Thrombosis and Anemia

Alvin H. Schmaier, MD

Case Western Reserve University, Cleveland, OH

Copyright of the American Society of Hematology, 2012. ISSN: 1931-6860.

IV. DIFFERENTIAL DIAGNOSIS

A. The differenial diagnosis of macrocytic anemias

The CBC in the previous section indicated that this patient has a macrocytic anemia. By size of the red blood cells alone, iron deficiency, thalassemias, and sideroblastic anemias are excluded. The reticulocyte count was only 1.1%, which indicated that the anemia was not due to heightened peripheral destruction, as one sees in hemolytic anemias. As shown in the table above, hemolytic anemias can be associated with macrocytosis, but only in those cases where the reticulocyte count is elevated. Thus, the present patient has a hypoproliferative macrocytic anemia.

By history and screening laboratory tests alone, this patient does not have liver disease, hypothyroidism, COPD, or has had her spleen previously removed. Hence, she must have a primary hematologic disorder to account for her anemia. Thus, examination of the peripheral blood smear is the first assay to perform.


The peripheral smear is as follows:
   
Macrocyte   Hypersegmented PMN
    (ASH Image Bank 00004051)

The peripheral smear on the left shows a photograph of a red blood cell without an area of central pallor. The diagnosis of a macrocyte (black arrow) can be made by the size of the red blood cell in relation to the nucleus of the small lymphocyte shown. Oval macrocytes (> 14 microns) are large cells that are produced by several causes.

B. Interpretation of the peripheral blood smear

In hemolytic anemias, red blood cell survival is shortened and younger cells populate the circulation. These cells are usually larger than older cells. These patients have an elevated reticulocyte count, polychromasia (a bluish hue of red blood cells seen in young reticulocytes on Wright-Giemsa stain), and if severe enough, nucleated red blood cells. In liver disease, red blood cells become stuffed with cholesterol and are larger. Likewise, in hypothyroidism, there are cholesterol-stuffed red blood cells and they are larger. In the latter instances, the clinical history for liver disease or hypothyroidism is obvious. The above peripheral smear on the right excludes macrocytosis due to hemolysis. In support of that, no polychromasia is described on the peripheral smear (consistent with the low reticulocyte count). Further, the absence of target cells and markedly misshapen red blood cells (some people call them “puzzlecytes”) makes the diagnosis of liver disease or hypothyroidism less likely.

C. Determination of megaloblastic changes in this anemia

Megaloblastic changes in red blood cells are seen in cases where there is specific deficiency in vitamin B12 or folic acid, two vitamins that are essential for normal DNA synthesis. Defects in DNA synthesis in the nucleus of red blood cell precursors are associated with larger red blood cells. This kind of change in red cell production is called megaloblastosis. In these vitamin deficiencies, the defects are seen in all cells where there is rapid turnover of cell production, such as red blood cells, white blood cells and epithelial cells in the GI tract.

The peripheral smear on the right above is a hypersegmented polymorphonuclear leukocyte (PMN). PMNs normally have 3 to 4 lobes. Three five-lobe PMNs or one six-lobe PMN is sufficient to make the diagnosis of megaloblastosis. Hypersegmentation of PMNs is a sign of megaloblastosis. The most likely cause of hypersegmented PMNs is B12 or folate deficiency.

Renal failure with uremia is also associated with hypersegmented PMNs, but no macrocytosis. The low reticulocyte count and macrocytosis with hypersegmented PMNs indicates that this anemia is most likely due to folic acid or B12 deficiency. These observations are consistent with a diagnosis of megaloblastic macrocytic anemia.

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