# 61 - 65 Interpreting Peripheral Blood Smears

### 65 Interpreting Peripheral Blood Smears

Section 9	 Hematologic Alterations
Dan L. Longo

Interpreting Peripheral 

Blood Smears
Some of the relevant findings in peripheral blood, enlarged lymph 
nodes, and bone marrow are illustrated in this chapter. Systematic his­
tologic examination of the bone marrow and lymph nodes is beyond 
the scope of a general medicine textbook. However, every internist 
should know how to examine a peripheral blood smear.
The examination of a peripheral blood smear is one of the most 
informative exercises a physician can perform. Although advances 
in automated technology have made the examination of a peripheral 
blood smear by a physician seem less important, the technology is not 
a completely satisfactory replacement for a blood smear interpretation 
by a trained medical professional who also knows the patient’s clinical 
history, family history, social history, and physical findings. It is useful 
to ask the laboratory to generate a Wright’s-stained peripheral blood 
smear and examine it. A normal peripheral blood smear is shown in 
Figure 65-1.
The best place to examine blood cell morphology is the feath­
ered edge of the blood smear where red cells lie in a single layer, 
side by side, just barely touching one another but not overlapping. 
The author’s approach is to look at the smallest cellular elements, 
the platelets, first and work his way up in size to red cells and then 
white cells.
Using an oil immersion lens that magnifies the cells 100-fold, 
one counts the platelets in five to six fields, averages the number per 
field, and multiplies by 20,000 to get a rough estimate of the platelet 
count. The platelets are usually 1–2 μm in diameter and have a blue 
granulated appearance. There is usually 1 platelet for every 20 or so 
red cells. Of course, the automated counter is much more accurate, but 
gross disparities between the automated and manual counts should 
be assessed. Large platelets may be a sign of rapid platelet turnover, as 
young platelets are often larger than old ones; alternatively, certain rare 
inherited syndromes can produce large platelets. If the platelet count 
is low, the absence of large (young) platelets may be an indicator of 
marrow production problems. Platelet clumping visible on the smear 
can be associated with falsely low automated platelet counts. Clumping 
may be caused by the anticoagulant into which the blood is drawn. 
Similarly, neutrophil fragmentation can be a source of falsely elevated 
automated platelet counts. The absence of platelet granules may be an 
artifact of the handling of the blood or may indicate marrow disease 
or a rare congenital anomaly, gray platelet syndrome. Elevated platelet 
counts usually signify a myeloproliferative disorder or a reaction to 
systemic inflammation.
Next one examines the red blood cells. One can gauge their size by 
comparing the red cell to the nucleus of a small lymphocyte. Both are 
normally about 8-μm wide. Red cells that are smaller than the small 
lymphocyte nucleus may be microcytic; those larger than the small 
lymphocyte nucleus may be macrocytic. Macrocytic cells also tend to 
be more oval than spherical in shape and are sometimes called mac­
roovalocytes. The automated mean corpuscular volume (MCV) can 
assist in making a classification. However, some patients may have 
both iron and vitamin B12 deficiency, which will produce an MCV 
in the normal range but wide variation in red cell size. When the red 
cells vary greatly in size, anisocytosis is said to be present. When the 
red cells vary greatly in shape, poikilocytosis is said to be present. The 
electronic cell counter provides an independent assessment of vari­
ability in red cell size. It measures the range of red cell volumes and 
reports the results as “red cell distribution width” (RDW). This value 
is calculated from the MCV; thus, cell width is not being measured 

but cell volume is. The term is derived from the curve displaying the 
frequency of cells at each volume, also called the distribution. The 
width of red cell volume distribution curve is what determines the 
RDW. The RDW is calculated as follows: RDW = (standard deviation 
of MCV ÷ mean MCV) × 100. In the presence of morphologic aniso­
cytosis, RDW (normally 11–14%) increases to 15–18%. The RDW 
is useful in at least two clinical settings. In patients with microcytic 
anemia, the differential diagnosis is generally between iron deficiency 
and thalassemia. In thalassemia, the small red cells are generally of 
uniform size with a normal small RDW. In iron deficiency, the size 
variability and the RDW are large. In addition, a large RDW can sug­
gest a dimorphic anemia when a chronic atrophic gastritis can pro­
duce both vitamin B12 malabsorption to produce macrocytic anemia 
and blood loss to produce iron deficiency. In such settings, RDW is 
also large. An elevated RDW also has been reported as a risk factor 
for all-cause mortality in population-based studies, a finding that is 
unexplained currently.

Interpreting Peripheral Blood Smears 
CHAPTER 65
After red cell size is assessed, one examines the hemoglobin con­
tent of the cells. They are either normal in color (normochromic) 
or pale in color (hypochromic). They are never “hyperchromic.” If 
more than the normal amount of hemoglobin is made, the cells get 
larger—they do not become darker. In addition to hemoglobin con­
tent, the red cells are examined for inclusions. Red cell inclusions 
are the following:
1.	 Basophilic stippling—diffuse fine or coarse blue dots in the red cell 
usually representing RNA residue—especially common in lead 
poisoning
2.	Howell-Jolly bodies—dense blue circular inclusions that repre­
sent nuclear remnants—their presence implies defective splenic 
function
3.	 Nuclei—red cells may be released or pushed out of the marrow pre­
maturely before nuclear extrusion—often implies a myelophthisic 
process or a vigorous narrow response to anemia, usually hemolytic 
anemia
4.	 Parasites—red cell parasites include malaria and babesia (Chaps. A2 
and A6)
5.	 Polychromatophilia—the red cell cytoplasm has a bluish hue, reflect­
ing the persistence of ribosomes still actively making hemoglobin in 
a young red cell
Vital stains are necessary to see precipitated hemoglobin called 
Heinz bodies.
Red cells can take on a variety of different shapes. All abnormally 
shaped red cells are poikilocytes. Small red cells without the central 
pallor are spherocytes; they can be seen in hereditary spherocytosis, 
hemolytic anemias of other causes, and clostridial sepsis. Dacrocytes 
are teardrop-shaped cells that can be seen in hemolytic anemias, 
severe iron deficiency, thalassemias, myelofibrosis, and myelodys­
plastic syndromes. Schistocytes are helmet-shaped cells that reflect 
microangiopathic hemolytic anemia or fragmentation on an artificial 
heart valve. Echinocytes are spiculated red cells with the spikes evenly 
spaced; they can represent an artifact of abnormal drying of the blood 
smear or reflect changes in stored blood. They also can be seen in 
renal failure and malnutrition and are often reversible. Acanthocytes 
are spiculated red cells with the spikes irregularly distributed. This 
process tends to be irreversible and reflects underlying renal disease, 
abetalipoproteinemia, or splenectomy. Elliptocytes are ellipticalshaped red cells that can reflect an inherited defect in the red cell 
membrane, but they also are seen in iron deficiency, myelodysplastic 
syndromes, megaloblastic anemia, and thalassemias. Stomatocytes are 
red cells in which the area of central pallor takes on the morphology 
of a slit instead of the usual round shape. Stomatocytes can indicate 
an inherited red cell membrane defect and also can be seen in alco­
holism. Target cells have an area of central pallor that contains a dense 
center, or bull’s eye. These cells are seen classically in thalassemia, but 
they are also present in iron deficiency, cholestatic liver disease, and 
some hemoglobinopathies. They also can be generated artifactually 
by improper slide making.

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 65-1  Normal peripheral blood smear. Small lymphocyte in center of field. 
Note that the diameter of the red blood cell is similar to the diameter of the small 
lymphocyte nucleus. (Source: From M Lichtman et al (eds): Williams Hematology, 
7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault, Hematology in General 
Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-2  Reticulocyte count preparation. This new methylene blue–stained 
blood smear shows large numbers of heavily stained reticulocytes (the cells 
containing the dark blue–staining RNA precipitates). (Source: From M Lichtman et 
al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA 
Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-3  Hypochromic microcytic anemia of iron deficiency. Small lymphocyte 
in field helps assess the red blood cell size. (Source: From M Lichtman et al (eds): 
Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: 
Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-4  Iron deficiency anemia next to normal red blood cells. Microcytes 
(right panel) are smaller than normal red blood cells (cell diameter <7 μm) and may 
or may not be poorly hemoglobinized (hypochromic). (Source: From M Lichtman et 
al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA 
Ault, Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-5  Polychromatophilia. Note large red cells with light purple coloring. 
(Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, 
McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. 
New York, McGraw-Hill, 2005.)
FIGURE 65-6  Macrocytosis. These cells are both larger than normal (mean 
corpuscular volume >100) and somewhat oval in shape. Some morphologists 
call these cells macroovalocytes. (Source: From M Lichtman et al (eds): Williams 
Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology 
in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 
65-7  Hypersegmented 
neutrophils. 
Hypersegmented 
neutrophils 
(multilobed polymorphonuclear leukocytes) are larger than normal neutrophils with 
five or more segmented nuclear lobes. They are commonly seen with folic acid or 
vitamin B12 deficiency. (Source: From M Lichtman et al (eds): Williams Hematology, 
7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General 
Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-8  Spherocytosis. Note small hyperchromatic cells without the usual 
clear area in the center. (Source: From M Lichtman et al (eds): Williams Hematology, 
7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General 
Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-9  Rouleaux formation. Small lymphocyte in center of field. These red 
cells align themselves in stacks and are related to increased serum protein levels. 
(Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, 
McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. 
New York, McGraw-Hill, 2005.)

Interpreting Peripheral Blood Smears 
CHAPTER 65
FIGURE 65-10  Red cell agglutination. Small lymphocyte and segmented neutrophil 
in upper left center. Note irregular collections of aggregated red cells. (Source: 
From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, 
McGraw-Hill, 2005.)
FIGURE 65-11  Fragmented red cells. Heart valve hemolysis. (Source: From M 
Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS 
Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 
2005.)
FIGURE 65-12  Sickle cells. Homozygous sickle cell disease. A nucleated red cell 
and neutrophil are also in the field. (Source: From M Lichtman et al (eds): Williams 
Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology 
in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 65-13  Target cells. Target cells are recognized by the bull’s-eye appearance 
of the cell. Small numbers of target cells are seen with liver disease and thalassemia. 
Larger numbers are typical of hemoglobin C disease. (Source: From M Lichtman et 
al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA 
Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-14  Elliptocytosis. Small lymphocyte in center of field. Elliptical shape 
of red cells related to weakened membrane structure, usually due to mutations in 
spectrin. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New 
York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th 
ed. New York, McGraw-Hill, 2005.)
FIGURE 65-15  Stomatocytosis. Red cells characterized by a wide transverse slit or 
stoma. This often is seen as an artifact in a dehydrated blood smear. These cells can 
be seen in hemolytic anemias and in conditions in which the red cell is overhydrated 
or dehydrated. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. 
New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 
4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-16  Acanthocytosis. Spiculated red cells are of two types: acanthocytes 
are contracted dense cells with irregular membrane projections that vary in 
length and width; echinocytes have small, uniform, and evenly spaced membrane 
projections. Acanthocytes are present in severe liver disease, in patients with 
abetalipoproteinemia, and in rare patients with McLeod blood group. Echinocytes 
are found in patients with severe uremia, in glycolytic red cell enzyme defects, 
and in microangiopathic hemolytic anemia. (Source: From M Lichtman et al (eds): 
Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: 
Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-17  Howell-Jolly bodies. Howell-Jolly bodies are tiny nuclear remnants 
that normally are removed by the spleen. They appear in the blood after splenectomy 
(defect in removal) and with maturation/dysplastic disorders (excess production). 
(Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, 
McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. 
New York, McGraw-Hill, 2005.)
FIGURE 65-18  Teardrop cells and nucleated red blood cells characteristic of 
myelofibrosis. A teardrop-shaped red blood cell (left panel) and a nucleated red 
blood cell (right panel) as typically seen with myelofibrosis and extramedullary 
hematopoiesis. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. 
New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 
4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-19  Myelofibrosis of the bone marrow. Total replacement of marrow 
precursors and fat cells by a dense infiltrate of reticulin fibers and collagen 
(hematoxylin and eosin stain). (Source: From M Lichtman et al (eds): Williams 
Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology 
in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-20  Reticulin stain of marrow myelofibrosis. Silver stain of a myelofibrotic 
marrow showing an increase in reticulin fibers (black-staining threads). (Source: 
From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, 
McGraw-Hill, 2005.)
FIGURE 65-21  Stippled red cell in lead poisoning. Mild hypochromia. Coarsely 
stippled red cell. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. 
New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 
4th ed. New York, McGraw-Hill, 2005.)

Interpreting Peripheral Blood Smears 
CHAPTER 65
FIGURE 65-22  Heinz bodies. Blood mixed with hypotonic solution of crystal violet. 
The stained material is precipitates of denatured hemoglobin within cells. (Source: 
From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, 
McGraw-Hill, 2005.)
FIGURE 65-23  Giant platelets. Giant platelets, together with a marked increase 
in the platelet count, are seen in myeloproliferative disorders, especially primary 
thrombocythemia. (Source: From M Lichtman et al (eds): Williams Hematology, 
7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General 
Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-24  Normal granulocytes. The normal granulocyte has a segmented 
nucleus with heavy, clumped chromatin; fine neutrophilic granules are dispersed 
throughout the cytoplasm. (Source: From M Lichtman et al (eds): Williams 
Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology 
in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 65-25  Normal monocytes. The film was prepared from the buffy coat of 
the blood from a normal donor. L, lymphocyte; M, monocyte; N, neutrophil. (Source: 
From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, 
McGraw-Hill, 2005.)
FIGURE 65-26  Normal eosinophils. The film was prepared from the buffy coat of the 
blood from a normal donor. E, eosinophil; L, lymphocyte; N, neutrophil. (Source: From 
M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; 
RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGrawHill, 2005.)
FIGURE 65-27  Normal basophil. The film was prepared from the buffy coat of the 
blood from a normal donor. B, basophil; L, lymphocyte. (Source: From M Lichtman et 
al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA 
Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-28  Pelger-Hüet anomaly. In this benign disorder, the majority of 
granulocytes are bilobed. The nucleus frequently has a spectacle-like, or “pince-nez,” 
configuration. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. 
New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 
4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-29  Döhle body. Neutrophil band with Döhle body. The neutrophil with a 
sausage-shaped nucleus in the center of the field is a band form. Döhle bodies are 
discrete, blue-staining nongranular areas found in the periphery of the cytoplasm 
of the neutrophil in infections and other toxic states. They represent aggregates 
of rough endoplasmic reticulum. (Source: From M Lichtman et al (eds): Williams 
Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology 
in General Practice, 4th ed. New York, McGraw-Hill, 2005.)
FIGURE 65-30  Chédiak-Higashi disease. Note giant granules in neutrophil. (Source: 
From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, 
McGraw-Hill, 2005.)