Anemia

Chapter 9 Anemia

1 Anemia refers to reduced red blood cell (RBC) mass.

2 The mean corpuscular volume represents the average RBC size and is used to classify the type of anemia as microcytic, normocytic, or macrocytic.

3 Microcytic anemia results from processes that impair hemoglobin synthesis in the RBC, such as iron deficiency, lead poisoning, sideroblastic anemia, and thalassemia.

4 Some causes of normocytic anemia include chronic renal failure, anemia of chronic disease, hypogonadism, aplastic anemia, myelodysplastic syndrome, and bone marrow infiltration.

5 Causes of macrocytic anemia include DNA synthesis defects (folate deficiency, vitamin B₁₂ deficiency, myelodysplastic syndrome, nucleotide analogs) hypothyroidism, liver disease, and alcoholism.

6 The reticulocyte count differentiates a hypoproliferative anemia (such as iron, folate, or B₁₂ deficiency) from a hyperproliferative anemia (such as hemolysis or acute blood loss).

7 Patients with anemia may be asymptomatic (especially if the anemia is mild or develops slowly) or may have symptoms of fatigue, lightheadedness, exercise intolerance, dyspnea, or worsening angina.

8 Initial testing should include a complete blood count with differential, reticulocyte count, and stool guaiac. Other useful tests include (a) lactate dehydrogenase, haptoglobin, and total and direct bilirubin if hemolysis is suspected, (b) ferritin, serum iron, and total iron binding capacity (TIBC) if the anemia is microcytic, and (c) vitamin B₁₂ and folate if the anemia is macrocytic.

9 When iron deficiency anemia is diagnosed, a search for the cause of the deficiency is mandatory.

10 Anemia of chronic disease can usually be distinguished from iron deficiency on the basis of the ferritin, serum iron concentrations, and TIBC.

11 Neurological disease (which can occur in the absence of anemia) is a potential complication of vitamin B₁₂ deficiency but not of folate deficiency.

12 Definitive diagnosis of vitamin B₁₂ deficiency in patients with low vitamin B₁₂ levels that are above the lower limit of the normal range requires measurement of methylmalonic acid and homocysteine.

13 Nonfasting serum folate concentrations < 2 ng/mL are diagnostic of folate deficiency whereas levels > 4 ng/mL essentially rule out folate deficiency.

14 Hemolytic anemia develops when the bone marrow cannot compensate for a shortened RBC lifespan. Findings supporting a diagnosis of hemolysis include reticulocytosis, splenomegaly, fragmented RBCs on the peripheral smear (“helmet cells,” or schistocytes), increased serum lactate dehydrogenase, unconjugated hyperbilirubinemia (unconjugated bilirubin comprising 80% of the total bilirubin), and reduced haptoglobin concentrations.

Definitions

Anemia: Reduced red blood cell (RBC) mass.

Hemoglobin concentration (Hgb): Grams of hemoglobin per 100 mL of whole blood (g/dL).

Red blood cell (RBC) count: Number of RBCs (in millions) per microliter of whole blood.

Mean corpuscular volume (MCV): Average RBC size. The MCV is commonly used to classify anemia as “microcytic” (RBCs smaller than normal), “normocytic” (normal-sized RBCs), or “macrocytic” (RBCs larger than normal), which provides a framework for determining the cause of the anemia (Box 9-1). Since the MCV is an average measure of RBC size, the MCV may be normal if microcytic and macrocytic cells are simultaneously present (for example, concurrent iron and vitamin B₁₂ deficiency). As a general rule of thumb, normal RBCs are approximately the size of a lymphocyte nucleus on the peripheral blood smear.

Box 9-1 Common Causes of Anemia

Adapted from Hematology/Oncology. In: Ferri FF, editor. Practical Guide to the Care of the Medical Patient, 6th ed. St. Louis: Mosby; 2004.

Microcytic

Iron deficiency

Anemia of chronic disease (typically normocytic)

Sideroblastic anemia

Normocytic

Subacute blood loss

Anemia of chronic disease

Bone marrow abnormality

Sickle cell disease

Renal insufficiency

Hematocrit: Percent of whole blood volume occupied by RBCs. The hematocrit is calculated using the RBC count and MCV as follows:

The normal value for the hematocrit depends on age, gender, and possibly race. The World Health Organization defines anemia as hematocrit < 39% in adult men and < 36% in adult women. Hemoglobin concentration, hematocrit, and RBC count are calculated using RBC mass and blood volume. Therefore, low blood volumes in patients with dehydration or acute blood loss may mask anemia that will become evident following volume repletion.

Mean corpuscular hemoglobin (MCH): Amount of hemoglobin (in picograms) per RBC and is calculated by:

Mean corpuscular hemoglobin concentration (MCHC): Hemoglobin concentration (gm/dL) per RBC (i.e., the amount of hemoglobin per RBC relative to the RBC size) and is calculated by:

Red cell distribution width (RDW): A measure of the variation in RBC size (expressed as a percentage). The greater the variation, the greater the RDW. The RDW provides useful information when used together with the MCV. For example, a patient with concurrent microcytic and macrocytic anemia may have a normal MCV but the RDW should be elevated (because there is variability in cell size).

Reticulocyte count: The reticulocyte is the precursor of the mature RBC and is formed when the nucleus is extruded from a normoblast. The reticulocyte retains its ribosomal machinery for approximately 4 days, of which 3 days are usually spent in the bone marrow. Reticulocytes spend 1 day in the peripheral blood, representing approximately 1% of total circulating RBCs. On a standard blood smear with Wright Giemsa stain, reticulocytes are the bluish cells without central pallor that are larger than mature RBCs.

The reticulocyte count facilitates the workup of anemia by differentiating a hypoproliferative (for example, iron, folate, or vitamin B₁₂ deficiency) from a hyperproliferative anemia (for example, hemolysis). The reticulocyte count should be corrected for the degree of anemia and the change in reticulocyte maturation time. This adjusted measure is known as the reticulocyte production index (RPI) and is calculated as follows:

Hematocrit (%)	Maturation Factor
45	1.0
35	1.5
25	2.0

In response to anemia, reticulocytes move from the bone marrow to the peripheral blood sooner. Therefore, reticulocytes can spend upwards of 2 days in the circulation. However, the increased numbers of circulating reticulocytes in this setting does not represent increased RBC production rates. Therefore, we recommend using the maturation factor so that the longer reticulocyte circulating times do not overestimate the reticulocyte response.

A low RPI (< 2) suggests a hypoproliferative anemia (i.e., impaired RBC production in response to the anemia). Typical causes of a low RPI include iron, folate, or vitamin B₁₂ deficiency, or bone marrow injury, failure, or infiltration (Box 9-2). A high RPI (> 3) suggests a hyperproliferative anemia (i.e., increased RBC production in response to anemia), as occurs with hemolysis, acute blood loss, and recovery of the bone marrow from infection or nutrient deficiency.

Box 9-2 The Reticulocyte Production Index (RPI)

RPI > 3 (Hyperproliferative Anemia)

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