Morfologi Platelet

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Chapter
5
Evaluation of Cell
Morphology and
Introduction to Platelet
and White Blood Cell
Morphology
Kathy W. Jones, MS, MT(ASCP), CLS(NCA)
Introduction OBJECTIVES
Examination of the Peripheral At the end of the chapter, the learner should be able to:
Blood Smear
1. Define the terms flagged and reflex test as they pertain to automated hematology
The Normal Red Blood Cell
results.
Assessment of Red Cell
Abnormality 2. Describe the importance of maintaining competency in morphological identification.
Variations in Red Cell 3. List justifications for performing a manual morphology review.
Distribution 4. List the steps in the performance of a peripheral blood smear examination.
Normal Distribution
Abnormal Distribution 5. Identify normal red blood cell morphology on a peripheral smear.
Variations in Size 6. List the terms referring to abnormal red cell distribution, variation in red cell size,
Anisocytosis and variations in red cell color/hemoglobin content, being able to identify each
Normocytes abnormality on a peripheral smear and specify the particular clinical conditions
Macrocytes associated with these abnormalities.
Microcytes
7. Define anisocytosis and poikilocytosis and list clinical conditions in which they may
Hemoglobin Content—Color be reported.
Variations
Normochromia 8. Define the terms normochromic, hypochromic, microcytic, and macrocytic as they
Hypochromia relate to red cell indices.
Hyperchromia 9. Correlate red cell indices with red cell morphology and the diagnosis of anemia.
Polychromasia
10. Define the following terms: target cells, spherocytes, ovalocytes, elliptocytes, stoma-
Variations in Shape tocytes, and be able to identify these cells on a peripheral smear.
Poikilocytosis
Target Cells (Codocytes) 11. List diseases that may show fragmented red cells and describe their pathophysiology.
Spherocytes 12. Describe the most common red blood cell inclusions and their composition, relating
Stomatocytes each inclusion to clinical conditions in which they may be found.
Ovalocytes and Elliptocytes
Sickle Cells (Drepanocytes) 13. Correlate pathophysiology of clinical conditions associated with abnormal appear-
Fragmented Cells ance of red cells noted on the peripheral blood smear.
(Schistocytes, Helmet 14. Describe normal platelet morphology and specify some platelet abnormalities seen in
Cells, Keratocytes) pathologic conditions.
Burr Cells (Echinocytes)
15. List conditions showing leukocyte cytoplasmic as well as nuclear changes.
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94 Chapter 5 Evaluation of Cell Morphology and Introduction to Platelet and White Blood Cell Morphology
Acanthocytes (Thorn Cells,

Spur Cells)
Teardrop Cells (Dacrocytes)
Red Cell Inclusions
Howell–Jolly Bodies
Basophilic Stippling
Pappenheimer Bodies and
Siderotic Granules
Heinz Bodies
Cabot Rings
Hemoglobin CC Crystals
Hemoglobin SC Crystals
Protozoan Inclusions
Examination of Platelet
Morphology
White Blood Cell Morphology
Case Study
Introduction From the educational perspective, it is essential that stu-

dents be trained to recognize cellular abnormalities, given that
Hematology, as a laboratory discipline, has changed dramati- the majority of the blood smears they review will be abnormal.
cally over the last three decades, primarily as a direct result of With the development of sophisticated automated blood-cell
automation and enhanced technology. Multichanneled auto- analyzers, the proportion of CBC samples that require a blood
mated hematology analyzers provide a reliable and accurate smear has steadily diminished and in many clinical settings is
complete blood count (CBC). The analyzers have evolved from 10 to 15 percent or less, depending on facility patient popula-
basic direct current impedance enumeration of cells, to very tion.1 Even with the wealth of information that may be derived
complex instruments involving multiple technologies in one from an analyzer, the blood smear remains a crucial diagnostic
instrument. These various technologies have significantly aid, and maintaining technologist competency in the identifica-
enhanced the ability of automation to reduce actual personnel tion of cellular abnormalities should be a priority in the labora-
time spent in performing and reporting CBC analysis. An exam- tory. There are morphologic abnormalities that are critical in
ple of such technology is flow cytometry, which actually pro- the differential diagnosis of anemia that can still be determined
duces qualitative as well as quantitative differential cell counts only from a blood smear. Because of financial constraints of
and analysis. With this technology, abnormalities are flagged, educational programs, students may have little or no training
which is an indication to the technologist the instrument has on sophisticated automation common in laboratories today.
identified results outside of the established parameters of the Regardless, students should have a strong background in man-
laboratory and some form of review must be completed before ual white blood cell (WBC) differential counting as well as red
reporting test results. The instrument, in most cases, will spec- cell and platelet morphology assessment.
ify the result with an indicator such as a symbol (i.e., an aster- This chapter guides the student in interpretation of red
isk) or a high (H) or low (L) designation depending on the cell, platelet, and white cell morphology by first defining
abnormality. The required review may include comparing cur- what is considered normal. Evaluation of abnormalities is
rent patient results with prior history or having set parameters discussed in terms of basic assessment techniques of the
that would automatically request further testing referred to as cellular morphology with particular emphasis on recogniz-
reflex testing. Reflex testing of an abnormal or flagged result ing a distinct morphology and relating it to the clinical con-
would include a slide review of abnormal morphology (usually dition. Physiologic mechanisms are explained to give the
scanning 8 to 10 oil immersion fields) and if necessary, a com- reader a better understanding of an abnormality and how it
plete white cell differential count. The proportion of required relates to different disease states. This description of blood
manual morphology reviews are determined by the parameters cell morphology maximizes the ability of each slide reviewer
set through laboratory policies which are based on financial to recognize and correlate the blood morphology to the
and regulatory standards as well as medical considerations. In clinical pathology and abnormal results. A careful and
comparison with the procedure for an automated CBC, the thorough examination via light microscopy in the optimal
examination of a peripheral blood smear is labor intensive, and area on a well made, well stained peripheral smear provides
therefore a relatively expensive investigation and must be used an experienced observer with valued information about
judiciously. morphology normal or abnormal.2
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Chapter 5 Evaluation of Cell Morphology and Introduction to Platelet and White Blood Cell Morphology 95
Examination of the Peripheral Blood 3. Find an optimal area for the detailed examination and
Smear enumeration of cells.
• The RBCs should not quite touch each other.
A blood smear examination may be performed for a variety • There should not be areas containing large amounts of
of reasons. It may be requested by the physician in response broken cells or precipitated stain.
to perceived clinical features or to an abnormality discovered • The RBCs should have a graduated central pallor.
in a previous CBC. The examination may also be initiated by
High-Power (40) Scan
the technologist as a result of an abnormality in the CBC or
in response to a flagged result reported from the hematology 1. Determine the WBC estimate.
analyzer. A flagged result is an indication that a particular • The WBC estimate is performed under high power (400
result has not met established laboratory criteria and must be magnification). WBCs are counted in ten fields and aver-
reviewed. All laboratories should have a documented proto- aged. The estimate is reported according to the values
col for the examination of a laboratory-initiated blood smear given in Table 5–1.
examination. This protocol may be derived from studies per- • The WBC estimate can also be performed using a factor
formed in the facility or may be based on consensus stan- which is based on the fact that each WBC seen in 400x
dards published by nationally recognized organizations. magnification (high power field) is equivalent to
The microscopic examination of a peripheral blood approximately 2000 cells per µL of blood. For example,
smear provides a wealth of information to the clinician. It is if the average number of WBCs counted per high power
used to detect or verify abnormalities and subsequently may field was 5, the WBC estimate would be 5 2000 or
provide the physician with information from which they may 10,000/µL.
be able to make a differential diagnosis. Various forms of 2. Correlate the WBC estimate with the WBC counts per mm3
anemia may actually be diagnosed from abnormal red cell from the automated instruments.
morphology reported on a blood smear examination. The 3. Evaluate the morphology of the WBCs and record
report of abnormal white cell morphology may in fact indi- any abnormalities, such as toxic granulation or Döhle
cate what additional testing may be required. Abnormal bodies
platelet morphology may detect a platelet function deficiency
Oil Immersion (100) Examination
even when sufficient numbers of platelets have been reported
from the analyzer. 1. Perform a 100 WBC differential count.
The examination of the blood smear should include eval- • Counting should be performed by moving in a zig-zag
uation of the red cell, white cell, and platelet morphology. To manner on the smear (Fig. 5–1).
evaluate the smear thoroughly the technologist should review • All WBCs are to be included until a total of 100 have been
at least 8 to 10 oil immersion fields (OIF). The red cell mor- counted.
phology evaluation should include examination for deviations 2. Evaluate the RBCs for anisocytosis, poikilocytosis,
in size, shape, distribution, concentration of hemoglobin, hypochromasia, polychromasia, and inclusions.
color, and the appearance of inclusions. The white cell mor- 3. Perform a platelet estimate and evaluate platelet morphology.
phology evaluation should consist of differentiation of the • Count the number of platelets in 10 OIFs.
white blood cells and their overall appearance including • Divide by 10.
nuclear abnormalities, cytoplasmic abnormalities, and the • Multiply by 15,000/mm3 if the slide was prepared by an
presence of abnormal inclusions that may denote a disease automatic slide spinner; multiply by 20,000/mm3 for all
process. Platelet counts should be verified, and in addition the other blood smear preparations.
smear should be reviewed for platelet shape and size abnor- 4. Correct any total WBC count per mm3 that has greater than
malities and for clumping. 10 nucleated red blood cells (NRBCs) per 100 WBCs.
When abnormal morphology is identified on the smear, • When performing the WBC differential, do not include
the technologist must determine if the abnormality is possibly NRBCs in your count, but report them as the number of
artifactual and not pathological. For instance, refractile arti- NRBCs per 100 WBCs.
facts may be the result of water contamination and should not • Use the following formula to correct a WBC count:
be confused with red cell inclusions. Echinocytes or crenated
WBC/mm3 100
cells may also be artifacts if practically every cell in the thin Corrected WBCs/mm3
100 No. of NRBCs/100 WBCs
portion of the film has a uniformly spiculed membrane.
The following describes the necessary steps in the exam- The examination of the peripheral blood smear is per-
ination of the peripheral blood smear. formed as part of the hematologic laboratory workup called
Low-Power (10) Scan the CBC.
1. Determine the overall staining quality of the blood smear.
2. Determine if there is a good distribution of the cells on the The Normal Red Blood Cell
smear.
• Scan the edges and center of the slide to be sure there are To identify abnormal morphology, one must be competent in
no clumps of RBCs, WBCs, or platelets. normal morphology identification, and more importantly,
• Scan the edges for abnormal cells. capable of differentiating them from abnormal cells, so we
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Table 5–1 Estimation of Total WBC

Count from the
Peripheral Blood Smear
No./High Power Field Estimated Total WBC Count/mm3
2–4 4000–7000
4–6 7000–10,000
6–10 10,000–13,000
10–20 13,000–18,000
begin this section with a description of normal red blood cell

(RBC) morphology. The mature erythrocyte (RBC, normo-
cyte, discocyte) has a remarkable structure in that it lacks a
nucleus and organelles, and yet all components necessary for
survival and function are present. It is described as a bicon-
cave disc with a survival time of approximately 120 days. On
a Romanowsky (i.e., Wright’s, Giemsa) stained blood smear,
this mature red cell has a reddish-orange appearance. The Figure 5-2 ■ Normal red blood cells.
RBC has an average diameter of 7 to 8 µm and an average
volume of 90 fL. The area of central pallor is approximately
2 to 3 µm in diameter (Fig. 5–2), and the size variation of red peripheral blood smear review. If these criteria are achieved,
cells from a normal patient is approximately 5%. The primary the reviewer must make a general assessment of whether the
function of the red cell is the transportation of O2 to the tis- morphological abnormality is due to shape change (poikilocy-
sues of the body and transportation of CO2 back to the lungs tosis) or size change (anisocytosis) or a change in color. Most
for expulsion. Fundamental to the red cell is the formation of assessments of anisocytosis are performed in concert with the
hemoglobin, which is ultimately responsible for binding the red cell indices and the red cell distribution width (RDW)
oxygen molecule for transport. The oxygen-carrying capacity rating obtained from the hematology analyzer. In assessing the
of each erythrocyte is dependent on the production of ade- smear, the reviewer takes into account the percentage of cells
quate amounts of functional hemoglobin. Also fundamental that vary in size in at least 10 OIFs. For example, if the mean
to the red cells functionality is the maintenance of the cellu- corpuscular volume (MCV) was 65 fL (80 to 100 for adults),
lar membrane. The red cell membrane is composed of equal the reviewer would expect to see a large percentage of small
weighted portions of lipids and proteins and is responsible cells. If the MCV were 105 fL, the reviewer would expect to
for sustaining a constant surface-to-volume ratio. Maintain- see primarily larger cells. More information on red cell indices,
ing the integrity of this membrane is essential to the cells including calculations, may be found in Chapter 31 of this text.
shape and deformability which allows the RBC to traverse The majority of laboratories use either qualitative
through the microvasculature of the body. An alteration of remarks (few or marked) or a numerical grading (1 to
this membrane may result in the inability of the red cell to 4) based on percentage of variation and to describe the
function efficiently and ultimately may lead to the cell’s type of cell or cells that have caused the variation from
early demise. the normal. With this method, a reviewer can present to the
clinician a series of objective ratings that can translate to a
visual impression of a patient’s peripheral smear. This
Assessment of Red Cell Abnormality assessment may be critical to the physician’s differential
diagnosis of certain forms of anemia. Reviewers are urged
A well-stained and well-made blood smear with an even distri-
to avoid the use of terms that are vague (e.g., the term pre-
bution of RBCs in the area to be examined is essential for any
sent) owing to the wide variations in the implication it may
have to clinicians. See Table 5–2 for an example of guide-
lines in grading anisocytosis and poikilocytosis. Please note
that the assessment of RBC morphologic abnormalities
remains a manual task that is inherently subjective, and it is
imperative that laboratories establish guidelines based on
their own patient and physician population. It is essential to
patient care that the laboratory and the clinician have simi-
lar interpretations of the results reported for all RBC mor-
phology. Figure 5–3 is a composite chart of normal and
Figure 5-1 ■ Blood smear.
abnormal red cell morphology.
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should be in the thin portion of the smear where the red cells
Table 5–2 Grading Scale for Red are slightly separated from one another or at most, barely
Cell Morphology touching, with no overlap. The thin area should represent at
(Anisocytosis/ least one-third of the entire film.2 The reviewer should avoid
Poikilocytosis) the thicker portion of the slide where cells are overlapping
and the edges of smear where cells may be artifactually dis-
Percentage of Cells that Differ in Size or Shape from Normal torted in size, shape, and color. An exception is to be made
RBCs when scanning for platelet clumping.
Normal 5%
Slight 5%–10%
1 10%–25%
Abnormal Distribution
2 25%–50%
AGGLUTINATION
3 50%–75%
4 75% Agglutination is an aggregation of red cells into random
clusters or masses. Agglutination is the result of an antigen–
Sample Situations antibody reaction within the body, and in cases of autoag-
2 Microcytes Few schistocytes glutination the reaction is actually with the patient’s own
1 Macrocytes Few burr cells cells and the patient’s serum or plasma. Such is the case with
1 Target cells cold antibody syndromes, for example, cold hemagglutina-
3 Anisocytosis 2 Poikilocytosis tion disease and paroxysmal cold hemoglobinuria (PCH).
Agglutination occurs at room temperature during sample
preparation and appears as interspersed areas of clumping
Included in this chapter are flowcharts that correlate the throughout the peripheral smear (Fig. 5–4). The use of saline
abnormal morphology with a possible pathology. This scheme will not disperse these agglutinated areas; however, warm-
should enable the learner to more easily associate an abnor- ing the sample to 37°C helps to break up the agglutinins,
mal morphology with the clinical condition. allowing for the possibility of normal slide preparation for
morphology review. The MCHC and MCV from these speci-
mens are usually falsely elevated in response to the agglutinin
Variations in Red Cell Distribution formation. Other forms of autoagglutination may also occur
Normal Distribution spontaneously but are more likely to be seen in connection
with certain hemolytic anemias, atypical pneumonia, staphy-
The area of smear that is reviewed for morphologic abnormal- lococcal infections, and trypanosomiasis. Agglutination is not
ities is of the utmost importance. The area to be reviewed to be confused with rouleaux which is described next.
RED BLOOD CELL MORPHOLOGY

Hemoglobin Red cell
Size variation distribution Shape variation Inclusions distribution
Normal Hypochromia Target cell Acanthocyte Pappenheimer bodies Agglutination
(siderotic granules)
1+
Microcyte Spherocyte Helmet cell Cabot’s ring

2+ (fragmented cell)
Macrocyte Ovalocyte Schistocyte Basophilic stippling Rouleaux

3+ (fragmented cell) (coarse)
Oval macrocyte Stomatocyte Tear drop Howell-Jolly

4+
Hypochromic
macrocyte Polychromasia Sickle cell Burr cell Crystal formation
HbSC HbC
(Reticulocyte)
Figure 5-3 ■ Normal and abnormal red blood cell morphology.

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rouleaux. This is considered artifactual and should not be

reported until it is verified in the thin portion of the smear or
a new slide is prepared.
Variations in Size
Anisocytosis
Any significant variation is size is known as anisocytosis. This
size variation is frequently found in the leukemias and in most
forms of anemia. The severity of the variation should also
correspond to an increased RDW. Anisocytosis results from
abnormal cell development, and typically results from a defi-
ciency in the raw materials (i.e., iron, vitamin B12, folic acid)
needed to manufacture them or by a congenital defect in the
Figure 5-4 ■ Note the agglutination on the smear from a patient cell’s structure. Cell size may deviate, from measuring smaller
with cold hemagglutinin disease.
than the normal 7 µm, to being larger than normal. The terms
ROULEAUX used to describe these abnormalities are microcyte (≤6 µm) and
Rouleaux is a condition in which red cells appear as stacks of macrocyte (≥9 µm). These terms are used in conjunction with
coins on the peripheral smear. The stacks may be short or the terms microcytosis and macrocytosis and should also corre-
long, but regardless of the length, the red cells appear stacked late with the red cell indice results. Anisocytosis is graded in
on one another. These stacks are rather evenly dispersed most facilities as 1 to 4 (see Table 5–2). When reporting
throughout the smear. Rouleaux formation is the result of anisocytosis, it is important to describe the morphology picture
elevated globulins or fibrinogen in the plasma where the red in terms of microcytosis or macrocytosis, or in cases of a dimor-
cells have been more or less “bathed” in this abnormal plasma phic population there may be the appearance of both (Fig. 5–6).
which gives them a sticky consistency. This lowers the zeta ()
potential, thus facilitating the stacking effect (Fig. 5–5). The Normocytes
use of a saline dilution of the serum disperses rouleaux.
Rouleaux formation correlates well with a high erythrocyte The average size of the erythrocyte is indicated by the mea-
sedimentation rate. surement of the MCV, a result generated by the automated
Rouleaux is seen in patients with hyperproteinemias hematology analyzer. The MCV is considered an integral part
such as multiple myeloma and Waldenstrom’s macroglobu- of a CBC. Observation of red cell morphology on the blood
linemia. It may also be seen in chronic inflammatory disor- smear provides a quality control check on the electronic
ders, and some lymphomas. It is important to note that in MCV, as well as the other two red cell indices, mean corpus-
cases of severe rouleaux it may be impossible to evaluate cell cular hemoglobin (MCH) and mean corpuscular hemoglobin
size or shape. concentration (MCHC).2 A “normal” MCV would correspond
Peripheral smears reviewed in the thick portions of the to the MCV reference range (80 to 100 fL for adults). Subse-
smear and entire smears made too thick may appear to exhibit quent review of the blood smear should yield no significant
Figure 5-6 ■ Note the different size (anisocytosis) and shape (poikilo-
Figure 5-5 ■ Peripheral blood showing marked rouleaux formation. cytosis) of the red cells. Compare the largest (macrocytic) cell below
Note the “stacked coin” appearance of the red cells. the arrow in the center of the field with the smaller (microcytic) cells.
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size variation from the normal 7- to 8-µm red cell. This sce- excess plasma cholesterol may be taken up by the red cell
nario is referred to as normocytic and the red cells are referred which subsequently leads to an increase in the surface area of
to as normocytes. This information would prove useful to the the cell. However, this last mechanism may not be reflective of
physician in the diagnosis of anemia. In the case of a normal a “true” macrocytosis (obstructive liver disease). Macrocytes
MCV and a high RDW (normal RDW is 11.5% to 14.5%), the should be evaluated for shape (oval versus round) as shown in
reviewer would expect to see a mixture of large and small Figure 5–6, color (red versus blue), pallor (if present), and the
cells.3 This scenario is referred to as a dimorphic population presence or absence of inclusions. The conditions in which
and may be the result of a recent blood transfusion, or possi- macrocytes may be seen are listed in Figure 5–7.
bly the patient may be in the recovery stages of anemia.
Patient history plays an important role in this situation.
Microcytes
Macrocytes A microcyte is a small cell having a diameter of less than 7 µm

and an MCV of less than 80 fL. Anemias associated with
Macrocytes are cells that are approximately 9 µm or larger in microcytes are said to be microcytic. The hemoglobin content
diameter, having an MCV of greater than 100 fL.4 Anemias of these cells may be normal to decreased. A consequence of
associated with these cells are referred to as macrocytic. These any defect that results in impaired hemoglobin synthesis may
cells may appear in the peripheral circulation by several mech- produce a microcytic, hypochromic (MCHC 32% and cells
anisms. One mechanism is impaired deoxyribonucleic acid with increased central pallor) blood picture. When erythroid
(DNA) synthesis, which results in megaloblastic erythro- cells are deprived of any of the essential elements in hemoglo-
poiesis leading to a decreased number of cellular divisions, bin synthesis (see Chap. 6), the result is an increase in cellular
and consequently a larger cell. This form of erythropoiesis divisions and consequently a smaller cell in the peripheral
produces a megaloblastic anemia and may be the result of B12 blood. This form of abnormal hemoglobin synthesis is seen in
or folate deficiency, chemotherapy, or any process producing a iron deficiency, deficiency of heme synthesis (sideroblastic
nuclear maturation defect. Macrocytes with an oval shape anemia), deficiency of globin synthesis (thalassemia), and
(macroovalocytes), neutrophilic hypersegmentation, as well as chronic disease states. In the case of iron deficiency, microcy-
MCV values exceeding 120 fL are typically seen in this type tosis will not be visually apparent until iron stores in the body
of anemia. have been completely exhausted and iron deficient erythro-
The most common cause of nonmegaloblastic macrocyto- poiesis takes place, as in iron deficiency anemia (IDA). Iron
sis is accelerated erythropoiesis which results from conditions deficiency is the most common cause of anemia, affecting
such as acute blood loss or alcoholism. The cells are released some 30% of the world population and accounting for up to
prematurely from the marrow, are non-nucleated, and appear 500 million cases worldwide, which also makes it the most
larger than a mature erythrocyte. On a Wright-stained smear the common microcytic/hypochromic anemia in the world.6 It is
cells will appear as round polychromatophilic macrocytes and especially common in women of childbearing age. The causes
on a supravitally (i.e., new methylene blue) stained smear they of this deficiency may vary depending on the age and sex of the
appear as reticulocytes. Neutrophilic hypersegmentation is not patient and it is important to determine what instigated the
typically seen in this form of macrocytosis.5 deficiency before treatment begins.
Macrocytosis may result from other conditions, such as Decreased or defective globin synthesis also presents
hypothyroidism and various bone marrow disorders, as well as as a microcytic/hypochromic anemia, but in most cases this
occur in neonatal blood, postsplenectomy, and in cases where results from a genetic abnormality producing a hereditary
MORPHOLOGY - MACROCYTE
Possible pathology
Megaloblastic High Liver Post- Chemotherapy Hypothyroidism

process reticulocyte disease splenectomy
count
Oval Hemolytic
macrocytes anemia/acute
blood loss Figure 5-7 ■ Correlation of macro-
cytes to pathologic processes.
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anemia known as thalassemia. This microcytic/hypochromic

anemia is rare and in the homozygous form it may result in a
severe anemia with a high rate of mortality. In the milder het-
erozygous form this anemic picture may be confused with
IDA. The appearance of target cells, family studies, as well
as additional hematological testing may be needed for a dif-
ferential diagnosis.
It is important to note that other disease processes such
as sideroblastic anemia and lead poisoning may produce
significant numbers of microcytic red cells, in most cases
without hypochromia. Clinical conditions in which micro-
cytes may be seen as the predominant cell morphology are
illustrated in Figure 5–8.
Hemoglobin Content—Color Variations Figure 5-9 ■ Note the large central pallor in many of the red cells
depicting hypochromia.
Normochromia
The term normochromic indicates the red cell is essentially red cells with increased central pallor or hypochromia. A lower
normal in color. A normochromic erythrocyte has a well MCHC result typically correlates with a larger central pallor in
hemoglobinized cytoplasm with a small but distinct zone of the affected red cells. In general, this is very reliable; however,
central pallor. The area of pallor does not exceed 3 µm when it does not take into account the situation in which a true
measured linearly. In a well stained peripheral smear, the nor- hypochromia is observed in the presence of a normal MCHC.
mal red cells will appear reddish-orange in color. The term In many cases, the MCHC will not be concordant with what is
normochromic is used to describe an anemia with a normal observed on the peripheral smear. The morphologist should not
MCHC and MCH. When used in conjunction with a normal be unduly influenced by the RBC indices in the evaluation of
MCV, the anemia would be described as a normochromic/ hypochromia. True hypochromia will appear as a delicate
normocytic anemia (see Fig. 5–2). shaded area of pallor as opposed to pseudohypochromia (the
water artifact), in which the area of pallor is distinctly outlined.
Hypochromia It is important to note that not all hypochromic cells are micro-
cytic. Target cells possess some degree of hypochromia, and
Any RBC having a central area of pallor of greater than 3 µm is there are macrocytes and normocytes that can be distinctly
said to be hypochromic. There is a direct relationship between hypochromic.
the amount of hemoglobin deposited in the red cell and the The most common condition manifesting hypochromia
appearance of the red cell when properly stained. The term is IDA. In severe cases of IDA, red cells exhibit an inordi-
hypochromia literally means “low color” and indicates that the nately thin band of hemoglobin. Patients with iron defi-
cells have less than the normal amount of hemoglobin. Typically ciency may have many hypochromic cells, depending on the
any irregularity in hemoglobin synthesis will lead to some magnitude of the deficiency. In addition to large numbers of
degree of hypochromia (Fig. 5–9). hypochromic cells, there may be large numbers of micro-
Most clinicians choose to assess hypochromia based on cytes as well. Iron deficiency anemia is commonly referred
the mean corpuscular hemoglobin concentration (MCHC), to as a microcytic/hypochromic anemia. Hypochromia in the
which by definition measures hemoglobin content in a given alpha () and beta ( ) trait thalassemia syndromes is much
volume of red cells (100 mL). When the MCHC is 32% the less pronounced. However red cells in the –thalassemias
anemic process is described as being hypochromic and the slide and –thalassemia homozygous states show significant
reviewer should scan the peripheral smear for the presence of amounts of pallor.7 Sideroblastic anemias show a prominent
MORPHOLOGY - MICROCYTE
Possible pathology
Iron Thalassemic Sideroblastic Anemia of Lead

deficiency conditions anemias chronic disease poisoning Figure 5-8 ■ Correlation of microcytes to pathologic
processes.
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however, the reticulum cannot be visualized without supravi-

Table 5–3 Hypochromia Grading tal staining.
It is not uncommon to find a few polychromatophilic
1 Area of central pallor is one-half of cell diameter
cells in a normal peripheral blood smear, because regenera-
2 Area of pallor is two-thirds of cell diameter
3 Area of pallor is three-quarters tion of red cells is a dynamic process. The reticulocyte count
4 Thin rim of hemoglobin should reflect the degree of polychromasia. In the blood
smear, polychromatophilic red cells appear in varying
shades of blue. Any clinical condition in which the marrow
is stimulated, particularly RBC regeneration, will produce a
dimorphic blood picture—macrocytic, normocytic, and polychromatophilic blood picture. This represents effective
microcytic cells together, only some of which show true erythropoiesis as well as an assessment of bone marrow
hypochromia. Some hypochromic cells may be seen in function. Examples of several conditions in which polychro-
patients with lead poisoning. Refer to Table 5–3 for a guide- masia is noted include acute and chronic hemorrhage,
line to grading hypochromia. hemolysis, and any regenerative red cell process. The degree
of polychromasia is an excellent indicator of therapeutic
effectiveness when a patient is given iron or vitamin therapy
Hyperchromia
as a treatment for anemia. Refer to Table 5–4 for a guideline
Red cells with a decreased surface-to-volume ratio and a to polychromasia grading.
decreased or absent central pallor may be described as hyper-
chomic. True hyperchromia exists when the MCHC is 36%
and may be seen in the peripheral smears of patients with
Variations in Shape
hemolytic anemias, including hemolysis caused by burns. Even Poikilocytosis
though true hyperchromia does exist it is not reported as such. It
is reported in terms of the cell abnormalities resulting from the Poikilocytosis is the term used to describe a variation in red
increased volume of hemoglobin and the decreased surface area. cell shape. Normal erythrocytes vary only slightly from the
The cell produced from these phenomena appears as a solid red- concise round shape of a biconcave disc, so even a slight
dish-orange disc with no central pallor and is referred to as a variation in significant numbers may prove to be important.
spherocyte, and is discussed later in this chapter. These poikilocytic cells may take on such peculiar shapes
as teardrops, pencils, and sickles. The differential diagnosis
of anemia cannot be determined from a reported poikilocy-
Polychromasia tosis. The term should be used in conjunction with more
descriptive terminology which would specify the particular
When RBCs are delivered to the peripheral circulation prema-
morphological abnormality observed. Examples of specific
turely, their appearance in the Wright-stained smear is distinc-
poikilocytes are sickle cells, which result from abnormal
tive. These red cells are described as polychromatophilic
hemoglobin, and spherocytes, which result from a red cell
(diffusely basophilic) and are gray-blue in color and usually
membrane abnormality as many of the poikilocytic cells do.
larger than normal red cells (Fig. 5–10). The basophilic color
The differential diagnosis of some forms of anemia may be
of the red cell is the result of the residual RNA involved in
determined by identification of a specific morphological
hemoglobin synthesis. Polychromatophilic macrocytes, as
abnormality.
seen on a Wright’s stained smear, are actually reticulocytes;
The term poikilocytosis refers to the entire red cell mor-
phology in the scanned area of a peripheral smear and is
graded as 1 to 4 (see Table 5–2). Many labs consider the
term poikilocytosis as a “catch all” phrase for abnormal red
cells and in lieu of grading the smear for poikilocytosis opt
only to grade the specific types of morphologically abnormal
cells seen. In these cases the particular cells should be
reported in terms of few, moderate, and many.
Table 5–4 Polychromasia Grading
Percentage of Red Cells that are Polychromatophilic
Slight 1%
1 3%
2 5%
3 10%
4 11%
Figure 5-10 ■ Note polychromasia in the cell with the arrow.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 102
Target Cells (Codocytes) (HS). This is an inherited, autosomal dominant condition and
is due to a deficiency of, or a dysfunction in, the membrane
Target cells appear on the peripheral blood as a result of an proteins spectrin, ankyrin, band 3 and/or protein 4.2.8 The
increase in RBC surface membrane. They are artificially membrane cytoskeleton is dependent on these particular pro-
induced on the smear and their true circulating form, as seen teins to maintain the shape, deformability, and elasticity of
with an electron microscope, is a bell-shaped cell. The name the red cell. The deficiency and/or dysfunction of any one
codocyte is from the Greek word kodon meaning bell. In air- these membrane components will destabilize the cytoskele-
dried smears, however, they appear as “targets,” with a large ton, resulting in abnormal red cell morphology and a shorter
portion of hemoglobin displayed at the rim of the cell and a lifespan for the affected red cells in circulation.8 Spherocytes
portion of hemoglobin that is central, eccentric, or banded are typically seen in large numbers in peripheral smears from
(Fig. 5–11). As the name implies, the cell actually resembles these patients. Premature destruction of these abnormal
a target and is sometimes referred to as a “bull’s eye” cell as erythrocytes in the spleen may produce a mild to severe
well as a “Mexican hat” cell. hemolytic anemia depending on the severity of the abnormal-
The mechanism of targeting is related to excess mem- ity. Erythrocytes from patients with hereditary spherocytosis
brane cholesterol and phospholipid and decreased cellular he- have a mean influx of sodium twice that of normal cells.
moglobin. This is well documented in patients with liver dis- Because these spherocytes have increased ability to metabo-
ease, in whom the cholesterol/phospholipid ratio is altered. lize glucose, they can handle the excessive intracellular
Mature red cells are unable to synthesize cholesterol and sodium while in the plasma, but when they reach the microen-
phospholipid independently. As cholesterol accumulates in vironment of the spleen, the active–passive transport system is
the plasma, as seen in liver dysfunction, the red cell is ex- unbalanced with increased sodium and decreased glucose
panded by increased membrane lipid, resulting in increased resulting in swelling and hemolysis of these cells (see Chap. 9).
surface area. Consequently, the osmotic fragility is also de- In more than one-half of these patients, the MCHC is greater
creased (see Chap. 31). Target cells are seen in many types of than 36%. Yet, for individuals not exhibiting an increased
anemia (Fig. 5–12); however, they are most prominent in the MCHC, a careful observation of their peripheral smear is the
hemoglobinopathies, thalassemias and liver disease. key to diagnosis.9 Figure 5–13 depicts a blood smear from a
patient with hereditary spherocytosis.
The acquired forms of spherocytosis share the mutual
Spherocytes
defect with HS in that there is a loss of membrane. In the nor-
Spherocytes have a reduced surface-to-volume ratio that results mal aging process of red cells they gradually lose their func-
in a cell with no central pallor. Because of their density tionality through loss of cellular lipids, proteins, etc.; thus,
(intense color) and smaller size, they are easily distinguished spherocytes are produced as a final stage before senescent red
in a peripheral smear. Their shape change is irreversible and cells are detained in the spleen and trapped by the reticuloen-
may also be seen as microspherocytes. They are considered dothelial system. This natural process does not typically
the most common form of the erythrocyte morphological dis- result in anemia. Another mechanism of producing sperocytes
orders stemming from an abnormality of the cell membrane. that may result in a mild to severe anemia is autoimmune
This abnormality may be hereditary or acquired and may be hemolytic anemia. The coating of the red cells with antibodies
produced by a variety of mechanisms affecting the red cell and the detrimental effect of complement activation
membrane. Perhaps the most detailed mechanism for sphering results in the membrane loss of cholesterol accompanied by a
is the congenital condition known as hereditary spherocytosis loss of surface area without hemoglobin loss producing sphero-
cytes. The reduced surface-to-volume ratio of all spherocytes
renders them abnormally susceptible to osmotic lysis; conse-
quently, they have an increased osmotic fragility. Hemolysis is
known to result from membrane abnormalities; therefore, other
hemolytic processes may also produce spherocytes. They may
also be seen as microspherocytes in the peripheral smears of
burn patients. Figure 5–14 lists the more common pathologic
conditions in which spherocytes are seen.
Stomatocytes
The word stomatocyte is derived from the Greek word stoma,
which means mouth. They have a central pallor which is said
to be slit-like or mouth-like on peripheral blood smears. These
red cells are of normal size, but are not biconcave, and in wet
preparations appear bowl-shaped (Fig. 5–15). The abnormal
morphology resulting in the stomatocyte is thought to be the
result of a membrane defect. Stomatocytosis is associated with
Figure 5-11 ■ Note the target cell at the arrow.
abnormalities in red cell cation permeability that lead to
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MORPHOLOGY - TARGET CELLS
Possible pathology
Hemoglobin C disease Post- Liver Iron deficiency Any hemoglobin

Hemoglobin C trait splenectomy disease anemia abnormality
Flattened
target
surface Figure 5-12 ■ Correlation of target cells to
pathologic processes.
changes in red cell volume, which may be either increased (hy- condition or at most a mild normochromic/normocytic
drocytosis) or decreased (xerocytosis), or is some cases, near anemia), hemolytic anemia, alcoholic cirrhosis, and acute
normal.9 Hydrocytosis and xerocytosis represent the alcoholism. Stomatocytosis is also present on peripheral
extremes of a spectrum of red cell permeability defects.9 The blood smears of patients with Rh deficiency syndrome, also
exact physiologic mechanism of stomatocytic shape is poorly known as Rh null disease, in which erythrocytes from these
understood and the molecular basis of this disorder is rare individuals have either absent (Rhnull) or markedly
unknown. Stomatocytosis may be acquired or congenital. As reduced (Rhmod)Rh antigen expression. This may result in a
with hereditary spherocytosis, stomatocytes are seen in sig- mild to moderate hemolytic anemia, and mutations in the Rh30
nificant numbers in the hereditary form known as hereditary and RhAG genes have been associated with this syndrome.9
stomatocytosis and in smaller numbers in the acquired form.
Many chemical agents can induce stomatocytosis in vitro
(phenothiazine and chlorpromazine); however, these changes Ovalocytes and Elliptocytes
are reversible.10 Stomatocytes are known to have an increased Many investigators consider the terms ovalocyte and ellipto-
permeability to sodium; consequently, their osmotic fragility cyte to be interchangeable; however, for the purposes of this
is increased. discussion, they are viewed as distinct and separate. This
Stomatocytes are more often artifactual than a true man- morphological abnormality is thought to be the result of a
ifestation of a particular pathophysiologic process. The arti- mechanical weakness or fragility of the membrane skeleton
factual stomatocyte has a distinct slit like area of central and may be acquired or congenital. The pathogenesis of the
pallor, whereas the area of pallor in the genuine stomatocyte formation of either of these cells is unknown. Ovalocytes may
appears shaded. Several of the associated disease states in be considered as more egg-shaped and have a greater ten-
which stomatocytes may be found are hereditary spherocyto- dency to vary in their hemoglobin content. They can appear
sis (the stomatospherocyte is best viewed in wet prepara- normochromic or hypochromic, normocytic or macrocytic.
tions); hereditary stomatocytosis (which is usually a benign Megaloblastic anemia is characterized by oval macrocytes
(macroovalocytes) that may be 9 µm or more in diameter and
lack central pallor (Fig. 5–16).2
MORPHOLOGY - SPHEROCYTES
Possible pathology
Immune Hereditary Post-

hemolytic spherocytosis transfusion
anemia
Figure 5-13 ■ Note the spherocyte at arrow in a blood smear from

Figure 5-14 ■ Correlation of spherocytes to pathologic processes.
a patient with hereditary spherocytosis.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 104
Figure 5-15 ■ Stomatocytes in peripheral blood.
Figure 5-17 ■ Note the oval macrocyte (microovalocyte) at the

Elliptocytes, on the other hand, are pencil, rod, or cigar- arrow. Smear from a patient with pernicious anemia.
shaped and hemoglobin appears to be concentrated on both
ends of the cell. They are invariably not hypochromic,
exhibiting a normal central pallor. Hereditary elliptocytosis Sickle Cells (Drepanocytes)
(HE) is an inherited condition with anywhere from 25% to
90% of all cells demonstrating the elliptical appearance. The Depranocytes or sickle cells are typically crescent or sickle
erythrocytes in HE, in most cases, have a normal survival shaped with pointed projections at one or both ends of the
time; patients are typically asymptomatic and are diagnosed cell. These cells have been transformed by hemoglobin poly-
incidentally during testing for unrelated conditions.9 In merization into rigid, inflexible cells no longer resembling the
approximately 10% of cases where red cell survival time is normal biconcave disc (Fig. 5–19). Patients may be homozy-
shortened, patients’ symptoms may vary from a mild to severe gous or in some cases heterozygous for the presence of the
transfusion-dependent hemolytic anemia. Mutations in the abnormal hemoglobin, hemoglobin S. In the homozygous
red cell membrane protein -spectrin account for a majority patient, physiologic conditions of low oxygen tension (in vivo
of cases of HE, with the remaining cases arising from muta- or in vitro) cause the abnormal hemoglobin to polymerize,
tions in -spectrin or protein 4.1R (Fig. 5–17).11 forming tubules that line up in bundles to deform the cell. The
Ovalocytes/elliptocyte may be seen in association with surface area of the transformed cell is much greater, and the
several disorders in addition to those already mentioned such normal elasticity of the cell is severely restricted. These cells
as microcytic/hypochromic anemia, myelodysplastic syn- have lost their ability to deform and in many cases are unable
dromes, and myelophthistic anemia.2 Refer to Figure 5–18 for to negotiate the microvasculature of the tissues, which leads
a description of pathologic processes associated with ovalo- to oxygen depravation in those areas (see Chap. 11).
cytes and elliptocytes (see Chap. 9). Most sickled cells possess the ability to revert to the disco-
cyte shape when oxygenated; however, approximately 10% are
incapable of reverting to their normal shape. These irreversibly
sickled cells (ISCs) are the result of repeated sickling episodes.
On the peripheral smear, they appear as crescent-shaped cells
with long projections. When reoxygenated, the ISCs may
undergo fragmentation. During a symptomatic period, the per-
centage of ISCs varies tremendously, and, consequently, it does
not correlate with symptomatology. Sickle cells are not usually
seen in the peripheral smears of individuals who are heterozy-
gous (Hgb AS), and are only rarely seen in conjunction with
other abnormal hemoglobins (i.e., Hgb CHarlem Hgb SMemphis).
Classically, sickled cells are best seen in wet preparations. Many
of the cells observed on the Wright–Giemsa stain are the oat
cell-shaped form of the sickled cell (Fig. 5–20). In this form, the
projections are much less pronounced and the central area of the
cell is fairly broad. This shape is reversible.12 The more promi-
nent pathologic conditions in which sickle cells may be observed
Figure 5-16 ■ Note the high percentage of elliptocytes in this are listed in Figure 5–21. In this figure, a morphological distinc-
blood smear from a patient with hereditary elliptocytosis. tion is made between ISCs and reversibly sickled cells.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 105
MORPHOLOGY - OVALOCYTE/ELLIPTOCYTE
Possible pathology
Egg shape Pencil shape
Myelodysplastic Thalassemic Megaloblastic Iron Hereditary Idiopathic

syndrome syndromes process deficiency elliptocytosis myelofibrosis
anemia
Figure 5-18 ■ Correlation of ovalo-

Macrocyte cytes and elliptocytes to pathologic
processes.
Fragmented Cells (Schistocytes, Helmet Schistocytes are the extreme form of red cell fragmen-
Cells, Keratocytes) tation (Fig. 5–22). Whole pieces of red cell membrane
appear to be missing, and bizarre red cells are apparent.
Schistocytes are split, cut, or cloven cells resulting from some Schistocytes may occur in patients with microangiopathic
form of trauma to the cell membrane. It is recognized that not hemolytic anemia, disseminated intravascular coagulation
all membrane alterations occur pathologically. However, (DIC), heart valve surgery, hemolytic uremic syndrome,
there are certain triggering events in disease that invariably thrombotic thrombocytopenic purpura,13 renal graft rejec-
lead to fragmentation such as alteration of normal fluid circu- tion, vasculitis, in severe burn cases, as well as march hemo-
lation. Examples of fluid alterations are the development of globinuria (a form of hemoglobinuria seen in soldiers and
fibrin strands, damaged endothelium, or a damaged heart long-distance runners).
valve prosthesis. The flow of blood in the circulation may Keratocytes are red cells that have been caught on fibrin
actually sweep the erythrocytes through the fibrin strands, strands in circulation, and rather than splitting, the cell hangs
splitting the red cell. The shapes of these cells vary based on over the fibrin fusing two sides of the cell together, creating a
the shear forces and presentation of the red cells as they are vacuole. Once the cell escapes from the fibrin strand it
cut by the fibrin. Intrinsic defects of the red cell make it less appears in the peripheral blood as a red cell with a vacuole in
deformable and, therefore, more likely to be fragmented as it one end resembling a blister and is called a blister cell. It also
traverses the microvasculature of the spleen. Examples such is said to resemble a women’s handbag and may be called a
as antibody-altered red cells and red cells containing inclu- pocket-book cell (see Fig. 5–22). Once the vacuole ruptures,
sions have significant alterations that increase their likelihood the resulting cell appears to have two horns. This “horned”
of being fragmented, consequently decreasing their survival cell also resembles a helmet and is sometimes reported as
time. such, but is actually a keratocyte (Greek for keras, horn).2 The
Figure 5-19 ■ Irreversibly sickled cells. Figure 5-20 ■ Reversible, oat-shaped sickle cell.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 106
MORPHOLOGY - SICKLE CELLS
Possible pathology
Sickle cell Hemoglobin C

anemia (SCA) Harlem
Irreversibly Boat
sickled shaped
cells
Figure 5-23 ■ Note the bite cell at the arrow.
A helmet cell and a bite cell are, therefore, one and the same.
One prominent Oat-shaped The helmet cells may also be seen in patients with pulmonary
pointed cells
projection
emboli, myeloid metaplasia and DIC. All fragmented red cells
are considered fragile and their survival time is diminished sig-
nificantly to days, if not hours, owing to splenic sequestration.
Please note that all laboratories may not report frag-
mented red cells in the same manner (i.e., all fragmented red
Figure 5-21 ■ Correlation of sickle cells to pathologic processes. cells reported as schistocytes) owing to the similarities in
their origins. Regardless of the specificity of the terminology
used, it is imperative that the morphologists give a qualitative
primary difference in the two cells is not in their appearance,
estimate of the abnormality seen in all fields. Especially in
but in their formation.
significant numbers, the appearance of fragmented red cells
The helmet cell also has distinctive projections, usually
will provide physicians with important information on the
two, surrounding an empty area of the red cell membrane.
condition of their patients.
Helmet cells are seen in hematological conditions in which
Refer to Figure 5–24 for a flowchart correlation of the
large inclusion bodies are formed (Heinz bodies, Howell–Jolly
fragmented cells matched to the pathologic processes in
bodies). Fragmentation occurs by the pitting mechanism of
which they may be observed.
the spleen. This pitting mechanism removes the inclusion from
the cell, giving the appearance of having taken a “bite out of the
cell” and is sometimes referred to as a bite cell (Fig. 5–23). Burr Cells (Echinocytes)
Burr cells (echinocytes) are red cells with approximately 10 to
30 rounded spicules evenly placed over the surface of the red
cells (see Fig. 5–22). They are normochromic and normo-
cytic, for the most part. They may be observed as an artifact,
usually as a result of specimen contamination, in which case
they will appear in large numbers and will present with evenly
dispersed smooth projections and may be referred to as cre-
nated. The terms crenated cell and echinocyte may be used
interchangeably by some reviewers and therefore are not
reported. “True” burr cells occur in small numbers and
appear irregularly sized with unevenly spaced spicules. They
may be seen in uremia, heart disease, cancer of the stomach,
bleeding peptic ulcer, immediately following an injection of
heparin, and in a number of patients with untreated hypothy-
roidism. In general, they may occur in situations that cause a
Figure 5-22 ■ Peripheral blood from a patient with renal disease. change in tonicity of the intravascular fluid (e.g., dehydration
Note the presence of fragmented cells: A. burr cells; B. acanthocyte; and azotemia). Burr cells may be considered pathologic and
C. blister/pocketbook cells; D. schistocyte. should be reported.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 107
MORPHOLOGY - FRAGMENTED CELLS
Possible pathology
Schistocyte
Burr cells Helmet cells
Prosthetic Microangiopathic Clostridial

heart valve H.A. infections
Renal Liver Burns DIC TTP HUS G6PD Pulmonary

diseases disease deficiency emboli
Figure 5-24 ■ Correlation of fragmented cells to pathologic processes. HA hemolytic anemia; DIC disseminated intravascular coagula-
tion; HUS hemolytic uremic syndrome; TTP thrombotic thrombocytopenic purpura.
Acanthocytes (Thorn Cells, Spur Cells) lecithin-cholesterol acyltransferase, which has been well doc-
umented in patients with severe hepatic disease. This enzyme
An acanthocyte is defined as a cell of normal or slightly reduced is synthesized by the liver and is directly responsible for
size, possessing 3 to 12 spicules of uneven length distributed esterifying free cholesterol; when this enzyme is deficient,
along the periphery of the cell membrane. The uneven projec- cholesterol is increased in the plasma. Acanthocytes may also
tions of the acanthocyte are blunt rather than pointed, and the be seen in myeloproliferative disorders, microangiopathic
acanthocyte can easily be distinguished from the peripheral hemolytic anemia (MAHA), and autoimmune hemolytic ane-
smear background because it appears to be saturated with hemo- mias. The presence of acanthocytosis in peripheral blood
globin. It appears essentially as a spherocyte with thorns. The smears remains the hallmark of the clinical diagnosis of most
MCHC is, however, always in the normal range (Fig. 5–25). neuroacanthocytosis syndromes, such as chorea-acanthocytosis
Specific mechanisms relating to the formation of acan- (ChAc) and McLeod syndrome.14
thocytes are unknown; however, some details about these The red cell responds to this excess cholesterol in one of
peculiar cells are of interest. Acanthocytes contain an excess two ways, depending on the balance of other lipids in the mem-
of cholesterol and have an increased cholesterol-to-phospho- brane. It will become a target cell or an acanthocyte. Once an
lipid ratio; consequently their surface area is increased. acanthocyte is formed, it is very liable to splenic sequestration
The lecithin content of acanthocytes is decreased. The only and fragmentation, and the fluidity of the membrane is directly
inherited condition in which acanthocytes are seen in high affected. The most prominent pathologies in which acantho-
numbers is the rare condition abetalipoproteinemia. Most cytes may be observed are listed in Figure 5–26.
cases of acanthocytosis are acquired, such as the deficiency of
Teardrop Cells (Dacrocytes)

Teardrop cells appear in the peripheral circulation as tear-
shaped or pear-shaped red cells (Fig. 5–27). The extent to
which a portion of the red cells form tails is variable, and
these cells may be normal, reduced, or increased in size. The
exact physiologic mechanism is unknown, yet teardrop for-
mation from inclusion-containing red cells is well docu-
mented. As cells containing large inclusions attempt to pass
through the microcirculation, the portion of the cells contain-
ing the inclusion cannot pass through and consequently gets
pinched, leaving a tailed end. For some reason, the red cell is
unable to maintain the discocyte shape once this has occurred.
Teardrop cells are seen most prominently in idiopathic
myelofibrosis with myeloid metaplasia. This type of morpho-
logical finding can also be seen in patients with the thalassemia
Figure 5-25 ■ Note the acanthocytes on this peripheral smear.
syndromes, in drug-induced Heinz body formation, in iron
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 108
MORPHOLOGY - ACANTHOCYTES
Possible pathology
Alcohol intoxication Pyruvate Congenital Vitamin E Post-

(Zieve’s syndrome) kinase abetalipoproteinemia deficiency splenectomy
deficiency
Figure 5-26 ■ Correlation of acanthocytes to pathologic processes.
deficiency, and in conditions in which inclusion bodies are with thalassemic syndromes, sickle cell anemia as well as
formed. They may also be seen in megaloblastic processes as other hemolytic anemias, and in megaloblastic anemias.
large tear-shaped cells (macroteardrops). Refer to Figure 5–3
for a composite of abnormal red cell morphology. Basophilic Stippling
Red cells that contain ribosomes can potentially form stippled
Red Cell Inclusions cells; however, it is thought that the actual stippling is the result
Howell–Jolly Bodies of the drying of cells in preparation for microscopic examina-
tion. Coarse, diffuse, or punctate basophilic stippling may occur
Howell–Jolly bodies (Fig. 5–28) are nuclear remnants con- and consist of ribonucleoprotein and mitochondrial remnants
taining DNA. They are 1 to 2 µm in size and may appear (Fig. 5–29). These aggregates of ribosomes result from an alter-
singly or doubly in an eccentric position on the periphery of ation in the biosynthesis of hemoglobin.
the cell membrane. They are thought to develop in periods of Diffuse basophilic stippling appears as a fine blue dusting,
accelerated or abnormal erythropoiesis. They may be seen in whereas coarse stippling is much more clearly outlined and eas-
Romanowsky, i.e., Wright’s, Giemsa, or supravitally stained ily distinguished. Punctate basophilic stippling is a coalescing of
peripheral smears. smaller forms and is very prominent and easily identifiable.
A fragment of the chromosome becomes detached and is Stippling may be found in any condition showing defective
left floating in the cytoplasm after the nucleus has been or accelerated heme synthesis, such as alcoholism, thalassemia
extruded. Under ordinary circumstances, the spleen effec- syndromes, megaloblastic anemias, and arsenic intoxication. It
tively pits these nondeformable bodies from the cell. How- is also considered a characteristic feature in the diagnosis of lead
ever, during periods of erythroid stress, the pitting mechanism poisoning. Basophilic stippling may be seen on a Romanowsky
cannot keep pace with inclusion formation. or supravitally stained peripheral smear. It is important for the
Howell–Jolly bodies may be seen after surgical splenec- reviewer not to confuse stippling with Pappenheimer bodies.
tomy, congenital absence of the spleen, or splenic atrophy The primary differentiation factors are that stippling appears
after multiple infarctions. They may also be seen in patients
Figure 5-27 ■ Teardrop cells (peripheral blood). Figure 5-28 ■ Howell–Jolly body.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 109
that Romanowsky stains visualize Pappenheimer bodies by

staining the protein matrix of the granule, whereas Prussian blue
stain is responsible for staining the iron portion of the granule.
Once the presence of siderotic granules has been con-
firmed by iron stains, the cells in which they are found are
termed siderocytes. Siderocytes containing a nucleus are
described as sideroblasts and are commonly seen in siderob-
lastic anemias. Sideroblasts exhibiting numerous siderotic
granules found within the mitochondria forming a ring around
at least one-third of the nucleus, are labeled as pathologic
ringed sideroblasts. Siderocytes are seen in any condition in
which there is iron overloading such as hemochromatosis or
hemosiderosis. They may also be seen in the hemoglo-
binopathies (e.g., sickle cell anemia and thalassemia) and in
patients following splenectomy.
Figure 5-29 ■ Note the cells with red cell inclusions: basophilic
stippling seen on a peripheral smear in a patient with lead poisoning.
Heinz Bodies
homogeneously over the cell, whereas Pappenheimers tend to Heinz bodies are formed as a result of denatured or precipi-
appear as clusters in the cells periphery. tated hemoglobin. They are large (0.3 to 2 µm) inclusions that
are rigid and severely distort the cell membrane. They can be
formed for visualization in vitro by incubation with phenylhy-
Pappenheimer Bodies and Siderotic drazine (a strong oxidizing agent). On initial exposure to
Granules phenylhydrazine, small crystalline bodies appear, coalesce,
Pappenheimer bodies (siderotic granules) are small, irregular and migrate to an area beneath the cell membrane. This pro-
magenta inclusions seen along the periphery of red cells. They cedure is used before staining with crystal violet or brilliant
usually appear in clusters, as if they have been gently placed on cresyl blue where the presence of Heinz bodies may be seen
the red cell membrane. Their presence on a Wright’s or a on the peripheral smear. Heinz bodies cannot be visualized
supravital stained peripheral smear is presumptive evidence for with Romanowsky stains (Fig. 5–31).
the presence of iron. However, the Prussian blue stain is the Heinz bodies may be seen in the -thalassemic syndromes,
confirmatory test for determining the presence of these inclu- glucose-6-phosphate dehydrogenase (G6PD) deficiency under
sions. These bodies/granules in RBCs are nonheme iron, oxidant stress, and in any of the unstable hemoglobin syn-
resulting from an excess of available iron throughout the body. dromes (i.e., hemoglobin Köln, hemoglobin Zurich). They may
Even though Pappenheimers and siderotic granules are the also be seen in red cell injury resulting from chemical insult.
same inclusion, they are designated differently depending on
the stain used. The inclusions are termed Pappenheimer Cabot Rings
bodies when seen in a Wright-stained smear (Fig. 5–30) and
siderotic granules when seen in Prussian blue or other kinds of The exact physiologic mechanism in Cabot ring formation
iron stain. The explanation for the difference in terminology is has yet to be elucidated. This structure may represent a part of
Figure 5-31 ■ Heinz body prep; note the appearance of Heinz

Figure 5-30 ■ Pappenheimer bodies (Wright stain).
body inclusions.
3705_Ch05_093_116.qxd 11/7/08 3:15 PM Page 110
Table 5–5 summarizes abnormal red cell morphologies and

associated disease states and RBC inclusions.
Hemoglobin CC Crystals
Hemoglobin (Hb) C crystals may be found in hemoglobin CC
disease. HbC disease is a mild chronic hemolytic anemia in
which the patient is homozygous for the abnormal hemoglobin
C.15 HbCC crystals are formed by the crystallization of the
abnormal hemoglobin into one end of the red cell membrane.
The crystal forms in a hexagonal shape with blunt ends, leaving
the remainder of the cell with the appearance of being empty.
These crystals tend to stain dark red and are said to resemble a
“bar of gold” and may be referred to as such (Fig. 5–33).
HbCC crystals may not always be demonstrated in HbC
Figure 5-32 ■ Note the appearance of a Cabot’s ring in the cell at
the arrow.
disease, but their appearance has been found to increase after
splenectomy. HbCC crystals are not seen in HbC trait (HbAC).
the mitotic spindle, remnants of microtubules, or a fragment
of the nuclear membrane. Cabot rings are found in heavily Hemoglobin SC Crystals
stippled cells and appear in a figure-of-eight conformation
similar to the beads of a necklace (Fig. 5–32). Cabot rings Hemoglobin SC (HbSC) crystals may be found on the periph-
may be found in megaloblastic anemias, dyserythropoiesis, eral smears of patients diagnosed with HbSC disease. SC dis-
homozygous thalassemia syndromes, and postsplenectomy. ease is a chronic hemolytic disorder punctuated by acute
Table 5–5 Summary of Abnormal Red Cell Morphologies and Disease States That
May Be Associated with These Abnormal Morphologies
Microcytes Sickle Cells

• Iron-deficiency anemia • Sickle cell anemia
• Thalassemias • Sickle thalassemia
• Lead poisoning
Acanthocytes
• Sideroblastic anemia
• Congenital abetalipoproteinemia
Macrocytes
• Vitamin E deficiency
• Megaloblastic anemias • Alcohol intoxication
• High reticulocyte count • Postsplenectomy
• Liver disease
Burr Cells
• Myelodysplatic syndromes
• Liver disease
Target Cells
• Renal disease
• Liver disease • Severe burns
• Hemoglobinopathies • Bleeding gastric ulcers
• Thalassemias
Helmet Cells
• Sideroblastic anemia
• G6PD deficiency
Spherocytes
• Pulmonary emboli
• Hemolytic anemias
Schistocytes
• Posttransfusion
• Hereditary spherocytosis • Disseminated intravascular coagulopathy (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
Elliptocytes
• Hemolytic uremic syndrome
• Hereditary elliptocytosis
Teardrop Cells
• Iron-deficiency anemia
• Thalassemias • Severe anemias
• Myeloproliferative disorders
Stomatocyte
• Pernicious anemia
• Acute alcoholism
• Malignancies
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 111
in order to recognize their appearance as an abnormality need-

ing further review or testing.
All four species of the malaria parasite will invade
RBCs. The species include Plasmodium vivax, Plasmodium
malaria, Plasmodium falciparum, and Plasmodium ovale and
are transmitted by the Anopheles mosquito. The parasite may
appear in different forms (i.e., ring, troph) and although it is
important to the physician for a differential diagnosis and
treatment, all reviewers are not expected to be proficient in
identification of the specific form. The primary concern is the
recognition of the abnormality as a parasite and that it is not
confused with normal morphology such as platelets superim-
posed over red cells.
Babesia microti is also an organism that invades red
cells. It is transmitted by tick bites and may appear as ring
Figure 5-33 ■ Note the hexagonal shaped crystal inclusions in a forms resembling some forms of malaria. The distinguishing
peripheral smear from a patient with HbC disease. These HbC feature of Babesia is that it also invades blood circulation and
crystals leave the remainder of the cellular cytoplasm to appear as
“empty.”
on blood smears may appear in groups outside the erythro-
cyte. Patient symptoms and travel history are also useful in
differentiating the two organisms (Fig. 5–35).
painful crisis and diverse chronic organ damage, secondary to
the presence of both HbS and HbC.15 The pathophysiology of
the disease is exacerbated by the presence of both hemoglo- Examination of Platelet Morphology
bins, as they tend to exhibit traits that are common to each The normal platelet has several distinctive morphological
such as sickling from HbS and crystallization from HbC. The characteristics. This structure measures approximately 2 to
result of this combination is the formation of crystals with fin- 4 µm, with a discoid shape and even blue granules dis-
gerlike blunt-pointed projections protruding from the cell persed throughout a light-blue cytoplasm (Fig. 5–36).
membrane. The projections have been said to resemble the In pathologic states, platelets may appear as blue or gray
Washington Monument and consequently SC crystals may be agranular discs; they may be extremely large and may show
referred to as “Washington Monument” crystals (Fig. 5–34). tailing or streaming of the cytoplasm. In rare instances,
one may see megakaryocytic fragments in the peripheral
Protozoan Inclusions circulation.
A close and thorough examination of platelet morphology
Two organisms are briefly discussed in this section because of provides important information about the patient’s hemostatic
their tendency to invade the red cells and the fact that their capability. Gross variation in platelet morphology may be seen
appearance on a peripheral blood smear is confirmation of infec- in infiltrative disease of the bone marrow (e.g., idiopathic
tion by the organism. Although only an experienced reviewer myelofibrosis or metastatic infiltrates). Large platelets may be
would be expected to differentiate these organisms, it is impor- seen in any disorder associated with increased platelet turnover,
tant that all slide reviewers have knowledge of these organisms such as may occur with idiopathic thrombocytopenic purpura
Figure 5-34 ■ Note the “fingerlike projections” in this peripheral

smear from a patient with HbSC disease. These HbSC crystals are Figure 5-35 ■ Comparison of babesiosis (left) and malarial forms
said to resemble the Washington Monument. (right).
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 112
infection, strongly suggests direct marrow architectural involve-

ment. This may indicate an infiltrative, neoplastic, or myelopro-
liferative process. Regardless of the reason for the appearance of
the immature cells, the reviewer should be able to identify the
cells accurately. Proper cellular identification at this point may
be critical to the patient’s diagnosis and subsequent prognosis.
Mature white blood cells may exhibit several morpho-
logical changes. In the performance of a slide review/WBC
differential the reviewer should take note of the appearance of
the nucleus of the white cells as well as the cytoplasm. Neu-
trophils tend to exhibit a wider variety of morphologic
changes than the other cell types with these changes originat-
ing in the cytoplasm in response to various pathologic
processes. The specific alteration may involve the appearance
or lack of cytoplasmic inclusions. Severe infections, inflam-
Figure 5-36 ■ Normal platelet at arrow. matory conditions, or other leukemoid reactions may be
accompanied by toxic granulation, toxic vacuolization, or the
presence of Dohle bodies (see Chap. 15). Toxic granulation
or bleeding disorders. In addition to the elevated platelet count, and Dohle bodies are generally considered nonspecific reac-
morphological changes may also occur postsplenectomy. tive changes, whereas vacuolization strongly indicates a
serious bacterial infection. This must also be noted with
its importance determined by the physician based on the
White Blood Cell Morphology patient’s condition.
Evaluation of white blood cells (WBCs, leukocytes) is per- Toxic granulation describes medium to large granules that
formed primarily in response to abnormalities identified by the are evenly scattered throughout the cytoplasm of segmented
automated blood cell counter. As with the evaluation of red cell polymorphonuclear neutrophil leukocytes. These granules are
morphology, the technologist must be proficient in identifica- seen in metabolically active neutrophilia and are composed of
tion of normal WBC morphology in order to adequately iden- peroxidases and acid hydrolases. Although nonspecific, they may
tify morphologic abnormalities. Figure 5–37 includes a normal occur in patients with severe bacterial infections, toxemia of
neutrophil as well as a normal lymphocyte. Slide reviewers pregnancy, or vasculitis, or in patients receiving chemotherapy.
must be able to recognize the appearance of normal cells, their Toxic vacuolization refers to the round, clear unstained
general size, their shape, and their overall appearance. They areas that are dispersed randomly throughout the cytoplasm
must also distinguish between normal granularity and the pres- of neutrophils in patients with overwhelming infections. Addi-
ence of abnormal inclusions. If immature cells are present, a tional cytoplasmic inclusions—Dohle bodies—are oval, blue,
skilled reviewer should be able to identify the cell line and the single or multiple inclusions originating in RNA, and are 1 to
stage of maturation. 3 µm in diameter. Dohle bodies may be seen in peripheral blood
The presence of immature cells is a significant finding, smears of patients with severe infections, in patients with severe
with the greater the immaturity, typically, the more severe the burns, in pregnant women, and in patients receiving chemotoxic
diagnosis. The presence of more immature forms such as drugs. In these conditions, they represent toxic changes; how-
promyelocytes or myeloblasts, in the absences of severe ever, Dohle body-like inclusions are also characteristically
observed in certain congenital qualitative WBC disorders such
as the May–Hegglin anomaly and Chédiak–Higashi disorder
(see Chap. 15).
In addition to these morphological changes, severe bacter-
ial infections are also commonly associated with a moderate
leukocytosis and a shift to the left in granulocytes. Mild infec-
tions are characterized by a slight leukocytosis, with or without
the shift to the left. “Shift to the left” implies a release of younger
granulocytes—specifically bands and metamyelocytes—from
the bone marrow storage pool. These particular cell populations
may often be observed during an infection or inflammatory
process. The degree of leukocytosis or neutrophilia is useful in
discriminating among bacterial, viral, or fungal conditions.
Leukocytosis commonly refers to an increase in peripheral blood
leukocyte (WBC) concentration of greater than 10,000 cells/µL.
Because acute infection can rapidly mobilize the neutrophilic
nondividing marrow storage pool, the patient usually has a WBC
Figure 5-37 ■ A, Normal neutrophil, B, normal lymphocyte.
count below 50,000 cells/µL (average is 25,000 cells/µL). A shift
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 113
to the left is seen in the peripheral blood smear; however, it is un-

usual to see cells as immature as myelocytes in the peripheral CBC Results Patient Results Reference Range
blood. Fungal infections may also be associated with neu-
trophilia and an increased WBC count, but a monocytosis is WBC 17.0 109/L 6.0–17.5 109/L
more commonly observed. Viral infections usually are not asso- RBC 2.4 1012/L 3.8–5.5 1012/L
Hgb 7.5 g/dL 12–14.5 g/dL
ciated with neutrophilia but rather with lymphocytosis (see Hct 22.0% 30%–43%
Chap. 15). MCV 92 fL 80–100 fL
Leukemoid reactions are characterized by a peripheral RDW 18% 11.5%–14.5%
neutrophilia that may resemble a chronic leukemia. The WBC
WBC Differential RBC Morphology
count is between 50,000 and 100,000 cells/µL, with immatu-
rity observed in one or more cell types. However, a high blast 40% Granulocytes Anisocytosis 3+
count is not part of the WBC differential picture, which can 58% Lymphocytes Poikilocytosis 3+
be helpful in eliminating leukemia as part of the differential 2% Monocytes Hypochromia 1+
Macrocytosis 1+
diagnosis. Acute infections, chronic infections such as tuber- Microcytosis 1+
culosis and chronic osteomyelitis, as well as severe metabolic Schistocytes 2+
inflammatory and neoplastic processes have all been associ- Sickled cells 1+
ated with leukemoid reactions. Extremely elevated WBC Targets 1+
counts (greater than 100,000 cells/µL) are more suggestive of Polychromasia 1+
a myeloproliferative process (see Chaps. 17 and 18), although Additional Tests Ordered
exceptions have been reported.
The reviewer should also take note of the appearance of Reticulocyte count 13%
Sickledex Positive
the nucleus, and in particular the number of segmentations. The Hgb electrophoresis Hgb SS pattern
appearance of increased segmentation (normal is three to five
lobes) may indicate a megaloblastic process. This is referred to
as hypersegmentation and is reported when neutrophils contain DISCUSSION
greater than five lobes or when significant numbers of neu- Sickle cell disease is a hereditary disease that results in a
trophils all contain at least five lobes or more. The decreased chronic moderate to severe hemolytic anemia. The disease is
segmentation should also be noted, as it may be an indication characterized by the substitution of valine from the normal
of a benign hereditary condition known as Pelger–Huet anom- glutamic acid at the sixth position in the -chain, resulting
aly or may actually be the result of a leukemic process. This in an abnormal hemoglobin that polymerizes when exposed
decreased segmentation consists of neutrophils with two lobes to low oxygen-tension conditions. This polymerization
or less and is described by the term hyposegmentation. results in the formation of sickle-shaped cells that are capa-
Physiologic leukocytosis is defined as an increased ble of temporarily or permanently blocking microcircula-
tion, and the resulting stasis may lead to hypoxia and
WBC count without a shift to the left or any associated mor-
ischemic infarcts of various organs.
phological changes previously described for granulocytes. The disease is not evident at birth and does not manifest
This transient condition may be associated with such stimuli itself until the gamma chains of the newborn are replaced by
as exercise, intense emotional stress, anesthesia, or the s-chains after 3 to 6 months of life.15 Clinical manifesta-
administration of epinephrine or glucocorticoids. tions may be divided into acute and chronic episodes. Acute
problems result from a vaso-occlusive crisis termed “sickle
cell crisis.” This “crisis” typically includes an acute
hemolytic episode as well. Patients in sickle cell crisis pre-
sent with acute pain, fatigue, and possibly jaundice. All
three of these symptoms were present in our case study, as
was evidence of some form of anemic process.
Case Study 1 Chronic manifestations of sickle cell disease usually
appear after mid-childhood.16 These include disturbances in
A 1-year-old African American child is brought to the growth and development, bone and joint disease, and organ
emergency department by her mother because the child had damage involving mostly all of the organ systems of the
no appetite and had not eaten in the last 2 days. Additional body at some point during the process of the disease.
information from the mother described a normally happy
child who had recently become restless and irritable. She QUESTIONS
was learning to walk, but now would not even attempt
standing. She has had a low-grade temp which is now ele- 1. Are the morphological findings on the blood film com-
vated to 102o F. On examination there is a definite yellow patible to the results from the analyzer?
tinge to the sclerae and the spleen is palpable. Also noted 2. Did the other tests ordered confirm a probable diagnosis?
was a spindle-shaped deformity of two fingers on the right 3. Is the reticulocytes count useful?
hand that were swollen and obviously painful to the touch. continued
The CBC results were as follows:
continued
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 114
ANSWERS instrument, for example, the RDW is elevated and this is

reflected on the smear as 3+ anisocytosis. Many more
1. (Note: manual differential and morphology review per- abnormalities are detected by reviewing the peripheral
formed due to flagging of analyzer results, Fig. 5–38.) smear. These abnormalities are typically seen in patients
Morphology results correlate with the values from the in crisis as was this child.
2. Yes. The sickledex is a screening test performed on
whole blood and is positive in both sickle cell disease
and sickle cell trait. The confirmatory test is the
hemoglobin electrophoresis, which will differentiate
abnormal hemoglobin traits from abnormal hemoglo-
bin disease. In this case the presence of the SS pattern
is diagnostic of Hgb S disease which will result in
sickle cell anemia.
3. Yes. The reticulocytes count is a valid indicator of
bone marrow performance. In cases of sickle cell
crisis, in which the nonfunctional sickle cells are be-
ing destroyed, a properly functioning marrow should
accelerate the hematopoietic process. The 13% reticu-
locytes count is indicative of a proper response by the
bone marrow to the hemolytic process the patient was
experiencing.
Figure 5-38 ■ Case study; note abnormal red cell morphology.
continued
Qu e s t i o n s
1. A prominent morphologic clue when suspecting lead 5. Morphological abnormalities found in cases of
poisoning is the presence of which of the following on a severe burns, microangiopathic hemolytic anemias,
peripheral smear? and disseminated intravascular coagulation
a. Heinz bodies (DIC) are:
b. Target cells a. Schistocytes
c. Siderotic granules b. Crenated cells
d. Basophilic stippling c. Ovalocytes
2. In which of the following disease states would you d. Stomatocytes
expect to find oval macrocytes on the peripheral smear? 6. Oat-shaped cells may be associated with:
a. Iron deficiency anemia a. Myelofibrosis
b. Lead poisoning b. Hereditary spherocytosis
c. Megaloblastic anemia c. Burns
d. Hereditary spherocytosis d. Sickle cell anemia
3. All but one of the following are possible mechanisms for 7. How would a cell be classified that has a diameter of
the production of macrocytes: 9 µm and an MCV of 104 fL?
a. Liver disease a. Macrocytic
b. Postsplenectomy status b. Microcytic
c. Pernicious anemia c. Normal
d. Thalassemia minor d. Either normal or slightly microcytic
4. An abnormal erythrocyte seen in liver disease and hemo- 8. Abnormal platelet morphology may be observed most
globinopathies and thalassemias and is characterized by prominently in:
the “bull’s eye” area is known as a: a. Idiopathic myelofibrosis
a. Stomatocyte b. Anemia of chronic disorders
b. Target cell c. Hereditary spherocytosis
c. Schistocyte d. Septic shock
d. Hypochromic cell
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 115
9. Which type of red cell inclusion is a DNA remnant? The following answer pool is used for items 15 to 29
a. Heinz body (Match)
b. Howell–Jolly body a. Anisocytosis f. Polychromasia k. Schistocytes
c. Pappenheimer body
d. Cabot ring b. Poikilocytosis g. Microspherocytes l. Rouleaux
10. Which of the following are considered microcytic/ c. Hypochromasia h. Target cells m. Acanthocytes
hypochromic anemias? d. Microcytic i. Stomatocytes n. Dacrocytes
a. Autoimmune hemolytic anemia e. Depranocyte j. Blister cells o. Echinocytes
b. Pernicious anemia
c. Iron deficiency anemia _____15. RBCs with a large area of central pallor
d. Megaloblastic anemia _____16. Variation in the size of the red blood cells
11. A hypersegmented neutrophil may be seen in which of _____17. Also known as codacytes
the following anemias? _____18. RBCs appearing stacked on each other
a. Iron deficiency
b. Megaloblastic _____19. MCV of 65%
c. Autoimmune hemolytic anemia _____20. RBCs with a mouthlike central pallor
d. Anemia of chronic disorders _____21. RBCs without an area of central pallor
12. Precipitates of denatured hemoglobin found primarily in _____22. RBCs with evenly distributed spicules on the
patients with hemolytic anemia resulting from oxidant membrane
stress describe:
a. Howell–Jolly bodies _____23. RBC fragments
b. Heinz bodies _____24. RBCs appearing bluish in color
c. Basophilic stippling _____25. Variation in the shape of the RBCs
d. Pappenheimer bodies
_____26. Congenital abetalipoproteinemia
13. Pappenheimer inclusions are formed from:
a. Excess -chains _____27. The formation of a vacuole in an RBC “trapped”
b. Excess -chains by fibrin
c. Excess iron _____28. Formed when an RBC with an inclusion squeezes
d. Oxidant stress out of a tight space
14. RBC inclusions resulting from an acceleration in hemo- _____29. Seen in HbS disease
globin biosynthesis and consists of RNA:
a. Howell–Jolly bodies See answers at the back of this book.
b. Heinz bodies
c. Basophilic stippling
d. Pappenheimer bodies
■ Macrocytes are associated with high reticulocyte counts

SUMMARY CHART and liver disease; oval macrocytes are associated with
megaloblastic processes.
■ A variation in cell size is termed anisocytosis.
■ Red cells that appear polychromatophilic on a Wright’s
■ A variation in cell shape is termed poikilocytosis. stained smear would appear as reticulocytes on a suprav-
■ On an automated cell counter, a flag is a signal that a sig- ital stain.
nificant abnormality may be present in the sample. ■ Spherocytes are associated with hereditary spherocytosis
■ Microcytes are associated with an MCV of less than 80 fL and an MCHC that is greater than 36% in many cases.
and are seen in IDA, thalassemias, sideroblastic anemias, ■ Spherocytes may also be seen in autoimmune hemolytic
and anemia of chronic disease. anemia (AIHA) and posttransfusion.
■ Macrocytes are associated with an MCV of more than ■ There are two types of sickle cells, irreversible sickle cells
100 fL and are seen in megaloblastic and nonmegaloblas- (ISCs) and oat-shaped, reversible sickle cells that are both
tic processes. commonly seen in HbS disease.
(continued)
3705_Ch05_093_116.qxd 11/7/08 3:16 PM Page 116
■ Helmet cells are seen in patients with G6PD syndrome

SUMMARY CHART—cont’d and occur as a result of Heinz body formation.
■ Any regenerative red cell process will result in inclusions ■ Heinz bodies cannot be seen on a Wright-stained periph-
such as Howell–Jolly bodies, basophilic stippling, and eral smear.
Pappenheimer bodies. ■ Abnormal platelet morphology includes lack of granula-
■ Howell–Jolly bodies, Pappenheimer bodies, and basophilic tion, giant platelets, and megakaryocytic fragments.
stippling may be seen in peripheral smears stained ■ Abnormal white cell morphology includes the presence or
with both Romanowsky type stain (i.e., Wright’s, absence of cytoplasmic granulation, or presence of cyto-
May–Grumwald) and supravital stain (i.e., new methylene plasmic vacuolizaton, as well the appearance of the cellu-
blue, brilliant cresyl blue) lar nucleus.
■ Siderotic granules and Pappenheimer bodies are basically ■ Hyposegmentation describes decreased neutrophil seg-
the same inclusion. The differentiating factor is that on an mentation (≤2 lobes).
iron stain the inclusions are known as siderotic granules ■ Hypersegmentation describes increased neutrophil seg-
where on Wright’s stain they are known as Pappenheimer mentation (≥5 lobes).
bodies.
■ Howell–Jolly bodies are seen in patients postsplenectomy.
REFERENCES 7. Orkin, SH, and Nathan, DG: The tha- Approach. Williams & Wilkins, Balti-
lassemias. In Nathan and Oski’s Hema- more, 1996, p 77.
1. Bain, B: Current concepts: Diagnosis tology of Infancy and Childhood, ed 5. 13. Womack, EP: Treating thrombotic
from the blood smear. N Engl J Med WB Saunders, Philadelphia,1998, p 818. thrombocytopenic purpura with plasma
353(5):498, 2005. 8. Bolton-Maggs, P, et al: Guidelines for exchange. Lab Med 30:276, 1999.
2. Stiene-Martin, E, et al: Clinical Hematol- the diagnosis and management of heredi- 14. Storch, A, et al: Testing for acanthocyto-
ogy Principles, Procedures, Correlations. tary spherocytosis. Br J Haematol sis. J Neuro l252(1):84, 2005.
ed. 2. Lippincott-Raven, Philadelphia, 126:455, 2004. 15. Lawrence, C, et al: The unique red cell
1998. 9. Gallager, P: Red cell membrane disor- heterogeneity of SC disease: Crystal for-
3. Shojana, AM: Protein synthesis in mega- ders. ASH Education Book, 2005, cited mation, dense reticulocytes, and unusual
loblastic disorders. In Gross, S, and from, http://www.asheducationbook.org/ morphology. Blood 78(8):2104, 1991.
Roath, S (Eds): Hematology: A Problem cgi/content/full/2005/1/13. pp 1–11. 16. Kaplan, L, et al: Clinical Chemistry The-
Oriented Approach. Williams & Wilkins, 10. Chen, J, and Huestis, W: Role of mem- ory, Analysis, Correlation, ed 2. Mosby,
Baltimore, 1996, p 27. brane lipid distribution in chlorpromazine- St. Louis, 2003, p 686.
4. Glassey, E (Ed): Color Atlas of Hematol- induced shape change of human erythro-
ogy. College of American Pathologists, cytes. Biochim Biophys Acta Biomembr See Bibliography at the back of this book
Hematology and Clinical Microscopy 1323(2):299, 1997.
Resource Committee, Northfield, IL, 11. Mohandas, N: A cell by any other name.
1998, p 86. Blood 106(13):4017, 2005.
5. Davenport, J: Macrocytic anemia. Am 12. Camilo, N, and Ravindranath, Y: Hemo-
Fam Physician 53(1):155(8), 1996. globinopathies: Abnormal structure in
6. Provan, D, and Weatherall, D: Red cells hematology. In Gross, S, and Roath, S
II: Acquired anaemias and poly- (Eds): Hematology: A Problem Oriented
cythaemia. Lancet 355:1260, 2000.

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3705_Ch05_093_116.

qxd 11/7/08 3:15 PM Page 93

Acanthocytes (Thorn Cells,

Introduction From the educational perspective, it is essential that stu-

Table 5–1 Estimation of Total WBC

begin this section with a description of normal red blood cell

RED BLOOD CELL MORPHOLOGY

Microcyte Spherocyte Helmet cell Cabot’s ring

Macrocyte Ovalocyte Schistocyte Basophilic stippling Rouleaux

Oval macrocyte Stomatocyte Tear drop Howell-Jolly

Figure 5-3 ■ Normal and abnormal red blood cell morphology.

rouleaux. This is considered artifactual and should not be

Macrocytes A microcyte is a small cell having a diameter of less than 7 µm

Megaloblastic High Liver Post- Chemotherapy Hypothyroidism

anemia known as thalassemia. This microcytic/hypochromic

Iron Thalassemic Sideroblastic Anemia of Lead

however, the reticulum cannot be visualized without supravi-

Table 5–4 Polychromasia Grading

Percentage of Red Cells that are Polychromatophilic

MORPHOLOGY - TARGET CELLS

Hemoglobin C disease Post- Liver Iron deficiency Any hemoglobin

Immune Hereditary Post-

Figure 5-13 ■ Note the spherocyte at arrow in a blood smear from

Figure 5-15 ■ Stomatocytes in peripheral blood.

Figure 5-17 ■ Note the oval macrocyte (microovalocyte) at the

Egg shape Pencil shape

Myelodysplastic Thalassemic Megaloblastic Iron Hereditary Idiopathic

Figure 5-18 ■ Correlation of ovalo-

MORPHOLOGY - SICKLE CELLS

Sickle cell Hemoglobin C

Figure 5-23 ■ Note the bite cell at the arrow.

MORPHOLOGY - FRAGMENTED CELLS

Prosthetic Microangiopathic Clostridial

Renal Liver Burns DIC TTP HUS G6PD Pulmonary

Teardrop Cells (Dacrocytes)

Alcohol intoxication Pyruvate Congenital Vitamin E Post-

Figure 5-26 ■ Correlation of acanthocytes to pathologic processes.

that Romanowsky stains visualize Pappenheimer bodies by

Figure 5-31 ■ Heinz body prep; note the appearance of Heinz

Table 5–5 summarizes abnormal red cell morphologies and

Microcytes Sickle Cells

in order to recognize their appearance as an abnormality need-

Figure 5-34 ■ Note the “fingerlike projections” in this peripheral

infection, strongly suggests direct marrow architectural involve-

to the left is seen in the peripheral blood smear; however, it is un-

ANSWERS instrument, for example, the RDW is elevated and this is

■ Macrocytes are associated with high reticulocyte counts

■ Helmet cells are seen in patients with G6PD syndrome

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