytic anemias with low or normal reticuclocyte counts include acquired and congenital (Diamond-Blackfan and Fanconi) aplastic anemias and hypothyroidism. Patients with trisomy 21 have macrocytic cells, although an accompanying anemia is generally not present. High MCV and reticulocytosis is seen in CDA I and III and in situations wherein hemolysis results in such a large outpouring of young red cells that the mean MCV is abnormally high.