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Red Cell Disorders: Peripheral Blood Clues to Nonneoplastic Conditions

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Introduction to Red Blood Cell Morphology: Normal Red Blood Cell Morphology
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Normal Red Blood Cell (RBC) Morphology
In order to properly understand and identify the abnormal red blood cell morphologies associated with RBC disorders, the laboratorian must first
become competent in normal RBC characteristics.
Normally, RBCs will display a defined morphology in the peripheral blood. Mature RBCs, under normal circumstances, are round, biconcave
disc-shaped, anuclear cells measuring approximately 7-8 microns in diameter with an internal volume of 80-100 fL. The term used to express
RBCs of normal size is normocytic. Mature red blood cells, under normal circumstances, will also have an appropriate hemoglobin content (a
normal MCH and MCHC), giving them a red-orange appearance on Wright-stained smears. These cells will display a central pallor (lighter area
inside of the cell) no larger than 3 microns in diameter. This normal morphology is indicated by the term normochromic. It is paramount for
RBCs to contain an adequate amount of hemoglobin for the purpose of transporting oxygen to the tissues and carbon dioxide back to the lungs.
An example of a normocytic, normochromic peripheral blood picture is shown on the right.
In addition, the RBC membrane plays a key role in allowing the deformability of the cell to take place in order to travel through smaller vessels.
Normally functioning RBCs survive for approximately 120 days in the peripheral blood circulation before being removed by the liver or spleen.
Under normal circumstances, the body produces enough RBCs each day to account for the senescent (old) cells that are removed.
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Evaluating Initial Red Blood Cell (RBC) Morphology
Evaluating RBC morphology can occur via automated blood cell counters and through visual, microscopic examination of peripheral blood
smears. Typically, after a sample has been analyzed for a complete blood count (CBC), various parameters will be visible to the laboratorian to
evaluate the RBCs. These primarily include the RBC count and red blood cell indices. The important RBC indices used to classify the population
of RBCs present are:
MCV (Mean Corpuscular Volume)

MCH (Mean Corpuscular Hemoglobin)
MCHC (Mean Corpuscular Hemoglobin Concentration)
These parameters will simply evaluate the overall size of the RBC population, along with the hemoglobin concentration of the red blood cells.
When abnormalities are noted within the RBC indices, further evaluation may be necessary to confirm RBC morphology.
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Criteria for Peripheral Blood Smear Review
When an Initial analysis of red blood cells (RBCs) from an automated instrument are found to be abnormal, many laboratories will
microscopically evaluate the peripheral blood morphology of the RBCs. This important step can help to establish which, if any, abnormalities
are present as well as correlate possible disease states or conditions associated with the findings.
Most laboratories will employ guidelines for review of the peripheral blood smear for RBC morphology. Though each laboratory will create
their own guidelines, the following are a few examples that could trigger a manual, microscopic peripheral blood smear review:
Hemoglobin: < 8 or >18 g/dL (<10 or > 21g/dL in a newborn)

Hematocrit: <20% or > 60% in adults (<40% or >65% in a newborn)
MCHC: <29 g/dL
MCV: <69 femtoliters (fl) or >110fl
Flags generated by the hematology analyzer that indicate possible red cell abnormalities or spurious results
In most laboratories, when these findings are noted, they should be followed up with a peripheral blood smear review for RBC morphology.
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Introduction to Red Blood Cell Morphology Reporting
After an automated complete blood count (CBC) analysis has determined that abnormal RBC morphology may be present, a well-made and
well-stained peripheral blood smear should be prepared. When a peripheral blood smear is made for the purpose of evaluating RBC morphology,
accurate recognition and identification of RBC morphologic abnormalities can be an invaluable aid in the diagnosis of a variety of disorders.
It is important to understand that red blood cell morphology report formats tend to vary widely among laboratories. Despite the standardization
of many laboratory technologies and test result formats, there are still various protocols in use in the area of red cell morphology reporting.
Current methods of reporting and quantifying red cell morphology include descriptive terms such as 'rare,' 'occasional,' 'many,' 'slight,' or
'moderate,' as well as numerical gradings of 1+, 2+, 3+, etc.
Regardless of the terminology used, consistency is of greater importance. There must be a defined, semi-quantitative scheme that dictates how
many cells with a specific morphologic abnormality qualify as "rare" or "many," and so on. The report format must be clear and useful to the
physician. Some morphologic abnormalities are quite specific and diagnostic, but others are ambiguous and of little diagnostic significance.
A well-defined, semi-quantitative report format for RBC morphology should be based on clinical significance. Some morphologic abnormalities
are significant, even when they occur in very low numbers. These include:
Schistocytes
Sickle cells
Acanthocytes
Spherocytes
Teardrop cells
Polychromatophilic cells
Other morphologic abnormalities are significant only when seen in considerable numbers. These include:
Macrocytes
Microcytes
Ovalocytes
Burr cells (echinocytes)
Target cells
Stomatocytes
Hypochromic cells
A final category includes morphologic abnormalities that do not need to be quantified as it serves no purpose; these findings can be noted as
"present." These include
RBC agglutination
Rouleaux
Dimorphic or double red cell population
An example of a standardized reporting format is given on the following pagGuidelines for Reporting Red Blood Cell Morphology
RBC Morphology Reporting Per High Power

Cell Type Field (400x)
Few Moderate Many
Acanthocytes (spur cells)
>
2.5%
Fragmented red cells (schistocytes, helmet cells, keratocytes/horn cells) 1-2.5% of of the
Polychromatophilic cells Up to 1% of the field the field field
Sickle cells (drepanocytes)
or or
Spherocytes or
1-2 cells per field 3-5 cells >5
per field
Teardrop cells (dacrocytes) cells
per
field
. Few Moderate Many
Echinocytes (burr cells) >
Hypochromic cells 25 - 50% 50%
Macrocytes of the of the
Microcytes
5-25% of the field field field
Ovalocytes (elliptocytes)
Stomatocytes or or or
10-50 cells per field 51-100 > 100

Target cells (codocytes) cells per cells
field per
field
. . . .
Double Cell Population
RBC Agglutination Report if present
Rouleaux
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Ungraded Practice Question
This oil immersion field (1000x) is representative of the peripheral blood smear. Which report is the most appropriate for documentation of the
finding of teardrop cells using the Guidelines for Standard Reports that were described on the previous pages and included as a PDF in this
question?
You answered the question incorrectly.
The correct answer is highlighted below
Few teardrop cells

Moderate teardrop cells
Many teardrop cells
Teardrop cells present
Feedback
There are six teardrop cells in this representative oil immersion field, which would fit the criteria of >5/HPF (400x magnification). According to
the guidelines that are given, they should be reported as "many."
Teardrop cells are morphologic abnormalities that are significant, even when they occur in very low numbers
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Red Cell Morphology Reference Tables
In the next few slides, red blood cell morphology reference tables will be available for your review. These summary tables include images with
descriptors and disease state associations. The information found in these tables may be of assistance in the case study sections of this course.
PDF copies of the pages are also included as printable resources
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Anisocytosis Reference Table

Cell Type Image Cellular Description Associated Diseases and Conditions
Normocyte MCV 80-100 fL (approximately the same size N/A; cell is normal
as the nucleus of a small lymphocyte)
MCHC 32-36 g/dL or 32%-36%
Microcyte Red blood cells are smaller than normal Iron deficiency anemia
MCV < 80 fL Sideroblastic anemia
Certain thalassemias
Lead poisoning
Certain hemoglobinopathies
Macrocyte Red blood cells are larger than normal Megaloblastic Anemia (Vitamin
MCV > 100 fL B12/Folate deficiency)
Myelodysplasia
Liver disease
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Hemoglobin Content Reference Table
Cell Type Image Cellular Description Associated Diseases and

Conditions
Normochromic Small and distinct central pallor Normal
Normal MCH and MCHC
Hypochromic Red blood cells (RBCs) have a larger than normal Iron deficiency anemia
central pallor (>3 in diameter) due to low Thalassemias
hemoglobin content Sideroblastic anemia
MCHC <32 g/dL or 32% Lead poisoning
Some cases of chronic
inflammation
Polychromatophilic Little or no central pallor
Reddish-blue in color
Slightly larger than normal RBCs
Supravital staining identifies these cells as
reticulocytes
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Poikilocytosis Review Table

Teardrop cell Red blood cells (RBCs) are shaped like a Myelofibrosis with myeloid
teardrop with a projection extending metaplasia (MMM)
from one end.
Spherocyte RBCs smaller than normal Hereditary spherocytosis

No central pallor Certain hemolytic anemias
Round rather than disc-shaped Severe burns
Target cell RBCs with characteristic bull's-eye Hemoglobinopathies (e.g., sickle cell
morphology due to hemoglobin disease)
distribution. Certain thalassemias
Iron deficiency anemia
Splenectomy
Severe liver disease
Sickle cell RBCs contain hemoglobin S. Sickle cell anemia
Thorn or crescent-shaped
Stomatocyte RBCs with thin, elongated area of central Hereditary stomatocytosis

pallor (slit-like, or coffee-bean-shaped on Alcohol-related disease
peripheral blood smears). Liver disease
Three-dimensionally, RBCs are cup- Rh null phenotype
shaped. Artifact
Schistocyte RBC blood cell fragments or pieces Severe burns

(fragmented red Vary widely in size and shape Hemolytic uremic syndrome (HUS)
cells) Microangiopathic hemolytic anemia
(MAHA)
Disseminated intravascular
coagulation (DIC)
Thrombotic thrombocytopenic
purpura (TTP)
Ovalocyte RBCs are elongated-oval, cigar, or Hereditary elliptocytosis
(elliptocyte) pencil-shaped Megaloblastic anemia
Myelophthisic anemia
Certain thalassemias
Severe iron deficiency
Acanthocyte RBCs demonstrating irregularly-spaced, Abetalipoproteinemia

(Spur cell) spiny projections that vary in size and Severe hepatic disease
number Myeloproliferative disorders
No central pallor MAHA
Neuroacanthocytosis
. syndromes
Echinocyte (Burr RBCs have short and evenly-spaced, Uremia

cell) rounded projections surrounding the cell Heart disease
Central pallor present Pyruvate kinase deficiency
Stomach cancers
Bleeding peptic ulcers
Bite cell Red cells that appear to have bites taken Disorders associated with Heinz body
out of them (Image A) formation:
Supravital stain reveals the presence of
Heinz bodies--precipitated denatured Unstable hemoglobins
masses of hemoglobin (Image B) Chemical poisoning
G-6PD
Hemolytic anemia associated with
severe alcoholic liver disease
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Rouleaux and Agglutination

Rouleaux Red blood cells (RBCs) appear as Conditions associated with increased
"stacked coins." concentrations of globulins and/or fibrinogen
Cells overlap each other Hyperparaproteinemias
Stacked-coin morphology is noted Waldenstrom's ,macroglobulinemia
throughout the peripheral blood Multiple myeloma
smear Chronic inflammatory disorders
Agglutination Clusters of RBCs due to Cold agglutinins (most often IgM antibodies)
antigen/antibody reactions in vivio Paroxysmal cold hemoglobinuria
Cannot distinguish the outlines of
individual RBCs
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Dimorphic (Double Cell) Population

Dimorphic is a term used to describe two circulating red cell populations. One is the patient's basic red cell population while the other is a
second population with distinct morphological features. The distinct populations can be observed in the top image on the right. The bottom
image on the right illustrates the two distinct peaks that are observed on the RBC histogram from the automated hematology analyzer.
Dimorphic red blood cell populations can be found in conditions/situations such as: red blood cell transfusions, myelodysplasia, refractory
anemia with ringed sideroblasts, hemolytic processes involving a reticulocyte response, and when patients are given erythropoietin therapy.
It is important to recognize when a population of cells in the peripheral smear is not in context with anticipated laboratory findings and the
clinicalIntroduction to Red Blood Cell Nonneoplastic Conditions Case Studies
Now that you have reviewed the red blood cell morphology tables, we will incorporate disease state correlations with the help of case studies and
questions with answers. The following case studies and questions will be presented in groups of related morphologic findings on the peripheral
blood smear. The case studies and questions will contain multiple choice and true/false questions for you to answer. There will be helpful
information regarding the morphologies noted and disease states present displayed in the feedback sections for each question- so be sure to
review the explanations after answering the questions. Enjoy!
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A 12-year-old child presents with jaundice and scleral icterus. The image to the right captures a representative section of the peripheral blood
smear. Which of the following are significant findings that should be included on the report?
That's partially correct.
The correct answers are highlighted below
Burr cells
Ovalocytes
Spherocytes
Feedback
The intended responses are spherocytes (microcytes without central pallor), indicated by the blue arrows and polychromatophilic cells (blue-gray
staining cells), indicated by the red arrows. Polychromatophilic cells are immature erythrocytes (reticulocytes) released from the bone marrow
early. The bone marrow rapidly releases young red blood cells in response to severe hemolysis. These young red blood cells (polychromatophilic
cells or reticulocytes) enter the circulation before completing their normal 24-hour maturation cycle.
In addition, there are a few burr cells present as well as an ovaloctye, but these are not significant findings according to most reporting systems.
However, the spherocytes and polychromatophilic cells should be reported, as they are significant, even in small numbersUngraded Practice
Question
A known case of hemolytic disease of the newborn (HDN) is presented in the image on the right. Many different cellular morophologies are
present. Apart from the obvious anisocytosis (microcytes and macrocytes), which additional red blood cell morphologies are worth reporting?

Nucleated red blood cells
Spherocytes
Schistocytes
Howell-Jolly bodies
Target cells
Feedback
Notice the size variation (anisocytosis) of the erythrocytes on the infant's peripheral smear. There are normal-sized red blood cells, microcytes,
spherocytes, macrocytes, and nucleated red blood cells present on this smear. Red cell variations are expected findings in healthy neonates, but
the variations here are exaggerated. There are spherocytes, Howell-Jolly bodies, nucleated red blood cells, and polychromatophilic cells present
in this image. A high (3-7%) reticulocyte count is not unusual during the first three or four days after birth, however, the bone marrow in this
infant is proliferating vigorously in response to the ongoing hemolysis associated with this condition
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A 49-year-old male with pneumonia was treated with high-dose intravenous penicillin. He became jaundiced with yellow sclera. The image on
the right is typical of other fields that were observed on his peripheral blood smear.
Since penicillin may, in some individuals, cause autoimmune hemolytic anemia, the clinician requested a direct antiglobulin test (DAT) be
performed. The DAT was positive, indicating that antibodies to the drug were produced, which then attached to the drug on the surface of the red
cells. Hemolysis occured due to the drug-induced antibody attachment, leaving the patient with various abnormal red blood cell morphologies.
Which of the following cell types would you report for this patient?
Acanthocytes
Target cells
Spherocytes
Feedback
In this case, the peripheral blood smear shown should have an associated report that includes: spherocytes, polychromatophilic cells, and
nucleated red blood cells. This peripheral blood picture is common in patients with drug-induced hemolysis
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The complete blood count was obtained from a patient recently admitted to the emergency room. The red blood cell indices obtained revealed an
MCV of 115 femtoliters (fL) (normal range 80 - 90 fL). The patient met the criteria for a peripheral blood smear examination. A representative
field is shown on the right.
Which of the following conditions may be indicated by the results seen on this peripheral blood smear?

Hemolytic anemia
Myelodysplasia
Iron deficiency
Liver disease
Feedback
Hemolytic anemia, myelodysplasia, and liver disease may each fit this peripheral blood picture. Each of these conditions is associated with a
peripheral blood macrocytosis. It is easy to observe the overall larger size of the red blood cells in this image compared to the normal
lymphocyte also present.
When macrocytes are present, they should be examined for their shape (round vs. oval), the hemoglobin content (central pallor), and whether or
not there are any inclusions present in the cell.
Iron deficiency would not be the correct answer in this case, since this condition is associated with microcytosis instead
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Conditions suggested by the macrocytes and the neutrophil in the photograph to the right include which of the following?
Thalassemia
Vitamin B12 deficiency
Pelger-Huet anomaly
Folate deficiency
Feedback
The intended response is Vitamin B12 and folate deficiencies. Each of these conditions lead to a megaloblastic production of the red blood cells
in the bone marrow. Since vitamin B12 and folate are needed in order to produce a synchronous development of the nucleus with the cytoplasm
in hematologic cells, oval-macrocytosis often occurs if these nutrients are not in adequate supply within the body. This can also affect
neutrophils, allowing for the characteristic hypersegmented nucleus.
The photographic field contains several oval-macrocytes and a hypersegmented neutrophil with greater than 5 nuclear segments. Oval
macrocytes are most commonly associated with pernicious anemia and malabsorption syndromes leading to vitamin B12 and folic acid
deficiencies.
Clinical information relating to chronic infection, aplastic anemia, and other hematologic maligancies provide the context for the presence of the
oval macrocyte.
Macrocytic erythrocytes and hypersegmented neutrophils are not present in thalassemias or in Pelger-Huet anomaly (hyposegmented
neutrophils)
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The RBC inclusions shown in the photograph represent which of the following?
Howell-Jolly bodies
Artifact
Pappenheimer bodies
Precipitated RNA
Feedback
The correct response is Howell-Jolly bodies. These intra-erythrocyte inclusions represent DNA nuclear fragments which are composed of
chromosome-material separated from their mitotic spindles.
Howell-Jolly bodies are usually single, round, and tend to be positioned at the periphery of the red blood cell. These inclusions are rarely found
on a routine peripheral blood smear, as they are usually removed by a functioning spleen. Howell-Jolly bodies appear after splenectomy, in
hereditary asplenia, and in splenic dysfunction as splenic fibrosis.
The blood smear represented by the photograph was from a twenty-five-year-old man with disseminated lymphoma whose spleen was removed
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The peripheral blood smear represented by the image on the right was submitted for hematologic review. The identification of the RBC
inclusions shown are most likely identified as:

Malarial pigment
Pappenheimer bodies
Howell-Jolly bodies
Basophilic stippling
Feedback
The intended response is basophilic stippling. Basophilic stippling represents particulate remains of an abnormal hemoglobin formed by
defective heme synthesis. These particles are diffusely scattered and stained blue (see erythrocyte at tip of blue arrow), representing precipitates
of ribosomes and polyribosomes (RNA). They are released in anemic conditions by the red cell proliferative response. A courser stippling may
be present in thalassemia and lead poisoning.
Malarial pigment is yellow-staining and found in phagocytes, not red blood cells. Pappenheimer bodies are much smaller and tend to group in
pairs at the cell periphery; Howell-Jolly bodies usually occur singly at the cytoplasmic periphery in hemolytic anemia, but multiple Howell-Jolly
bodies may be observed in cases of megaloblastic anemias
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By utilizing a Prussian Blue stain, which of the following red blood cell inclusions would be identifiable if present?
Note: Upper image = Wright-Giemsa stain
Lower image = Prussian Blue stain
Cabot rings
Pappenheimer (siderotic) bodies
Howell Jolly bodies
Malarial parasites
Feedback
Pappenheimer bodies (when found with Wright-Giemsa stain), also known as siderotic granules (when found with Prussian Blue stain), are iron-
containing granules that aggregate with mitochondria and are deposited in RBC or normoblast cytoplasm. These inclusions are small and
irregular and are found only in pathological states as thalassemia and sideroblastic anemias(upper image).
Wright-Giemsa stain defines the cytoplasmic content (protein) of the Pappenheimer bodies, but Prussian blue staining is necessary to define the
iron content, the essence of the siderotic granules (lower image).
Pappenheimer bodies lie typically in small clusters (upper image) and tend to locate at the periphery of the red cell cytoplasm. A cluster is
typically smaller than a single Howell-Jolly body.
When iron granules are found surrounding the nucleus of red blood cell precursors in the bone marrow, it is termed ringed sideroblasts. The
excess of iron surrounding the nucleus is due to the inappropriate incorporation of iron into the developing cell. This phenomenon is highly
associated with sideroblastic anemia.
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A ten-year-old boy came to a physician's attention because of recent jaundice and icteric sclerae after taking the medication Primaquine before a
trip to Africa. The immediate laboratory work revealed: Hct 24%(normal 36%-47%), MCV 79.5 fl (normal 78-95fl),RDW 13%(normal 11.5-
15.0%).
His blood smear findings are reflected in the images to the right. The upper image is a Wright-Giemsa stained smear while the lower is a
supravital-stained smear. Which condition should be considered for this patient when analyzing his symptoms, history, and laboratory results?
G6PD deficiency
Pyruvate kinase deficiency
Megaloblastic anemia
Feedback
Note particularly the spherocytes in the upper image to the right. Some resemble a half-blister with the other half of the cell containing solidly-
staining hemoglobin. These are called eccentrocytes. When present, along with a suspicious patient history, they should trigger an evaluation for
G6PD deficiency.
Upper image: The blue arrows in the upper photomicrograph are directed toward solid-staining spherocytes in which the cell membrane is
beaded by inclusions wrapped within the cell membrane, suggesting the remains of denatured hemoglobin. Included on the smear is a target cell,
several acanthocytes, a smudge cell, and a few schistocytes.
Lower image: This is a supravital staining of the affected red blood cells, confirming the presence of Heinz bodies, a key diagnostic feature of
this condition.
Pyruvate kinase deficiency is associated with a normocytic, normochromic anemia with poikilocytosis and anisocytosis, but Heinz bodies are not
found in this condition. Iron deficiency anemia is assoicated with a microcytic, hypochromic anemia and is not associated with the presence of
Heinz bodies. Finally, megaloblastic anemia is considered a macrocytic, normochromic anemia associated with abnormal red blood cell
development. This condition is also not associated with the presence of Heinze body inclusions
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A blood smear represented by the photograph was submitted for hematologic review. Based on the erythrocyte morphology and the
accompanying histogram, which of the following choices is the most likely situation or condition?
Normal smear
Congenital spherocytosis
Dimorphic red cell population
Feedback
Dimorphic is a term used to describe two circulating red cell populations. One is the patient's basic red cell population while the other is a
second population with distinct morphological features. Note the normal lymphocyte for size comparison with the two populations of red blood
cells. In addition, the graphic illustration demonstrates two peaks in the red blood cell histogram.
Dimorphic red blood cell populations can be found in conditions/situations such as: red blood cell transfusions, myelodysplasia, refractory
anemia with ringed sideroblasts, hemolytic processes involving a reticulocyte response, and when patients are given erythropoietin therapy.
It is important to recognize when a population of cells in the peripheral smear is not in context with anticipated laboratory findings and the
clinical situation. Hemoglobin E (Hb E) and HbE/Beta Thalassemia
Homozygous Hb E is common in Southeast Asia and presents with very mild anemia and seldom requires transfusion. Over 30 million people in
the world are HbE carriers, making this abnormal hemoglobin almost as common as HbS. Hb E is uncommon in North America and in Europe,
but with changing immigration patterns, Hb E and related diseases cannot be ignored. Peripheral blood smear findings of target cells,
microspherocytes, red cell hypochromia, red blood cell fragments, and nucleated red blood cells may be noted. Evidence from hemoglobin
electrophoresis is required to establish a diagnosis.
Clinically, a very important and severe disease is Hb E/beta thalassemia in which there is hemolysis requiring repeated transfusions. Severe
anemia, low MCV, and elevated RBC are characteristic of Hb E/beta thalassemi
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Case Study
The image on the right is representative of the peripheral blood smear from a five-month-old immigrant from Asia. Her mother was concerned
that the child was not eating well. Her spleen was palpable.
These blood count results were reported:
Parameter Patient Result Reference Interval

RBC 5.5 x 1012/L 3.1 - 4.5 x 1012/L
Hgb 9.6 g/dL 9.5 - 13.5 g/dL
HCT 30.4% 29- 41%
MCV 55.4 fl 74 - 108 fl
MCH 17.5 pg 25 - 35 pg
MCHC 31.6 g/dL 30 - 36 g/dL
RDW 34.9% 11 - 15%
Reticulocyte 10.9% 0.5 - 4.0%
Knowing that the family is from a region of Thailand where HbE carriers are prevalent, the physician ordered a hemoglobin electrophoresis. The
hemoglobin electrophoresis detected HbE.
Based on the blood count results and this representative microscopic field, which of the following peripheral blood findings should be reported?
Microcytes (microspherocytes)
Macrocytes
Sickle cells
Target cells
Parasitic inclusions
Feedback
Peripheral blood smear findings of microcytes or microspherocytes, target cells, and nucleated red blood cells should be reported. Macrocytes
are not present. The MCV result correlates with a finding of microcytes. A few red blood cell fragments may be seen, but sickle cells are not
present. The inclusion that is noted in this field is a cell nucleus in a nucleated red blood cell and not a blood parasite.
Homozygous hemoglobin E is common in Southeast Asia and presents with very mild anemia and seldom requires transfusion. Over 30 million
people in the world are HbE carriers, making this abnormal hemoglobin almost as common as HbS. Hemoglobin E is uncommon in North
America and in Europe, but with changing immigration patterns, Hb E cannot be ignored.
Clinically, a very important and severe syndrome is hemoglobin E/beta thalassemia in which there is hemolysis requiring repeated transfusions. The patient has a severe
anemia, low MCV, and high RBC. This is characteristic of Hgb E/beta thalassemia
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Case Study

RBC 5.5 x 1012/L 3.1 - 4.5 x 1012/L
Hgb 9.6 g/dL 9.5 - 13.5 g/dL
HCT 30.4% 29- 41%
MCV 55.4 fl 74 - 108 fl
MCH 17.5 pg 25 - 35 pg
MCHC 31.6 g/dL 30 - 36 g/dL
RDW 34.9% 11 - 15%
Macrocytes
Sickle cells
Target cells
Feedback
anemia, low MCV, and high RBC. This is characteristic of Hgb E/beta thalassemiaHemoglobin E (Hb E) and HbE/Beta Thalassemia
Homozygous Hb E is common in Southeast Asia and presents with very mild anemia and seldom requires transfusion. Over 30 million people in
the world are HbE carriers, making this abnormal hemoglobin almost as common as HbS. Hb E is uncommon in North America and in Europe,
but with changing immigration patterns, Hb E and related diseases cannot be ignored. Peripheral blood smear findings of target cells,
microspherocytes, red cell hypochromia, red blood cell fragments, and nucleated red blood cells may be noted. Evidence from hemoglobin
electrophoresis is required to establish a diagnosis.
Clinically, a very important and severe disease is Hb E/beta thalassemia in which there is hemolysis requiring repeated transfusions. Severe
anemia, low MCV, and elevated RBC are characteristic of Hb E/beta thalassemia.
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Case Study

RBC 5.5 x 1012/L 3.1 - 4.5 x 1012/L
Hgb 9.6 g/dL 9.5 - 13.5 g/dL
HCT 30.4% 29- 41%
MCV 55.4 fl 74 - 108 fl
MCH 17.5 pg 25 - 35 pg
MCHC 31.6 g/dL 30 - 36 g/dL
RDW 34.9% 11 - 15%
Macrocytes
Sickle cells
Target cells
Feedback
anemia, low MCV, and high RBC. This is characteristic of Hgb E/beta thalassemia
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A peripheral smear with red blood cells photographed in a typical field was submitted for review. Which of the following conditions might be
eliminated because of the red blood cell population found here?
You answered the question correctly.
Severe liver disease

Hemoglobinopathy
Beta thalassemia
None of the above
Feedback
Target cells have a central area of hemoglobin surrounded by an area of pallor and a band of hemoglobin at the periphery of the cell. Their
presence in disease is diverse, including all of the above conditions as well as post-splenectomy, other thalassemias, and occasionally in iron
deficiency anemia.
In target cells, the surface area to volume ratio of the cell is increased. In a sense, target cells may be viewed in morphological contrast to
spherocytes whose hemoglobin content fits tightly within the cellular membrane. Target cells may be macrocytic or normocytic.
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Case Studies in Red Blood Cell Nonneoplastic Conditions: Target cells and Sickle CellsContents
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A CBC performed on a 10-year-old African-American male who was brought to the emergency department with rapid, shallow breathing and
fever provided the following results:
WBC 28.0 x 109/L 3.2- 9.8 x 109/L
RBC 3.88 x 1012/L 4.50 - 5.70 x 1012/L
Hemoglobin 10.0 g/dL 13.6 - 17.2 g/dL
MCV 82 fL 80 - 110 fL
RDW 23 11 - 14.5
The image on the right is a representative field from the peripheral blood smear. What cells are indicated by the arrows in this smear?
Sickle cells
Ovalocytes
Schistocytes
Acanthocytes
Feedback
The cells are sickle cells, which are crescent-shaped red blood cells
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Sickle cells along with target cells, as shown in this image, confirm a diagnosis of sickle cell disease (HbSS).
True
False
Feedback
The statement is not true. Although both sickle cells and target cells are present in this blood smear, hemoglobin electrophoresis is necessary to
establish the underlying condition.
A double heterozygous condition known as Hemoglobin SC disease also exists where one beta chain carries the mutation for HbS and the other beta chain carries the
mutation for HbC.
In addition, HbS can be present with thalassemia.
Sickle cell anemia can also demonstrate hereditary persistance of fetal hemoglobin (HbS/HPFH).
Other rare HbS combinations are also possible and need to be determined through hemoglobin electrophoresis or other appropriate methods
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Sickle cells along with target cells, as shown in this image, confirm a diagnosis of sickle cell disease (HbSS).

True
False
Feedback
The statement is not true. Although both sickle cells and target cells are present in this blood smear, hemoglobin electrophoresis is necessary to
establish the underlying condition.
A double heterozygous condition known as Hemoglobin SC disease also exists where one beta chain carries the mutation for HbS and the other beta chain carries the
mutation for HbC.
In addition, HbS can be present with thalassemia.
Sickle cell anemia can also demonstrate hereditary persistance of fetal hemoglobin (HbS/HPFH).
Other rare HbS combinations are also possible and need to be determined through hemoglobin electrophoresis or other appropriate methods
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The erythrocyte at the tip of the arrow in the image to the right is an echinocycte (burr cell).

True
False
Feedback
This statement is false. The cell at the tip of the arrow is an acanthocyte. It has no central pallor, is smaller than a normal erythrocyte, and the
spicules are irregularly placed. This modeling is believed to depend on changes of lipid content in the surface membrane and architectural
changes influenced by splenic activity.
Echinocytes have central pallor and are usually larger than acanthocytes. Their spicules are blunt, uniformly smaller, and evenly distributed.
Echinocytes (burr cells) are often found as artifacts on a blood smear, but they can be observed on blood smears in cases of uremia and chronic
liver disease.
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The peripheral blood picture shown in the image below is most consistent with an artifact of smear preparation.
True
False
Feedback
When echinocytes dominate, as presented in this photograph, an artifact of smear preparation should be considered. Artifactual burr cells are
more commonly found in the center of the smear, as the increased surface tension at the feather edges tend to flatten the RBC's and round off the
projections. If burr cells still predominate on a new preparation, further investigation of their presence may be necessary
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Contents
Case Studies in Red Blood Cell Nonneoplastic Conditions: Echinocytes and Acanthocytes
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An isolated acanthocyte is most likely of little importance on an otherwise normochromic, normocytic peripheral blood smear.
True
False
Feedback
The statement is true. If only an occasional acanthocyte is found when scanning a peripheral smear, the cell in question most likely is
approaching the end of its 120-day life span. Further studies probably are not necessary, although further clinical information might be useful
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Case Studies in Red Blood Cell Nonneoplastic Conditions: Schistocytes, Bite Cells, and Teardrop Cells
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The presence of erythrocytes with altered morphology (as indicated by the arrows in the image to the right) has a close association with each of
the following conditions EXCEPT:
Disseminated intravascular coagulation (DIC)

Severe burns
Bone marrow metastasis
Thrombotic thrombocytopenic purpura (TTP)
Feedback
The intended response is bone marrow metastasis. Schistocytes are less likely present in a peripheral blood smear from a patient with bone
marrow metastasis. Nucleated RBCs, teardrop forms, and ovalocytes are more likely findings.
Atypical, fragmented, and triangulated erythrocytes devoid of central pallor (schistocytes) are found in conditions of erythrocytic membrane
damage. These changes follow as red blood cells are forced through a dense fibrin mesh of clot formation. DIC, severe burns, and TTP are all
associated with fragmented red cells
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Which of the following conditions is associated with the defective erythrocytes that are indicated by the arrows in this image?

G6PD deficiency
Microangiopathic hemolytic anemia
Abetalipoproteinemia
Beta thalassemia
Feedback
The intended response is G6PD deficiency.
These atypical erythrocytes are bite cells, associated with Heinz body formation. Note the multiple nibbles in many of the erythrocytes. Heinz
bodies represent the presence of denatured hemoglobin associated with G6PD deficiency.
Schistocytes, keratocytes, and tear drop cells are more common in microangiopathic anemia. Atypical RBCs in abetalipoproteineima are
typically acanthocytes; the predominant abnormal red cells in thalassemia are target cells(codocytes)
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The cells marked by blue arrows in the image below are associated with all of the following conditions except:

Myelofibrosis
Hepatic cirrhosis
Thalassemia
Myelophthisis
Feedback
The intended response is hepatic cirrhosis.
Tear drop cells are formed in each of the disorders listed except in hepatic cirrhosis. Tear drop red cells form when they squeeze through the
narrow configurations of fibrin strands in a clotting meshwork of the spleen and in marrow fibrosis. The squeezing process and mechanical
tampering destroys and molds the erythrocyte membranes, resulting in tear drop formations.
In the accompanying photograph, the presence of the Howell-Jolly body (red arrow) suggests splenic interventions; the spherocytes point to
hemolysis
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A 5-year-old girl was brought to the emergency department with bloody diarrhea and severe abdominal pain. A complete blood count produced
these results:
CBC Parameter Patient Result Reference Interval

WBC 9.6 x 109/L 4.3 - 10.8 x 109/L
Hemoglobin 9.1 g/dL 11.5 - 13.5 g/dL
HCT 28% 37 - 48%
MCV 80 fL 86 - 98 fL
RDW 13.1 11 - 15
Platelets 90.1 x 10 /L 150 - 450 x 109/L
9
The peripheral blood smear is represented in the image to the right. Which of the following condition(s) could be present in this patient when
considering the information above and the cells indicated by the arrows on the peripheral smear?
Hereditary spherocytosis
Hemolytic uremic syndrome (HUS)
Beta thalassemia
Feedback
The intended response is HUS
Scattered schistocytes and helmet cells are present in HUS. The presence of polychromatic erythrocytes and scattered spherocytes would also
support a hemolytic process. HUS is usually seen in children; it is the most common cause of acute renal failure in children. Patients may have bloody diarrhea
and symptoms resembling colitis. Diarrhea-related HUS is usually associated with ingestion of undercooked beef contaminated with Ecoli O157:H7; it is the Shiga-
like toxin from this serotype that causes the illness.
Spherocytes would appear as the predominate erythrocytes in a case of hereditary spherocytosis. Hemoglobin is often normal, but infection,
fever, and stress can cause the spleen to destroy more red blood cells. If this had occurred, the hemoglobin would be low, but the patient would
also appear jaundiced due to an increase in bilirubin
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Stomatocytes
Stomatocytes are erythrocytes with a slit-like central pallor, given them the appearance of "coffee beans" or "kissing lips". In three dimensions,
the stomatocyte is actually the shape of a bowl, as the cell has lost its biconcave morphology due to a membrane defect. Most cases of
stomatocytosis are due to alteration in permeability, leading to an increase in red cell volume. Stomatocytes form at a low blood acidic pH as
seen in exposure to cationic detergents, and in patients receiving phenolthiazine or chlorpromazine. Stomatocytosis can be an inherited or
acquired condition.
In hereditary stomatocytosis, mild anemia and findings of on-going hemolysis may be evident if the condition presents as a clinical problem at
all. Individuals who possess the Rh null phenotype have osmotically fragile red cells, which take the form of stomatocytes. Individuals with this
phenotype tend to experience varying degrees of chronic hemolytic anemia.
Note: Unless 10% or more of the RBC's are stomatocytes, their presence is probably artifactual
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A teenage boy is visiting his doctor uder the suspicion of a viral illness. He has always been relatively healthy without many illness-related
complaints. The doctor decides to order a laboratory workup including a complete blood count. A peripheral blood smear is reviewed. The image
on the right is a representative field, with a predominance of the arrowed cells throughout the smear. Which of the following conditions would
be most consistent with this patient's history and peripheral blood picture?
Hereditary Spherocytosis
Hereditary Stomatocytosis
Hereditary Elliptocytosis
Feedback
The correct response is hereditary elliptocytosis. This particular condition is associated with very few patient symptoms. In fact, many
individuals do not know that they have the condition until a routine blood smear review reveals the overwhelming presence of elliptocytes.
This peripheral smear is not consistent with hereditary spherocytosis or stomatocytosis, as these conditions would show their own distinct red
blood cell morphology. In hereditary spherocytosis, there is a predominance of spherocytes, which are not present in this peripheral smear. The
same concept applies to hereditary stomatocytosis, with the predominance of stomatocytes.
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Case Studies in Red Blood Cell Nonneoplastic Conditions: Rouleaux and Erythrocyte Agglutination
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The arrangement of erythrocytes on this peripheral blood smear can be associated with each of the following conditions except:
Multiple myeloma
Cold agglutinin disorders
Chronic inflammatory disorders
Waldenstrom's macroglobulinemia
Feedback
The intended response is cold agglutinin disorders.
The arrangement of the RBC's documented in the photograph is called rouleaux formation, resembling a stack of falling dominoes. Rouleaux
may be seen on the blood smear when plasma proteins are increased, particularly fibrinogen and gamma globulin.
True rouleaux may be assessed only in the thin portion of the smear. Pseudorouleaux of less than four cohorting red cells form artifacts in thicker
areas of the smear.
Erythrocyte agglutination (clumping) rather than rouleaux formation appears in those conditions when cold reactive antibodies, most commonly
IgM or IgG, are circulating in the plasma.
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Case Studies in Red Blood Cell Nonneoplastic Conditions: Rouleaux and Erythrocyte Agglutination
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The arrangement of the erythrocytes in this peripheral smear should be reported out as rouleaux formation.
True
False
Feedback
The red cells are not arranged in rouleaux formations. They are gathered in small, irregularly distributed, grape-like clusters, representing
agglutination.
In contrast to rouleaux formation, where RBC's are linearly arranged simulating a stack of coins, RBC clumping associated with cold agglutinins
(often IgM antibodies) is found in immune hemolytic anemias, in infections such as mycoplasma pneumonia, and in certain malignancies.
Rouleaux formation related to increased plasma proteins, primarily fibrinogCase History

A 54 year-old man was brought to the clinic by his sister who was emphatic that her brother was "not taking care of himself."
The patient had a previous gastrectomy and splenectomy. He also had a diagnosis of alcoholism, malnutrition, and hepatic cirrhosis. The
following content pages discuss a variety of erythrocyte changes that have occurred as a result of his various conditions
en or globulins, is found on peripheral smears in monoclonal gammopathies as multiple myeloma or Waldenstrom's macroglobulinemia
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Splenectomy Morphologies
Several erythrocyte abnormalities are present in both the upper and lower images. Many of these atypical cells are most likely present as a result
of the patient's splenectomy.
Considerable anisocytosis and poikilocytosis with many tear-drop cells, bite cells, fragmented forms, and a few target cells are apparent. Some
of the erythrocytes in the upper image contain Howell-Jolly bodies (DNA fragments) that may be single or multiple, especially in
myeloproliferative disorders. These inclusions stain negatively for iron and are eccentrically placed in the red cell cytoplasmPoikylocytosis and
Basophilic Stippling
In the images to the right, the poikilocytosis present includes tear-drop shaped erythrocytes, schistocytes, and target cells. In addition,
macrocytes are present, two of which (one in each field) have coarse basophilic stippling. The stippling may represent abnormal hemoglobin
synthesis. These stippled erythrocytes remain in circulation in the absence of pitting by a spleen
.


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Red Cell Disorders: Peripheral Blood Clues to Nonneoplastic Conditions

Normal Red Blood Cell (RBC) Morphology

Evaluating Initial Red Blood Cell (RBC) Morphology

MCV (Mean Corpuscular Volume)

Continue to the next page

Criteria for Peripheral Blood Smear Review

Hemoglobin: < 8 or >18 g/dL (<10 or > 21g/dL in a newborn)

Introduction to Red Blood Cell Morphology Reporting

RBC Morphology Reporting Per High Power

10-50 cells per field 51-100 > 100

Ungraded Practice Question

The correct answer is highlighted below

Few teardrop cells

Red Cell Morphology Reference Tables

Anisocytosis Reference Table

Hemoglobin Content Reference Table

Cell Type Image Cellular Description Associated Diseases and

Poikilocytosis Review Table

Cell Type Image Cellular Description Associated Diseases and Conditions

Spherocyte RBCs smaller than normal Hereditary spherocytosis

Stomatocyte RBCs with thin, elongated area of central Hereditary stomatocytosis

Schistocyte RBC blood cell fragments or pieces Severe burns

Acanthocyte RBCs demonstrating irregularly-spaced, Abetalipoproteinemia

Echinocyte (Burr RBCs have short and evenly-spaced, Uremia

Rouleaux and Agglutination

Cell Type Image Cellular Description Associated Diseases and Conditions

Dimorphic (Double Cell) Population

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These blood count results were reported:

Parameter Patient Result Reference Interval

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Parameter Patient Result Reference Interval

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