Introduction

"Anemia" is not truly a diagnosis but rather a general term that encompasses many different disorders affecting red blood cells in which there is some type of impairment of oxgen transport. An anemia is first evaluated using the complete blood count (CBC), one of the most commonly ordered blood tests.

Because of the bewildering array of specific types of anemia, the physician must use a logical approach to the interpretation of the CBC so that the list of differential diagnoses is narrowed down to a reasonable number and appropriate confirmatory tests can be ordered. Many types of anemias share the same general symptoms, such as fatigue or lethargy, so the CBC can help point the physician in the right direction.

 

Important definitions for this topic

 

 

 

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[venipuncture photos courtesy of Jim Gathany of the Centers for Disease Control and Public Health. Released for public domain through the CDC Public Health Image Library]

Morphologic
"Morphologic" is derived from the Greek roots morphe, meaning form, and logis, meaning reason. Thus, morphologic relates to the shape or form of something. For this topic, morphologic pertains to evaluating anemias by looking at parameters on the CBC (see below) that assess the size of red blood cells.
CBC - Complete Blood Count
The CBC is panel of measurements done on whole blood, typically including the following components: number of red blood cells, number of total white blood cells, number or percentage of each type of white blood cell, number of platelets, amount of hemoglobin, the hematocrit (percentage of whole blood composed of red blood cells), and the measurement or calculation of the average red blood cell volume (MCV), the average red blood cell amount of hemoglobin (MCH), and the average red blood cell concentration of hemoglobin (MCHC). Depending on the laboratory, there may also be a measurement of the variability in the size of the red blood cells (RDW) and a description of the appearance of the cells under a microscope.
RBC - Red blood cell count
The RBC component of the CBC is the measurement of the number of red blood cells per unit of blood. This is typically expressed as the number of cells (millions) per microliter; for example, 5.95 million/mcL.
MCV - Mean cell volume
The MCV is the measurement of the average (mean) volume of the individual red blood cells. This very small number is typically expressed in femtoliters (10-15 liters); for example, 88 fL.
Microcytic anemia
"Microcytic" is derived from the Greek roots mikros, meaning small, and kytos, meaning cell. Thus, microcytic literally means small cell. In a microcytic anemia, the red blood cells are smaller than normal. This is demonstrated by having a MCV which is below the normal reference range. The microscopic examination may show many or all of the red blood cells to be decreased in size.
Normocytic anemia
"Normocytic" is derived from the Latin root norma, meaning rule or normal, and the Greek root kytos, meaning cell. Thus, normocytic literally means normal cell. In a normocytic anemia, the red blood cells are normal in size. This is demonstrated by having a MCV which falls into the normal reference range.
Macrocytic anemia
"Macrocytic" is derived from the Greek roots makros, meaning larger, and kytos, meaning cell. Thus, macrocytic literally means large cell. In a macrocytic anemia, the red blood cells are larger than normal. This is demonstrated by having a MCV which is above the normal reference range. The microscopic examination may show many or all of the red blood cells to be increased in size.
Anisocytosis and the RDW
"Anisocytosis" is derived from the Greek roots anisos, meaning unequal, kytos, meaning cell, and osis meaning condition. Thus, anisocytosis literally means a condition in which the cells are unequal. In an anemia with anisocytosis, the red blood cells are vary in their sizes or shapes. This is demonstrated quantitatively by having a "red cell distribution width" (RDW) which is above the normal reference range. Unfortunately, not all labs include the RDW measurement on their CBC and instead the microscopic examination is used to detect the variation in the red blood cells.

Preliminary Analysis of Anemias Using a Morphologic Approach

The morphologic approach to the differential diagnosis of anemias is a simple method to begin the process of narrowing down the list of possible causes of an anemia. Not all anemias will result in a decrease in the number of red blood cells, so it is important to look at more than the rbc count on the cbc report. In many early anemias, the RDW or the MCV will become abnormal before other parameters. Of these two parameters, the MCV is reported by more labs than is the RDW, so we will rely most heavily upon the MCV in our initial assessment. Here are the simple steps for the morphologic approach:

  1. Look at the MCV and determine if the reported value is:
    1. Low - microcytic
    2. Normal - normocytic
    3. High - macrocytic
  2. Look at the RBC count and determine if the reported value is:
    1. Low - probable anemia
    2. Normal - doesn't rule out anemia unless the MCV is also normal
    3. High - can be seen in some anemias (e.g., thalassemia minor); can also be seen in other non-anemic disorders.
  3. Classify the anemia using the chart below:

Anemia classification chart

The 3 Patterns

As you can see, the use of the MCV allows for rapid classification of anemias into one of three types: microcytic, normocytic and macrocytic. The section below summarizes those types and provides some additional information on the types of laboratory tests that might be next used in the evaluation of anemias in each of those categories.

It is also a good idea to routinely obtain a reticulocyte count in any patient who has an anemia. The reticulocyte count is a measure of the number of newly produced red blood cells circulating in the bloodstream. A patient who has an anemia accompanied by a low reticulocyte count most likely has a problem with red cell production, as is seen in nutrient deficiencies, bone marrow suppression or bone marrow replacement. An anemia accompanied by a high reticulocyte count is most likely to be due to either acute blood loss or some type of hemolytic disorder.

Microcytic anemias

picture of thalassemia

This is a CBC microscopic blood smear from a patient with thalassemia minor. The red blood cells are smaller than normal. Notice that some of the red blood cells have dark central stains; these cells are referred to as target cells.[Image courtesy of Christine Lawrence, M.D. in the Albert Einstein College of Medicine Gallery of Hematology Images at the HEAL digital library - permission granted under terms of Creative Commons]

 

The most common types of microcytic anemias include iron-deficiency anemia, the thalassemias, anemia accompanying lead poisoning, some cases of anemia secondary to chronic inflammation or disease, and sideroblastic anemia.

In addition to the reticulocyte count (which is typically elevated in thalassemia and low in the others), useful tests include:

  • iron status tests (serum iron, iron-binding capacity, transferrin, ferritin)
  • stool occult blood studies (if iron-deficiency is suspected, this is useful to determine if the patient is losing iron by chronic bleeding into the GI tract)
  • HbA2 and HbF measurements if thalassemia is suspected
  • If lead poisoning is suspected, then serum lead and free erythrocyte protoporphyrin levels may be useful.

Normocytic anemias

Picture of sickle cell anemia

This is a CBC microscopic blood smear from a patient with homozygous sickle cell anemia. Many of the red blood cells show the classic distorted sickle shape. Note that the term "normocytic" has to do with the average volume, not the shape of red cells; in most patients the number of normal cells far exceeds the number of sickled cells, so the average size is normal.[Image courtesy of Christine Lawrence, M.D. in the Albert Einstein College of Medicine Gallery of Hematology Images at the HEAL digital library - permission granted under terms of Creative Commons]

 

The most common types of normocytic anemias include iron-deficiency anemia, the thalassemias, anemia accompanying lead poisoning, some cases of anemia secondary to chronic inflammation or disease, and sideroblastic anemia.

In addition to the reticulocyte count (which is typically elevated in hemolytic anemias, hypersplenism, and low in the others), useful tests include:

  • Coombs antibody tests
  • Hemoglobin electrophoresis
  • Renal function tests
  • Inflammation markers
  • Protein electrophoresis and immunophoresis
  • Platelet studies

Macrocytic anemias

Picture of pernicious anemia

This is a CBC microscopic blood smear from a patient with pernicious anemia, an immune disorder in which the body loses the ability to absorb vitamin B12. The red blood cells are larger than normal. Also seen is a neutrophil (the most common type of white blood cell) with an abnormal number of nuclear lobes. This is common in B12 and folic acid deficiencies because of impaired nuclear synthesis in cells.[Image courtesy of Christine Lawrence, M.D. in the Albert Einstein College of Medicine Gallery of Hematology Images at the HEAL digital library - permission granted under terms of Creative Commons]

 

The most common types of macrocytic anemias include vitamin B12 deficiency (including pernicious anemia), folic acid deficiency (include folate interference from oral contraceptives and other drugs), hypothyroidism, chronic liver diseases, and severe hemolytic anemias.

In addition to the reticulocyte count (which is typically elevated in hemolysis and low in the others), useful tests include:

  • B12 and folate status measurements
  • Thyroid panel
  • Liver panel