Red blood cells (RBCs) perform the vital physiologic function of oxygen delivery to the tissues. The hemoglobin within the erythrocyte has the remarkable capacity to bind oxygen in the lungs and then release it appropriately in the tissues.¹ The term anemia is derived from the Greek word anaimia, meaning “without blood.”² A decrease in the number of RBCs, or the amount of hemoglobin in the RBCs, results in decreased oxygen delivery and subsequent tissue hypoxia. Anemia is a commonly encountered condition affecting an estimated 1.62 billion people worldwide.³ Anemia should not be thought of as a disease, but rather as a manifestation of other underlying disease processes.^4,5 Therefore, the cause of all anemias should be thoroughly investigated. This chapter provides an overview of the diagnosis, mechanisms, and classification of anemia. In the following chapters, each anemia is discussed in detail.

Definition of Anemia

A functional definition of anemia is a decrease in the oxygen-carrying capacity of the blood. It can arise if there is insufficient hemoglobin or the hemoglobin is nonfunctional. The former is the more frequent cause.

Anemia is defined operationally as a reduction, from the baseline value, in the total number of RBCs, amount of circulating hemoglobin, and RBC mass for a particular patient. In practice, this definition is not applicable, because a patient’s baseline value is rarely known.5,6 A more conventional definition is a decrease in RBCs, hemoglobin, and hematocrit below the reference range for healthy individuals of the same age, sex, and race, under similar environmental conditions.^4–8 Problems with this conventional definition may occur for several reasons. The reference ranges are derived from large pools of “normal” individuals; however, the definition of normal is different for each of these data sets. This has led to the development of different reference ranges, depending on which pool of individuals was used. Furthermore, these pools of individuals lack the heterogeneity required to be universally applied to all the different populations.⁶

Examples of hematologic reference ranges for the adult and pediatric populations are included on the inside cover of this text. They are listed according to age and sex, but race, environmental, and laboratory factors can also influence the values. Each laboratory must determine its own reference ranges based on its particular instrumentation, the methods used, and the demographics and environment of its patient population. For the purpose of the discussion in this chapter, a patient is considered anemic if the hemoglobin value falls below those listed in these tables.

Clinical Findings

The history and physical examination are important components in making a clinical diagnosis of anemia. The classic symptoms associated with anemia are fatigue and shortness of breath. If oxygen delivery is decreased, then patients will not have enough energy to perform their daily functions. Obtaining a good history requires carefully questioning the patient, particularly with regard to diet, drug ingestion, exposure to chemicals, occupation, hobbies, travel, bleeding history, ethnic group, family history of disease, neurologic symptoms, previous medication, jaundice, and various underlying diseases that produce anemia.4,7–9 Although inquiry in these areas can reveal common conditions that can lead to anemia, there are numerous other possibilities as well. Therefore, a thorough discussion is required to elicit any potential cause of the anemia. For example, iron deficiency can lead to an interesting symptom called pica.¹⁰ Patients with pica have cravings for unusual substances such as ice (pagophagia), cornstarch, or clay. Alternatively, individuals with anemia may be asymptomatic, as can be seen in mild or slowly progressive anemias.

Certain features should be evaluated closely during the physical examination to provide clues to hematologic disorders, such as skin (for pallor, jaundice, petechiae), eyes (for hemorrhage), and mouth (for mucosal bleeding). The examination should also look for sternal tenderness, lymphadenopathy, cardiac murmurs, splenomegaly, and hepatomegaly.4,7–9 Jaundice is important for the assessment of anemia, because it may be due to increased RBC destruction, which suggests a hemolytic component to the anemia. Measuring vital signs is also a crucial component of the physical evaluation. Patients experiencing a rapid fall in hemoglobin concentration typically have tachycardia (fast heart rate), whereas if the anemia is long-standing, the heart rate may be normal due to the body’s ability to compensate for the anemia.

Moderate anemias (hemoglobin concentration of 7 to 10 g/dL) may not produce clinical signs or symptoms if the onset of anemia is slow.⁴ Depending on the patient’s age and cardiovascular state, however, moderate anemias may be associated with pallor of conjunctivae and nail beds, dyspnea, vertigo, headache, muscle weakness, lethargy, and other symptoms.^4,7–9 Severe anemias (hemoglobin concentration of less than 7 g/dL) usually produce tachycardia, hypotension, and other symptoms of volume loss, in addition to the symptoms listed earlier. The severity of the anemia is gauged by the degree of reduction in RBC mass, cardiopulmonary adaptation, and the rapidity of progression of the anemia.⁴

Physiologic Adaptations

Reduced delivery of oxygen to tissues caused by reduced hemoglobin causes an increase in erythropoietin secretion by the kidneys. Erythropoietin stimulates the RBC precursors in the bone marrow, which leads to the release of more RBCs into the circulation (see Chapter 8). With persistent anemia, the body implements physiologic adaptations to increase the oxygen-carrying capacity of a reduced amount of hemoglobin. Heart rate, respiratory rate, and cardiac output are increased for a more rapid delivery of oxygenated blood to tissues. In addition, the tissue hypoxia triggers an increase in RBC 2,3-bisphosphoglycerate that shifts the oxygen dissociation curve to the right (decreased oxygen affinity of hemoglobin) and results in increased delivery of oxygen to tissues (see Chapter 10).¹¹ This is a significant mechanism in chronic anemias that enables patients with low levels of hemoglobin to remain relatively asymptomatic. With persistent and severe anemia, however, the strain on the heart can ultimately lead to cardiac failure.

Mechanisms of Anemia

The life span of the RBC in the circulation is about 120 days. In a healthy individual with no anemia, each day approximately 1% of the RBCs are removed from circulation due to senescence, but the bone marrow continuously produces RBCs to replace those lost. Hematopoietic stem cells develop into erythroid precursor cells, and the bone marrow appropriately releases reticulocytes that mature into RBCs in the peripheral circulation. Adequate RBC production requires several nutritional factors, such as iron, vitamin B₁₂, and folate. Globin synthesis also must function normally. In conditions with excessive bleeding or hemolysis, the bone marrow must increase RBC production to compensate for the increased RBC loss. Therefore, the maintenance of a stable hemoglobin concentration requires the production of functionally normal RBCs in sufficient numbers to replace the amount lost.4,7,8

Ineffective and Insufficient Erythropoiesis

Erythropoiesis is the term used for marrow erythroid proliferative activity. Normal erythropoiesis occurs in the bone marrow (see Chapter 8).⁴ When erythropoiesis is effective, the bone marrow is able to produce functional RBCs that leave the marrow and supply the peripheral circulation with adequate numbers of cells.

Ineffective erythropoiesis refers to the production of erythroid progenitor cells that are defective. These defective progenitors are often destroyed in the bone marrow before their maturation and release into the peripheral circulation. Several conditions, such as megaloblastic anemia, thalassemia, and sideroblastic anemia, are characterized by ineffective erythropoiesis. In these anemias, the peripheral blood hemoglobin is low despite an increase in RBC precursors in the bone marrow. The effective production rate is considerably less than the total production rate, which results in a decreased number of normal circulating RBCs. Consequently, the patient becomes anemic.¹²

Insufficient erythropoiesis refers to a decrease in the number of erythroid precursors in the bone marrow, resulting in decreased RBC production and anemia. Several factors can lead to the decreased RBC production, including a deficiency of iron (inadequate intake, malabsorption, excessive loss from chronic bleeding); a deficiency of erythropoietin, the hormone that stimulates erythroid precursor proliferation and maturation (renal disease); loss of the erythroid precursors due to an autoimmune reaction (aplastic anemia, acquired pure red cell aplasia) or infection (parvovirus B19); or suppression of the erythroid precursors due to infiltration of the bone marrow with granulomas (sarcoidosis) or malignant cells (acute leukemia).¹²

Acute Blood Loss and Hemolysis

Anemia can also develop as a result of acute blood loss (such as traumatic injury) or premature hemolysis resulting in a shortened RBC life span. (Note that chronic blood loss leads to iron deficiency and is covered under insufficient erythropoiesis in the previous section.) With acute blood loss and excessive hemolysis, the bone marrow is able to increase production of RBCs, but the level of response is inadequate to compensate for the excessive RBC loss. Numerous causes of hemolysis exist, including intrinsic defects in the RBC membrane, enzyme systems, or hemoglobin, or extrinsic causes such as antibody-mediated processes, mechanical fragmentation, or infection-related destruction.4,8,12

Laboratory Diagnosis of Anemia

Complete Blood Cell Count with Red Blood Cell Indices

To detect the presence of anemia, the medical laboratory professional performs a complete blood count (CBC) using an automated hematology analyzer to determine the RBC count, hemoglobin concentration, hematocrit, RBC indices, white blood cell (WBC) count, and platelet count. The RBC indices include the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) (see Chapter 14).¹³ The most important of these indices is the MCV, a measure of the average RBC volume in femtoliters (fL). Reference ranges for these determinations are listed on the inside front cover of the text. Automated hematology analyzers also provide an RBC histogram and the red blood cell distribution width (RDW). A relative and absolute reticulocyte count, described subsequently, should be performed for every patient when anemia is found. Automated analyzers are available to perform reticulocyte counts with greater accuracy and precision than manual counting methods.

The RBC histogram is an RBC volume frequency distribution curve with the relative number of cells plotted on the ordinate and RBC volume in femtoliters on the abscissa. With a normal population of RBCs, the distribution is approximately gaussian. Abnormalities include a shift in the curve to the left (microcytosis) or to the right (macrocytosis), and a widening of the curve caused by a greater variation of RBC volume about the mean or by the presence of two populations of RBCs with different volumes (anisocytosis). The histogram complements the peripheral blood film examination in identifying variant RBC populations.¹² (A discussion of histograms with examples can be found in Chapter 39.)

The RDW is the coefficient of variation of RBC volume expressed as a percentage.¹³ It indicates the variation in RBC volume within the population measured and correlates with anisocytosis on the peripheral blood film. Automated analyzers calculate the RDW by dividing the standard deviation of the RBC volume by the MCV and then multiplying by 100 to convert to a percentage. The usefulness of the RDW is discussed later.

Reticulocyte Count

The reticulocyte count serves as an important tool to assess the bone marrow’s ability to increase RBC production in response to an anemia. Reticulocytes are young RBCs that lack a nucleus but still contain residual ribonucleic acid (RNA). Normally, they circulate peripherally for only 1 day while completing their development. The adult reference range for the reticulocyte count is 0.5% to 1.5% expressed as a percentage of the total number of RBCs.¹³ The newborn reference range is 1.5% to 5.8%, but these values change to approximately those of an adult within a few weeks after birth.^7–9 An absolute reticulocyte count is determined by multiplying the percent reticulocytes by the RBC count. The reference range for the absolute reticulocyte count is 25 to 75 × 10⁹/L, based on a normal adult RBC count.⁴ A patient with a severe anemia may seem to be producing increased numbers of reticulocytes if only the percentage is considered. For example, an adult patient with 1.5 × 10¹²/L RBCs and 3% reticulocytes has an absolute reticulocyte count of 45 × 10⁹/L. The percentage of reticulocytes is above the reference range, but the absolute reticulocyte count is within the reference range. For the degree of anemia, however, both of these results are inappropriately low. In other words, production of reticulocytes within the reference range is inadequate to compensate for an RBC count that is approximately one third of normal.

The reticulocyte count may be corrected for anemia by multiplying the reticulocyte percentage by the patient’s hematocrit and dividing the result by 45 (the average normal hematocrit). If the reticulocytes are released prematurely from the bone marrow and remain in the circulation 2 to 3 days (instead of 1 day), the corrected reticulocyte count must be divided by maturation time to determine the reticulocyte production index (RPI). The RPI is a better indication of the rate of RBC production than is the corrected reticulocyte count (Table 18-1).⁴

TABLE 18-1

Formulas for Reticulocyte Counts and Red Blood Cell Indices

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