Although anemia may be defined as a decrease in Hb concentration, it may result from a pathologic decrease in the RBC count. Since mature RBCs are fully saturated with Hb, such a decrease means that total blood Hb value will also be affected.

Before commencing transfusion therapy or an extensive workup for the etiology of anemia, one should consider the possibility of pseudoanemia Pseudoanemia may be associated with either a Hb value below reference range limits or a drop in Hb level of 2 gm/100 ml (20 g/L) or more from a previous value. Accuracy of the values, especially those below the reference range, should be verified by redrawing the specimen. It is also possible that a patient could have true anemia simultaneously with one of the conditions in the box on this page.

One frequently overlooked cause of Hb decrease is iatrogenic blood loss due to laboratory test specimens. Several studies document that a surprising amount of blood can be withdrawn, especially in critically ill patients or those with diagnostic problems. Whereas the majority of patients contributed an average of 10-20 ml of blood per day, those in critical care units may average 40-50 ml/day and sometimes even as much as 150-500 ml per patient per day for several days’ time. In some cases this may total more than 1,000 ml during the hospital stay. (The data sometimes include blood withdrawn to clear arterial lines and sometimes not; this blood also may represent a considerable total quantity.)

Some Conditions That Produce or Contribute to False Anemia
Overhydration or rehydration of a dehydrated patient
Specimen obtained with intravenous (IV) fluid running
Fluid retention
Posture changes (from upright to recumbent)
Laboratory variation in hemoglobin assay (approximately ± 0.5 gm/dl) or laboratory error

Classification of Anemia

Classification of anemia is helpful because it provides a handy reference for differential diagnosis. There are several possible classifications; each is helpful in some respects.

Anemia may be classified by pathogenesis. According to pathogenesis, three mechanisms may be responsible.

Deficiency of vital hematopoietic raw material (factor deficiency anemia). The most common causes of factor deficiency anemia are iron deficiency and deficiency of vitamin B12, folic acid, or both.
Failure of the blood-forming organs to produce or to deliver mature RBCs to the peripheral blood (production-defect anemia). This may be due to (1) replacement of marrow by fibrosis or by neoplasm (primary or metastatic); (2) hypoplasia of the bone marrow, most commonly produced by certain chemicals; or (3) toxic suppression of marrow production or delivery without actual marrow hypoplasia, found to a variable extent in some patients with certain systemic diseases. The most common of these diseases are severe infection, chronic renal disease, widespread malignancy (without extensive marrow replacement), rheumatoid-collagen diseases, and hypothyroidism. (These conditions may sometimes be associated with an element of hemolytic anemia.)
RBC loss from the peripheral blood (depletion anemia). This is commonly due to (1) hemorrhage, acute or chronic (causing escape of RBCs from the vascular system), (2) hemolytic anemia (RBCs destroyed or RBC survival time shortened within the vascular system), or (3) hypersplenism (splenic sequestration).

A second classification is based on RBC morphology. Depending on the appearance of the RBC on a peripheral blood smear, Wintrobe indices, or both, anemias may be characterized as microcytic, normocytic, or macrocytic. They may be further subdivided according to the average amount of RBC hemoglobin, resulting in hypochromia or normochromia. (Macrocytic RBCs may appear hyperchromic on peripheral smear, but this is an artifact due to enlarged and thicker cells that, being thicker, do not transmit light through the central portion as they would normally.) The box on this page lists the more common etiologies.

Investigation of a Patient With Anemia

Anemia is a symptom of some underlying disease and is not a diagnosis. There always is a cause, and most of the causes can be discovered by a relatively few simple procedures. Knowing the common causes of anemia, getting a good history, doing a thorough physical examination, and ordering a logical sequence of laboratory tests based on what the clinical picture and other findings suggest provide the greatest assistance in identifying which underlying disease is responsible. When anemia is discovered (usually by the appearance of a low Hb or Hct value), the first step is to determine whether anemia really exists. The abnormal result should be confirmed by drawing a second specimen. Then, if the patient is not receiving excess intravenous (IV) fluid that might produce hemodilution, the next step is to obtain a WBC count, differential, RBC indices, reticulocyte count, and a description of RBC morphology from the peripheral smear. It is wise for the physician to personally examine the peripheral smear, because many technicians do not routinely pay much attention to the RBCs. A careful history and physical examination must be performed. To some extent, the findings on peripheral smear and RBC indices (including the RDW, if available) help suggest areas to emphasize:

If the RBCs are microcytic, the possibility of chronic blood loss must always be carefully excluded.
If the RBCs are macrocytic, the possibility of megaloblastic anemia or reticulocytosis due to acute bleeding must always be investigated.
If the RBCs are not microcytic, if megaloblastic anemia is ruled out in patients with macrocytosis, and if the reticulocyte count is significantly elevated, two main possibilities should be considered: acute blood loss and hemolytic anemia. The reticulocyte count is usually 5% or higher in these cases. However, the possibility of a deficiency anemia responding to therapy should not be forgotten.
In a basically normocytic-normochromic anemia without significant reticulocytosis and in which either leukopenia or thrombocytopenia (or both) is present, hypersplenism, bone marrow depression, or a few systemic diseases (e.g., systemic lupus erythematosis) are the main possibilities. In patients over age 40 with normocytic-normochromic anemia and without WBC or platelet decrease, myeloma should be considered, especially if rouleaux or other abnormalities are present that are commonly associated with myeloma. The possibility of chronic iron deficiency should not be forgotten, even though the typical RBC morphology of iron deficiency is microcytic-hypochromic. Occasionally, patients with B12 or folate deficiency have an MCV in the upper normal range.
Appearance of certain RBC abnormalities in the peripheral blood suggests certain diseases. A considerable number of target cells suggests one of the hemoglobinopathies or chronic liver disease. Marked basophilic stippling points toward lead poisoning or reticulocytosis. Sickle cells mean sickle cell anemia. Nucleated RBCs indicate either bone marrow replacement or unusually marked bone marrow erythropoiesis, most commonly seen in hemolytic anemias. Significant rouleaux formation suggests monoclonal gammopathy or hyperglobulinemia. Spherocytes usually indicate an antigen-antibody type of hemolytic anemia but may mean congenital spherocytosis or a few other types of hemolytic anemia. Schistocytes (burr cells) in substantial numbers are usually associated with microangiopathic hemolytic anemias or with uremia, alcoholism, and hypothyroidism. Macrocytes are frequently produced by reticulocytosis but are also associated with megaloblastic anemias, cirrhosis, chronic alcoholism, hypothyroidism, and aplastic anemia.

Some Common Causes of Anemia According to RBC Morphology*

Chronic iron deficiency (most frequent cause)
Occasionally in chronic systemic diseases
Some cases of chronic systemic diseases
(May be simulated by spherocytosis or polycythemia in some patients)


Some cases of anemia due to systemic diseases
Many cases of lead poisoning


Many cases of anemia due to systemic disease (most common cause)
Many cases of anemia associated with pituitary, thyroid, or adrenal disease
Acute blood loss
Hemolytic anemia
Bone marrow replacement or hypoplasia
Distance-runner anemia (most persons)


Some cases of macrocytic anemia with superimposed iron deficiency


Vitamin B12 or folic acid deficiency
Malabsorption (vitamin B12 or folic acid)
Chronic alcoholism
Some cases of chronic liver disease and some cases of hypothyroidism
Myelodysplasia syndromes/aplastic anemia

*All patients with any disease do not fit into any one category.

Once the basic underlying process is identified, the cause can usually be identified by using selected laboratory tests with the help of history, physical findings, and other diagnostic procedures. In general it is best to perform diagnostic laboratory studies before giving blood transfusions, although in many cases the diagnosis can be made despite transfusion. Blood specimens for the appropriate tests can usually be obtained before transfusion is actually begun, since blood for type and crossmatching must be drawn first. Serum can be saved or frozen for additional studies, if needed.