History

There are several important aspects of the history that can assist in the evaluation of a patient with pallor and suspected anemia. A child with pallor is not necessarily anemic. Assessment of sun exposure and familial patterns of complexion are crucial because many patients are intrinsically pale. A careful evaluation of the medical history is fundamental in the assessment of a patient with suspected pallor ( Table 37.3 ).

Obtaining a dietary history is very important when evaluating a patient for anemia. Infants delivered prematurely or exclusively breast-fed infants without adequate iron supplementation from infant foods in the 2nd half of their 1st year of life are at risk for iron or iron deficiency anemia. Toddlers who consume large amounts of cow’s milk and children and adolescents who consume little meat are also at risk for iron deficiency anemia. In addition, patients and breast-fed infants of mothers who follow a strict vegan diet may become deficient in vitamin B ₁₂ .

A neonatal history of hyperbilirubinemia supports a possible diagnosis of congenital hemolytic anemia such as hereditary spherocytosis. This can be further supported by a family history of anemia, blood transfusions, splenectomy, and/or cholecystectomy.

Medication history is pertinent because certain drugs, including antimalarial agents and sulfonamide antibiotics, can induce oxidant-associated hemolysis in the patient deficient in glucose-6-phosphate dehydrogenase (G6PD), whereas other medications may cause immune hemolysis (penicillin) or decreased RBC production (chloramphenicol). Travel history may suggest exposure to infections such as malaria.

Physical Examination

The general appearance of the child can provide clues to the severity and chronicity of the problem. Severe anemia that develops slowly over weeks or months is often well tolerated. Vital signs (including orthostatic blood pressure), height, weight, and growth offer further insight into the severity of the problem. Isolated pallor in a well-appearing child who does not have evidence of systemic disease is usually much less ominous than pallor noted in a child who is ill-appearing, has bruising, petechiae, lymphadenopathy, hepatosplenomegaly, or abdominal mass. Pallor at any site increases the likelihood of anemia; pallor of the face, nail beds, tongue, palms and palmar creases as well as conjunctival pallor enhance the likelihood of anemia. Conjunctival rim pallor when compared to the usually more fleshlike pallor of the deeper posterior region of the palpebral conjunctiva is highly specific in adult patients with anemia. Table 37.4 outlines physical examination findings that may provide clues to the underlying cause of the anemia.

Prominent cheekbones, dental malocclusion, and frontal bossing may occur in patients with chronic hemolytic anemias (i.e., thalassemia major) because of the expansion of bone marrow space. Tortuosity of conjunctival vessels occurs in sickle cell disease. Splenomegaly is often present in children with congenital hemolytic anemia. Lymphadenopathy and hepatosplenomegaly may indicate the presence of infiltrative disease of the bone marrow and visceral organs such as leukemia. Purpura in the anemic child is suggestive of associated thrombocytopenia that may accompany aplastic anemia or leukemia.

Many congenital anomalies and/or dysmorphic features have been associated with hematologic syndromes. Patients with Fanconi anemia are often short, have hyperpigmentation, hypoplastic “finger-like” thumbs, radial bone anomalies, and structural renal abnormalities. Patients with Diamond–Blackfan anemia are often short and have a “curious, intellectual” facial expression.

When pallor and anemia are seen in the context of other signs that suggest chronic inflammation, infection or systemic disease, a diligent general physical examination may yield substantive information. Hypertension and short stature may suggest chronic renal disease. Joint swelling and/or pain may suggest rheumatologic disorders. Digital clubbing may suggest advanced cyanotic cardiopulmonary diseases. Abdominal pain, diarrhea, and poor growth may suggest inflammatory bowel disease.

Recent onset of pallor is suggestive of anemia. The child who has always appeared somewhat pale but is otherwise well with normal growth and development likely has an intrinsic constitutional characteristic. In such instances, the child and other family members often have light hair and skin complexion. An unremarkable general medical history and physical examination support a physiologic explanation for pallor. Some children may appear pale as a result of limited sun exposure as might occur during the winter in cooler climates.

Children with malignant disease or chronic illness (e.g., rheumatologic disorders, inflammatory bowel disease, chronic cardiopulmonary disorders, diabetes) may have a pale appearance that is unrelated or out of proportion to the degree of associated anemia. Atopic children often have distinctly pale mucosa as a result of local edema. Children with generalized edema caused by hypoproteinemia, congestive heart failure, or vasculitis often appear pale as a result of excess interstitial fluid within the mucosal or cutaneous tissues. Patients with hypothyroidism are pale because of myxedematous changes in the skin, subcutaneous tissue, and mucosa.

Laboratory Evaluation

The initial laboratory test in a child with pallor should be a complete blood cell count (CBC) including a manual white blood cell (WBC) differential. Significant pallor from anemia usually does not occur until the hemoglobin level falls below 8 g/dL. “False anemia” (resulting from laboratory error, sampling difficulty, or “statistical anemia”) should be considered whenever a child is said to be anemic and laboratory findings are not consistent with clinical impressions. Capillary blood sampling can be associated with substantial error, depending on the difficulty in performing the procedure and the use of mechanical force necessary to promote blood flow. When laboratory or sampling errors are suspected, a venipuncture sample should be obtained for confirmation. By definition, 2.5% of the general population has hemoglobin levels below the lower limit of normal, which is termed “statistical anemia.” This phenomenon should be considered when mild, unexplained normocytic anemia is identified in a healthy child.

Almost all laboratories perform CBCs with automated technology systems. Hemoglobin level (grams per deciliter), RBC count (cells per cubic millimeter), and mean corpuscular volume (MCV) (expressed in femtoliters [fL]) are directly measured. Hematocrit value, mean corpuscular hemoglobin (MCH), and MCH concentration (MCHC) are derived values and therefore are less accurate. Other important information reported includes RBC distribution width (RDW), WBC count (cells per cubic millimeter), and platelet count. In addition to the hemoglobin values, careful attention should be given to the MCV, RDW, RBC morphology, platelet count, and WBC count.

Reticulocyte Count

The reticulocyte count, reported as a percentage of total RBCs, is essential in categorizing anemia. An elevated reticulocyte count implies a bone marrow response to either increased RBC destruction (hemolysis) or acute or chronic blood loss. In cases of acute blood loss, there is an average delay in bone marrow response of 3-4 days. Thus, in the setting of acute blood loss, the reticulocyte count is most helpful when the bleeding and subsequent anemia have been present for more than a few days.

Anemias are categorized on the basis of the adequacy of the reticulocyte response. The reticulocyte count is expressed as a percentage of the total number of RBCs. In the setting of a normal hemoglobin, the reticulocyte count is about 1-2%. In patients with moderate or severe anemia, the reticulocyte count may appear elevated, but in absolute terms, it may be insufficient for the degree of anemia. Therefore, the reticulocyte count must be corrected using the following formula:

If the corrected reticulocyte count is greater than 2%, then the bone marrow is producing RBCs at an accelerated pace ( Fig. 37.1 ).

Diagnostic approach to anemia.

Red Blood Cell Size

The MCV is vital to the classification of anemia. High MCV is termed macrocytosis, and low MCV is termed microcytosis. Normal standards for MCV are age related; a simple guideline is that the lower normal limit of MCV for children older than 6 months is 70 fL plus the patient’s age in years until the adult standard of 80-100 fL is reached ( Table 37.2 ). The MCV must always be interpreted in conjunction with a review of the peripheral blood smear, RDW, and reticulocyte count. A varied population of both smaller and larger RBCs (e.g., reticulocytes) may yield a falsely normal MCV and be diagnostically misleading. A high RDW in the setting of a normal MCV is a clue that 2 populations of RBCs exist. Microcytosis is associated with iron deficiency, thalassemia, and long-standing anemia of inflammation ( Table 37.5 ). Macrocytosis, an unusual finding in children, is associated with vitamin B ₁₂ or folate deficiency, bone marrow failure syndromes (Fanconi anemia, Diamond–Blackfan anemia), and some cases of hypothyroidism ( Table 37.5 ).

An individual with small RBCs may have a normal or near-normal hemoglobin level if the RBC count is increased as occurs in patients with thalassemia minor who often have RBC counts of more than 5 × 10 ⁶ . The MCHC reflects the level of hemoglobin per cell and would be expected to be low in patients with anemias in which RBCs are “underhemoglobinized,” such as the hypochromic anemia of iron deficiency.

The RDW is derived from the histogram of RBC volumes. A normal RDW (11.5-14.5%) implies a uniform population of RBCs that are similar in size. In α-thalassemia trait or β-thalassemia trait, a uniform population of small cells exists; hence, the MCV is low and the RDW is normal or minimally elevated. An elevated RDW is seen in iron deficiency where the population of small cells is variably sized; hence, the MCV is low and the RDW is elevated. In some hemolytic anemias the RDW is elevated because of the presence of large reticulocytes ( Table 37.6 ). An elevated RDW in the setting of a normocytic anemia suggests 2 populations of RBCs, namely large cells (elevated MCV) and small cells (low MCV) and is concerning for a combined anemia (i.e., concomitant iron deficiency and vitamin B ₁₂ or folate deficiency).

Red Blood Cell Morphology

Abnormalities of RBC structure may be readily apparent on inspection of the peripheral blood smear and provide helpful diagnostic hints ( Table 37.7 and Fig. 37.2 ).

TABLE 37.7

Peripheral Blood Morphologic Findings in Various Anemias

Microcytes

Iron deficiency Thalassemias Lead toxicity Anemia of chronic disease

Macrocytes

Newborns Vitamin B 12 or folate deficiency Diamond–Blackfan anemia Fanconi anemia Aplastic anemia Liver disease Down syndrome Hypothyroidism

Spherocytes

Hereditary spherocytosis Immune hemolytic anemia (newborn or acquired) Hypersplenism

Sickled Cells

Sickle cell anemias (SS disease, SC disease, Sβ + thalassemia, Sβ 0 thalassemia)

Elliptocytes

Hereditary elliptocytosis Iron deficiency Megaloblastic anemia

Target Cells

Hemoglobinopathies (especially hemoglobin C, SC, and thalassemia) Liver disease Xerocytosis

Basophil Stippling

Thalassemia Lead intoxication Myelodysplasia

Red Blood Cell Fragments, Helmet Cells, Burr Cells

Disseminated intravascular coagulation Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Kasabach–Merritt syndrome Waring blender syndrome Uremia Liver disease

Hypersegmented Neutrophils

Vitamin B 12 or folate deficiency

Blasts

Leukemia (ALL or AML) Severe infection (rarely)

Leukopenia/Thrombocytopenia

Fanconi anemia Aplastic anemia Leukemia Hemophagocytic histiocytosis

Howell-Jolly Bodies

Asplenia, hyposplenia Severe iron deficiency

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