Pallor and Anemia

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, bone marrow response demonstrated by reticulocytosis occurs at an average 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. Likewise, in patients with nutritional anemias, a reticulocyte count should be checked several days after the initiation of therapy (e.g., iron supplementation) to assess appropriate response.

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 >2%, then the bone marrow is producing RBCs at an accelerated pace ( Fig. 49.1 ).

Red Blood Cell Size

The MCV is vital to the classification of anemia. High MCV is termed macrocytosis, and low MCV is termed microcytosis. MCV in the normal range is termed normocytic . 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 (see Table 49.2 ). 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 two populations of RBCs exist. Microcytosis (low MCV) is associated with iron deficiency, thalassemia, and long-standing anemia of inflammation ( Table 49.5 ). Macrocytosis (high MCV), an unusual finding in children, is associated with vitamin B ₁₂ or folate deficiency, bone marrow failure syndromes (e.g., Fanconi anemia, Diamond-Blackfan anemia), and some cases of hypothyroidism (see Table 49.5 ).

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 “under-hemoglobinized,” 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. The RDW is often the last hematologic parameter to normalize after successful therapy for iron deficiency. In some hemolytic anemias the RDW is elevated because of the presence of large reticulocytes ( Table 49.6 ). An elevated RDW in the setting of a normocytic anemia suggests two populations of RBCs, namely large cells (elevated MCV) and small cells (low MCV), and is concerning for a combined anemia (e.g., 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 49.7 and Fig. 49.2 ).

Other Laboratory Abnormalities Associated with Anemia

Evaluation of the WBC count, differential, and platelet count is imperative in the setting of anemia. Leukopenia, neutropenia, and/or thrombocytopenia occurring in a patient with anemia of underproduction are suggestive of aplastic anemia or infiltrative bone marrow disease such as leukemia (see Chapter 50 ). The presence of immature leukocytes on a smear associated with either a high or a low WBC count is suggestive of leukemia. Mild neutropenia may be seen in patients with transient erythroblastopenia of childhood but children are otherwise well appearing, in contrast to children with underlying malignancy. Thrombocytosis may be present in patients with iron deficiency, blood loss, inflammatory disease, infection, malignancy, or asplenia.

Elevated serum indirect bilirubin, lactate dehydrogenase, and urinary urobilinogen levels occur in patients with increased rates of RBC destruction (hemolysis). Immune-mediated hemolytic anemia should be suspected when anemia, jaundice, reticulocytosis, splenomegaly, and microspherocytes are noted. To investigate the underlying cause of the hemolysis, a direct Coombs test should be performed to detect the presence of an autoantibody on the RBC surface. An iron panel, ideally drawn when fasting, that demonstrates a low serum iron level, elevated total iron-binding capacity, and a low percentage of iron saturation (% saturation = serum iron/total iron-binding capacity × 100) and/or decreased serum ferritin level is helpful in establishing a diagnosis of iron deficiency. Hemoglobin identification via electrophoresis or high-performance liquid chromatography is necessary to identify hemoglobinopathies such as sickle cell disease or thalassemia. Assessment of RBC enzyme levels (e.g., G6PD) may be necessary when infection- or medication-related hemolytic anemia is suspected in a male of Mediterranean or African descent. True macrocytic anemia with megaloblastic neutrophils should prompt assessment for vitamin B ₁₂ or folate deficiency. Bone marrow aspirate and biopsy should strongly be considered when other cytopenias exist such as thrombocytopenia or neutropenia.

Anemia Secondary to Acute Blood Loss

Significant blood loss on an acute or subacute basis results in anemia. In subacute bleeding, the fall in hemoglobin occurs gradually and a period of about 24 hours may be required for full intravascular equilibration after acute blood loss. When severe acute blood loss occurs, intravascular volume depletion is the primary concern, which cannot be assessed by hemoglobin level. Therefore, in the setting of severe blood loss, blood pressure, heart rate, adequacy of peripheral perfusion, and mental status are the best ways to assess patients. In most instances, an obvious history of blood loss is apparent (e.g., epistaxis, heavy menstrual bleeding, hematemesis, lower GI bleeding, trauma). In some cases, intraabdominal bleeding can occur that is not clinically apparent. Large amounts of blood may accumulate in the GI tract before the development of hematemesis, hematochezia, or melena. Intraabdominal bleeding may occur after trauma or may result from an ulcer (see Chapter 16 ) and may be associated with progressive anemia in the absence of an obvious source of bleeding. The clinical history coupled with the physical examination (including rectal examination) and tests for occult blood in the stool generally define the source of blood loss. Pulmonary hemorrhage may not be readily apparent, especially if chronic; thus, evaluation with pulse oximetry and chest X-ray or chest CT scan may be indicated in a child with concerns for blood loss without an obvious source.

In anemia associated with blood loss, the RBC size and morphology are normal and appropriate reticulocytosis should occur within 3–5 days from the start of the blood loss. If hemorrhage has ceased, the hemoglobin level should gradually increase unless supervening factors such as iron deficiency exist.

Severe hemorrhage associated with intravascular volume depletion warrants immediate intervention to avoid shock. RBC transfusions are necessary until hemorrhage has ceased. Less severe hemorrhage that is not associated with intravascular volume depletion will likely manifest with moderate to severe anemia. Transfusions may be necessary when the oxygen-carrying capacity of the blood is diminished to the point of impending tissue hypoxia. In these cases, the need for transfusion therapy is based on clinical symptoms including tachycardia, dyspnea, heart failure, fatigue, or lightheadedness. If hemorrhage has ceased, intravascular volume is replete, and if the patient is not manifesting signs of cardiorespiratory compromise, transfusion therapy may be avoided. In such instances, it is appropriate to supply therapeutic doses of iron with close follow-up to ensure adequacy of the reticulocyte response ( Table 49.8 ).

Anemia Secondary to Underproduction

Anemia caused by the underproduction of RBCs (see Figs. 49.1 and 49.4 ) is characterized by a suboptimal bone marrow response to the anemia reflected by a corrected reticulocyte count of <2%. Associated clinical symptoms can provide clues to the etiology of underproduction, especially for nonhematologic causes of anemia. Common nonhematologic causes of underproduction include chronic renal disease, chronic inflammation, or infection. Hematologic causes of underproduction are outlined in subsequent text. Anemia due to underproduction of RBCs should be evaluated in the context of RBC size: microcytic, normocytic, or macrocytic.