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356 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 16-1. Reference Ranges and Interpretative Comments for Common Hematologic Tests (Typical CBC)
TEST NAME RANGEa REFERENCE SI UNITS COMMENTS
RBC
Men: 4.5–5.9 × 10
Women: 4.1–5.1 ×
106 cells/µL
6
cells/µL
4.5–5.9 × 1012 cells/L
4.1–5.1 × 1012 cells/L
Hgb Men: 14–17.5 g/dL
Women: 12.3–15.3 g/dL
140–175 g/L or
8.68–10.85 mmol/L
123–153 g/L or
Amount of Hgb in given volume of whole blood;
indication of oxygen-
transport capacity of blood; may
be falsely elevated in hyperlipidemia
7.63–9.49 mmol/L
Hct Men: 42% to 50%
Women: 36% to 45%
RBC indices
80–96 fL/cell 80–96 fL/cell Hct/RBC: average size of RBCs in a specimen;
MCV
0.42–0.5
0.36–0.45
Percentage volume of blood comprised of RBCs;
usually approximately three times Hgb
decreased in iron deciency; increased in vitamin
and folate deciency, cold agglutinins,
B
12
reticulocytosis, hyperglycemia, and leukemias
MCH 27–33 pg/cell 27–33 pg/cell Hgb/RBC: average amount of Hgb in RBCs in a
specimen; decreased in iron deciency; increased in
vitamin B
and folate deciency
12
MCHC 33.4–35.5 g/dL 334–355 g/L Hgb/Hct: average concentration of Hgb in RBCs in a
specimen; decreased in iron deciency, increased in
hyperlipidemia and cold agglutinins
Reticulocyte
count
0.5% to 2.5% of RBCs 0.005–0.025 Immature RBCs; increased in acute blood loss and
hemolysis; decreased in untreated iron, vitamin B
12
and folate deciency
RDW 11.5% to 14.5% 0.115–0.145 Measure of variation in RBC volumes (anisocytosis):
the larger the width percent, the greater the variation
in size of RBCs; increased in early iron deciency
anemia and mixed anemias
WBC count
4.4–11.3 × 10
3
cells/µL 4.4–11.3 × 109 cells/L
Elevated by neutrophil demargination with exercise,
glucocorticoids, epinephrine; decreased with cold
agglutinins
Platelet count
150,000–450,000 cells/µL 150–450 × 10
9
cells/L
Elevated in presence of RBC fragments and microcytic
erythrocytes; decreased in presence of large numbers
of giant platelets and platelet clumps
,
MPV 6.8–10 fL 6.8–10 fL
SI = International System of Units.
Source: Adapted with permission from references 7 and 8.
because the marrow in these bones is gradually replaced by
fatty tissue. Radiation directed to large portions of hematopoietic bones, such as in patients treated for cancerous lesions such
as bony metastases, can lead to decient hematopoiesis. Similarly, preparation for a bone marrow transplant may include
total body irradiation to destroy the hematopoietic cells of the
recipient so that the graed cells are not destroyed by residual
host defenses.
Although most hematopoiesis occurs in the marrow,
modern methods of identifying cellular characteristics have
demonstrated that pluripotential cells— identied by a cellular
expression of the surface marker CD34— also normally circulate in the blood.
3
Although most of this chapter discusses laboratory analysis
of blood obtained from the vein (peripheral venipuncture), an
analysis of the bone marrow itself may be needed to diagnose or
monitor various disease states, most commonly leukemias. Bone
marrow specimens are usually obtained from the posterior iliac
crest of the pelvis or, less commonly, from the sternum. Bone
marrow sampling can involve an aspirate, a core biopsy, or both.
CHAPTER 16 • HEmATology: REd And WHiTE BloodCEll TEsTs 357
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e biopsy provides the advantage of examining the structure
of the marrow stroma as well as the spatial relationship of the
various hematopoietic cells.
4
Blood pluripotential (stem) cells become increasingly differentiated in the bone marrow until they are committed to
develop further into erythrocytes, platelets, or various leukocytes (Figure16-1). Many regulatory proteins, including
colony- stimulating factors, are involved in the dierentiation
and proliferation phases of hematopoiesis, but their functions
and interrelationships are not yet fully understood. In addition to the colony- stimulating factors mentioned previously,
proteins that stimulate hematopoiesis include erythropoietin, thrombopoietin, and various interleukins. Inhibitors of
hematopoiesis are not as well dened but include interferons
and lymphotoxins. When considering the response of neutrophils or erythrocytes to exogenously administered hematopoietic stimulants (eg, lgrastim, epoetin alfa), it is important
to recall that normal physiologic hematopoietic regulation
is more complex than the eect of one therapeutic protein
would suggest. WBC formation involves local production of
a combination of signaling proteins by cells of the hematopoietic microenvironment (eg, macrophages, T lymphocytes,
osteoblasts, broblasts, and endothelial cells). Leukocytestimulating proteins, such as granulocyte- colony stimulating
factor and granulocyte- macrophage colony- stimulating factor, are normally directed toward adjacent or closely approximated dierentiating hematopoietic cells.3 In contrast, renal
synthesis of the hormone erythropoietin is increased when
oxygen tension in one or both kidneys decreases. Once it is
released into the systemic circulation, erythropoietin stimulates erythrocyte precursors in the blood- forming areas of
bone marrow.
Committed blood precursor cells undergo further dierentiation in the bone marrow until they develop into mature cells.
ese developmental stages can be identied by diering morphologic or immunochemical staining characteristics. ese
same imaging techniques are used to identify the developmental
phenotype of the cancerous WBCs of leukemia and lymphoma.
Generally, only mature cellular forms are found in the circulating blood, and it is from this blood that clinical specimens
are usually taken. As discussed later, the presence of immature
forms of WBCs or RBCs in the blood typically indicates the
presence of a pathologic process.
COMPLETE BLOOD COUNT
e complete blood count (CBC) is a frequently ordered laboratory test. It supplies useful information regarding the concentration of the dierent cellular and noncellular elements of blood
and applies to multiple disorders. CBC is a misnomer because
concentrations of cells/microliter, not counts, are measured and
reported, and many hematologic tests are not included. Functionally, the CBC can be thought of as a routine or screening
blood analysis given several tests are performed.
Most clinical laboratories use an automated method to determine the CBC. Results are usually accurate, reproducible, and
rapidly obtained. Numerous measured and calculated values
are included in a CBC (Tab le16-1). ese results traditionally
include the following values:
• Erythrocyte count or RBC
• Leukocyte count or WBC
• Hemoglobin (Hgb)
• Hematocrit (Hct)
•
RBC (Wintrobe) indices: mean cell (corpuscular) volume
(MCV), mean Hgb content, mean cell Hgb concentration
(MCHC), and RBC distribution width (RDW)
• Platelet estimate or count and mean platelet volume
• Reticulocyte count
• Erythrocyte sedimentation rate (ESR)
When a “CBC with dierential” is ordered, the various types
of WBCs are also analyzed (see White Blood Cell Count and
Dierential section). e reliability of the results can be doubtful
if (1) the integrity of the specimen is questionable (inappropriate handling or storage) or (2) the specimen contains substances
that interfere with the automated analysis. Grossly erroneous
results are usually agged for verication by another method.
Manual microscopic review of the blood smear may be used to
resolve unusual automated results (and if the counts are lower
in specic pathologic or spurious myeloid conditions).
1
Note that laboratory value reference ranges vary slightly
among laboratories.
Red Blood Cell Count
Normal adult range: men, 4.5 to 5.9 × 106 cells/mL (4.5 to 5.9×
1012 cells/L); women, 4.1 to 5.1 × 106 cells/mL (4.1 to 5.1 ×
1012 cells/L)
e red blood cell (RBC) count is the number of red cells in
a given volume of blood. e international unit for reporting blood cells is for a 1-L volume, but it is still common to
see values reported in cells/microliter (µL), or less commonly
in cells/cubic millimeter (mm3). Aer puberty, women have
slightly lower counts (and Hgb/Hct) than men, partly because
of their menstrual blood loss and because of higher concentrations of androgens (an erythropoietic stimulant) in men. e
RBC count in all anemias is by denition below the normal
range, and this decrease causes a proportionate decrease in Hct
and Hgb. In clinical practice, the Hgb and Hct are more commonly used to dene the presence or absence of anemia. e
reticulocyte is the cell form that precedes the mature RBC or
erythrocyte. During the entire maturation process, Hgb is produced, gradually lling the cytoplasm. e reticulocyte does
not contain a nucleus but possesses remnants of the nucleus
or endoplasmic reticulum. e mature erythrocyte contains
neither an organized nucleus nor nucleic acids. Reticulocytes
persist in the circulation for 1 to 2 days before maturing into
erythrocytes.
Mature erythrocytes have a median lifespan of 120 days
under normal conditions. ey are removed from the circulation by macrophages in the liver, spleen, bone marrow, and other
reticuloendothelial organs. e erythrocytes are tested for exibility, size, and integrity in these organs as the cells pass through
areas of osmotic, pH, or hypoxic stress.
2,5,6
5
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Variability in the size of RBCs is termed anisocytosis, and
variation in the normal biconcave disc shape is termed poikilocy-
tosis. Such abnormalities are seen with iron deciency or periods
of increased erythrocyte production and RBC damage.
6
White Blood Cell Count
Normal range: 4.4 to 11.3 × 103 cells/mL (4.4 to 11.3 ×
109 cells/L)
e white blood cell count is an actual count of the number of leukocytes in a given volume of blood. Unlike RBCs, leukocytes have a
nucleus and normally represent ve dierent mature cell types. e
various percentages of the ve mature and WBC types comprise the
WBC dierential, which is discussed later in this chapter.
Hemoglobin
Normal range: men 14 to 17.5 g/dL (140 to 175 g/L); women
12.3 to 15.3 g/dL (123 to 153 g/L)
The hemoglobin (Hgb) value is the amount of this
metalloporphyrin- protein contained in a given volume (100
mL or 1 L) of whole blood. e Hgb concentration provides a
direct indication of the oxygen- transport capacity of the blood.
As the major content of the RBCs, Hgb is proportionately low in
patients with anemia. Fluid volume must be taken into consideration because Hgb and Hct are sensitive to the volume status of
a patient, making the setting of the evaluation paramount in its
interpretation (ambulatory versus acute care versus critical care).
Hematocrit
Normal range: men 42% to 50% (0.42 to 0.5); women 36% to
45% (0.36 to 0.45)
e hematocrit (Hct), also known as the packed cell volume, is
the percentage volume of blood that is composed of erythrocytes. To manually perform the Hct test, a blood- lled capillary
tube is centrifuged to settle the erythrocytes. en, the percentage volume of the tube that is composed of erythrocytes is calculated.7 e Hct is usually about three times the value of the Hgb,
but disproportion can occur when cells are substantially abnormal in size or shape. Like Hgb, Hct is usually low in patients with
anemia and is useful in evaluation for surgical procedures and
reversal of coagulopathies.
Red Blood Cell Indices
Because the following laboratory tests specically assess RBC
characteristics, they are called RBC indices. ese indices,
which assess the size and Hgb content of the RBC, may be useful in the evaluation of anemias, polycythemia, and nutritional
disorders. e MCV is measured directly, whereas the MCHC
and MCH are calculated from the Hgb, MCV, and RBC count
using predetermined formulas. Because of its dependence on
cell size, MCH is rarely used in clinical practice, whereas the
MCHC is sometimes used to assess RBCs for their Hgb concentration and color.
Mean Corpuscular Volume
Normal range: 80 to 96 fL/cell (80 to 96 f L/L SI)
e mean cell (corpuscular) volume (MCV) is an estimate of the
average volume of RBCs and is the most clinically useful ofthe
RBC indices. It can be calculated by dividing the Hct by the RBC
count, but it is now determined by averaging the directly measured size of thousands of RBCs with modern hemocytometry
instruments.
Abnormally large cells have an increased MCV and are called
macrocytic. Vitamin B12 and folate deciency cause the forma-
tion of macrocytic erythrocytes, which corresponds to a true
increase in MCV. In contrast, a false increase in MCV may be
observed when a patient has reticulocytosis, an increase in the
number of reticulocytes in the peripheral blood, because reticulocytes are larger than mature erythrocytes.
also be falsely increased in hyperglycemia due to osmotic expansion of the erythrocyte. When erythrocytes are mixed with diluting uid to perform the test, the cells swell because the diluent is
relatively hypotonic compared with the patient’s hyperglycemic
blood. Abnormally small cells with a decreased MCV are called
microcytic. A decrease in the MCV implies some abnormality
in Hgb synthesis. e most common cause of microcytosis is
iron deciency.9 Some patients have simultaneous microcytic
and macrocytic anemias (eg, iron and folic acid deciencies),
and in those patients, the MCV may not be predictive of the
patient’s overall status.
7,8
e MCV may
Mean Corpuscular Hemoglobin
Normal range: 27 to 33 pg/cell
e mean cell (corpuscular) hemoglobin (MCH) is a measure
of the oxygen- carrying capacity (ie, Hgb) of each cell. It is calculated as the quotient of Hgb/RBC. e presence of Hgb adds
color to the erythrocyte and picks up the dyes of RBC stains
for microscopic viewing. Cells that have decreased amounts
of Hgb are referred to as being hypochromic, such as in iron
deciency.
Mean Corpuscular Hemoglobin Concentration
Normal range: 33.4 to 35.5 g/dL (334 to 355 g/L)
e mean cell (corpuscular) hemoglobin concentration (MCHC)
is the Hgb divided by the Hct, and this calculation is usually
around 33 g/dL (330 g/L) because the Hct is usually three times
the Hgb. Some laboratories do not report the MCH, as the
MCHC reports the Hgb per volume of blood rather than per
erythrocyte and, therefore, provides a more direct index of the
oxygen carrying capacity of the blood. Iron deciency is the
only anemia in which the MCHC is routinely low although it
can also be decreased in other disorders of Hgb synthesis.
this case, RBCs are described as hypochromic (pale). MCHC
can be falsely elevated in hyperlipidemia. e Wintrobe indices
are averages for the patient’s blood, and normal values may be
reported by automated methods, even in the presence of a mixed
(normal + abnormal) erythrocyte population.
7,8
In
Red Blood Cell Distribution Width
Normal range: 11.5% to 14.5% (0.115 to 0.145)
e RBC distribution width (RDW) is an indication of the variation in RBC size, termed anisocytosis.8 e RDW is reported as
the coecient of variation of the MCV (standard deviation/mean
value). is value is used primarily with other tests to dierentiate iron deciency anemia from thalassemias and to identify the
presence of a mixed anemia. e RDW increases in macrocytic
CHAPTER 16 • HEmATology: REd And WHiTE BloodCEll TEsTs 359
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anemias and in early iron deciency, oen before other tests show
signs of this kind of anemia. However, it is not specic for iron
deciency anemia. Mild forms of thalassemia oen are microcytic but have a normal or only slightly elevated RDW.
Platelet Count and Mean Platelet Volume
Normal range: 150,000 to 450,000 cells/mL (150 to 450 ×
109 cells/L)
e platelet estimate or count, oen included routinely in the
CBC with dierential, and mean platelet volume are discussed
with other coagulation tests in Chapter 17.
Reticulocyte Count
Normal range: 0.5% to 2.5% of RBCs (0.005 to 0.025)
Reticulocytes are almost-mature RBC that contain nuclear
fragments. Normally, only a small number of reticulocytes are
in the peripheral circulation. When the bone marrow increases
the production of RBC, more reticulocytes are released into
the peripheral circulation. In anemia, the reticulocyte count
or reticulocyte index (RI) reects not only the level of bone
marrow production but also a decline in the total number of
matureerythrocytes that normally dilute the reticulocytes.
erefore, the reticulocyte count would double in a person
whose bone marrow production is unchanged but whose Hct
has fallen from 46% to 23%. e RI corrects for the transient
increase in reticulocyte release that may be seen even in hypoproliferative anemias. It is calculated as follows:
RI = measured % reticulocytes × (patient’s Hct/normal Hct)
where a normal RI is <3%.
7
In persons with anemia secondary to acute blood loss or
hemolysis, even the corrected reticulocyte count is increased.
5,7
is increase reects an attempt by the bone marrow to compensate for the lack of circulating erythrocytes by speeding bone
marrow production and release of RBCs. In contrast, persons
with untreated anemia secondary to iron, folate, or vitamin B12
deciency are unable to increase their reticulocyte count appropriate to the degree of their anemia. Appropriate treatment of
an anemia should be accompanied by an increase in the reticulocyte count, typically in 5 to 7 days.
e reticulocyte count can be useful in identifying druginduced bone marrow suppression in which the percentage of
circulating reticulocytes may be close to zero.
ERYTHROCYTE
SEDIMENTATION RATE
Normal range: men 1 to 15 mm/hr; women 1 to 20 mm/hr
(increases with age)
Numerous physiologic and disease states are associated with
the rate at which erythrocytes settle from blood, termed the
erythrocyte sedimentation rate (ESR). Erythrocytes normally
settle slowly in plasma but settle rapidly when they aggregate becauseof electrostatic forces. Each cell normally has a
net negative charge and repels other erythrocytes because like
charges repel each other. Many plasma proteins are positively
charged and are attracted to the surface charge of one or more
erythrocytes, thereby promoting erythrocyte aggregation.10
Nonmicrocytic anemia, pregnancy, multiple myeloma, and various inammatory diseases (including infections) can increase
the ESR. Sickle cell disease, high doses of corticosteroids, liver
disease, microcytosis, carcinomas, and congestive heart failure
can decrease the ESR.
7
Although the ESR may be used to conrm a diagnosis supported by other tests, it is rarely used alone for a specic diagnosis. Rather, the ESR is sometimes useful as a nonspecic
biomarker for monitoring the activity of inammatory conditions (eg, temporal [giant cell] arteritis, polymyalgia rheumatica, rheumatoid arthritis, and osteomyelitis).10 e ESR
is oen higher when the disease is active due to increased
amounts of circulating proteins, termed acute phase reactants
(eg, brinogen), and falls when the intensity of the disease
decreases.
e ESR is usually measured using either the Wintrobe or the
Westergren method. Anticoagulated blood is diluted and placed
in a vertical glass tube of standard size. Aer 1 hour, the distance
from the plasma meniscus down to the top of the erythrocyte
column is recorded as the ESR in millimeters per hour.
LABORATORY ASSESSMENT
OFANEMIA
e functions of the erythrocyte are to transport and protect
Hgb, the molecule used for oxygen and carbon dioxide transport. Anemia is practically dened by a decrease in either the
Hct or the Hgb concentration below the normal range for age
and gender. Anemia is not a disease in itself but a manifestation of an underlying disease process. Appropriate treatment of
the patient with anemia must include identication and treatment of the underlying cause of the condition. Signs and symptoms of anemia depend on its severity (how low is the Hgb/Hct
or H/H) and the rapidity with which it has developed. Severe,
acute blood loss results in more dramatic symptoms than an
anemia that took months to develop because with chronic loss
some compensatory adaptation may occur. Patients with mild
anemia are oen asymptomatic (ie, absence of pallor, weakness,
and fatigue), but severely symptomatic patients may manifest
shortness of breath, tachycardia, and palpitations even at rest.
e presence of patient signs and symptoms must always be
considered when interpreting test results.
Anemia can be caused by decreased production, increased
destruction, or loss of RBC.
be dierentiated by the reticulocyte count, which is decreased
in the former and increased in the latter. e MCV is commonly used to characterize the possible etiology of anemia.
is method is useful because dierent causes of anemia lead
to dierent erythrocyte morphology. Figure 16-2 outlines
this approach. Only the more common causes of anemia are
included, but others can be t into this outline. Other laboratory
tests that are useful in dierentiating the anemias are described
later. Usual laboratory ndings are also included in each section (Table16-2).
12,13
e rst two situations can oen
10,11
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Patient with Anemia
(RBC Hbg)
Review RBC indices,
especially MCV
MCV 100 fL
Macrocytic anemia
Possible causes:
Vitamin B
Folic acid deficiency
Drug-induced bone marrow toxicity
Helpful Laboratory Tests
Schilling’s urinary excretion test
Serum methylmalonate
serum homocysteine
deficiency
12
Vitamin Levels
Normochromic, normocytic anemia
MCV 81–99 fL
Possible causes:
Acute blood loss anemia
Hemolytic anemia
Anemia of chronic disease
Helpful laboratory tests:
Reticulocyte count
Antiglobulin test
Serum hemoglobin
FIGURE 16-2. Use of erythrocyte morphology in differential diagnosis of anemia.
TABLE 16-2. Qualitative Laboratory Findings for Various Types of Anemia
RBC
Hgb
Hct
MCV
MCH
MCHC
RDW
Reticulocyte count
Serum vitamin B
12
Serum folate
Serum methylmalonate
Serum homocysteine
Ferritin
Serum iron
TIBC
Transferrin saturation
Serum haptoglobin
Plasma- free Hgb
Autoantibodies
VITAMIN B12
DEFICIENCY
↓ ↓ ↓ ↓ ↓ ↓
↓ ↓ ↓ ↓ ↓ ↓
↓ ↓ ↓ ↓ ↓ ↓
↑ ↑ ↓ ↔ ↔ ↔↓
↑ ↑ ↓ ↔ ↔ ↔↓
↔ ↔ ↔ ↔ ↔ ↔↓
↑ ↑ ↑ ↔ ↔ ↔
↓ ↓ ↓ ↑ ↑ ↔↓
↓ ↔
↔ ↓
↑ ↔
↑ ↑
FOLATE
DEFICIENCY
IRON
DEFICIENCY
ACUTE
BLOOD LOSS
↓ ↔
↓ ↓
↑ ↓
↓
MCV 80 fL
Microcytic anemia
Possible causes:
Iron deficiency
Anemia of chronic disease
Helpful laboratory tests:
Serum ferritin
Serum iron
Total iron binding capacity
RDW
Transferrin receptor
a
HEMOLYTIC
ANEMIA
↓
↑
+
ANEMIA OF
CHRONIC DISEASE
a
Some tests with no change (↔) are left empty for clarity. Autoantibodies positive for antibody- mediated immune hemolysis. Patients with
multiple causes of anemia, such as iron deciency and inammation, may have a confusing laboratory picture.
CHAPTER 16 • HEmATology: REd And WHiTE BloodCEll TEsTs 361
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Macrocytic Anemia
Macrocytic anemia is a lowered Hgb value characterized by
abnormally enlarged erythrocytes. e two most common
causes are vitamin B12 and folic acid deciencies. Drugs that
cause macrocytic anemia mainly interfere with proper use,
absorption, and metabolism of these vitamins (Tabl e 16-3)
(Minicase 1).
Vitamin B12 Deficiency
Vitamin B12 is also known as cobalamin. e normal daily
requirement of vitamin B12 is 2 to 5 mcg.
ily in the liver, which contains approximately 1 mcg of vitamin/g
of liver tissue. Overall, the body has B12 stores of approximately
2,000 to 5,000 mcg. erefore, if vitamin B12 absorption suddenly ceased in a patient with normal liver stores, several years
would pass before any abnormalities occurred because of vitamin deciency.
TABLE 16-3. Examples of Causes of Drug-Induced
Macrocytic Anemia
ALTERED FOLATE ABSORPTION
Alcohol Aminosalicylic acid
Antimalarials Erythromycin
Estrogen Oral contraceptives
Ampicillin and other penicillins Phenytoin
Nitrofurantoin Tetracyclines
VITAMIN B
Colchicine Isoniazid
Metformin Neomycin
Para- aminosalicylic acid Proton pump inhibitors
ALTERED PURINE METABOLISM
Allopurinol Azathioprine
Fludarabine Cladribine
Mercaptopurine Methotrexate
Mycophenolate mofetil Pentostatin
Thioguanine
MALABSORPTION
12
14-16
It is stored primar-
MINICASE 1
Anemia with Increased Mean
Cell Volume
Anna B., a 45- year- old woman with alcoholism, is admitted
to the hospital because of pneumonia. Her physical exam
reveals an emaciated patient with ascites, dyspnea, fever,
cough, and weakness. No cyanosis, jaundice, or peripheral
edema is evident. Her peripheral neurologic exam is within
normal limits, as are her serum electrolytes, urea nitrogen,
creatinine, and glucose. The following CBC results are
obtained:
REFERENCE
TEST NAME RESULT
RBC 3 × 10
WBC 4.6 × 10
Hgb 10.3 g/dL 12.3–15.3 g/dL for
Hct 30.9% 36% to 45% for
MCV 110.8 fL/cell 80–96 fL/cell
RDW 15.4% 11.5% to 14.5%
Platelets 174,000 cells/μL 150,000–450,000
Neutrophils 68% 45% to 73%
Bands 6% 3% to 5%
Monocytes 11% 2% to 8%
Eosinophils 2% 0% to 4%
Basophils 2% 0% to 1%
6
cells/μL 4.1–5.1 × 106
3
cells/μL 4.4–11.3 × 103
RANGE
cells/μL for
women
cells/μL
women
women
cells/μL
ALTERED PYRIMIDINE SYNTHESIS
Capecitabine Cytosine arabinoside
Fluorouracil Gadolinium
Gemcitabine Hydroxyurea
Leunomide Methotrexate
Mercaptopurine Nitrous oxide
Teriunomide Trimethoprim
VITAMIN B
INACTIVATION
12
Nitrous oxide
UNCLEAR MECHANISM
Imatinib Sunitinib
Source: Adapted with permission from references 14–16,18.
Lymphocytes 11% 20% to 40%
QUESTION: What abnormalities are present? What is the
likely cause?
DISCUSSION: The patient has anemia, evidenced by the
low RBC, Hgb, and Hct. The increased MCV identifies this
as a macrocytic anemia. The RDW is elevated, indicating
variability in the size of the erythrocytes. These findings are
typical of folic acid deficiency, a common finding in persons
with alcoholism due to poor nutrition. Folic acid deficiency
is more common than vitamin B12 deficiency because body
stores of folic acid are not as large. However, vitamin B12
deficiency must also be ruled out as it may arise with or
without a concurrent folate deficiency. Vitamin B12 deficiency
Continued
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MINICASE 1 (cont’d)
may arise from poor nutrition but is more commonly caused
by disorders such as pernicious anemia. It is critical that both
serum folate and vitamin B12 concentrations be measured
in this patient to guide appropriate supplementation.
Replenishment of folate in a patient with vitamin B
deficiency may temporarily improve the values of the CBC,
but failure to appropriately replenish vitamin B12 can lead to
irreversible brain and nerve damage.
e absorption of vitamin B12 is complex, and the mechanisms responsible are still being dened. Vitamin B12 is ingested
mostly in meats, eggs, and dairy products. erefore, strict vegans may develop vitamin B12 deciency over time if supplements are not ingested. Some supplements have forms of B12,
such as those made by the blue- green algae Spirulina, which
are active vitamins in bacterial assays but are not active vitamins for humans. Other cobamides structurally related to
cobalamin are found in plasma aer ingesting other animal
and plant-
based foods. Only the cobamide with an attached
5,6- dimethylbenzimidazole group is correctly termed cobala-
min and is active in humans.
14
Dietary B12 is usually bound nonspecically to food proteins,
and gastric acid and pepsin are required to hydrolyze the vitamin from the protein. Aging patients with decreasing stomach
acid production may be less able to free vitamin B12 from meat
protein. Freed B12 is bound with high anity to protein R, which
is a large protein secreted in saliva. e cobalamin–protein R
complex moves to the duodenum, where proteases denature
protein R and allow the freed vitamin to bind to intrinsic factor, which is secreted by the parietal cells of the stomach and is
resistant to the intestinal proteases. Patients may develop autoantibodies to intrinsic factor and thereby develop vitamin B12
deciency. e B12–intrinsic factor complex binds to cubulin at
the ileal epithelium. e B12 translocates, dissociates, and then
enters the circulation bound to transcobalamin, which is largely
homologous with intrinsic factor.14 When vitamin B12 deciency
occurs, there are several steps in the absorption of vitamin B12
that may be responsible for the deciency.
Vitamin B
deciency may arise from inadequate intake of
12
the vitamin or from a deciency of the intrinsic factor required
for the eective ileal absorption of the vitamin. Inadequate
dietary intake is a rare cause of vitamin B12 deciency, usually
occurring only in vegans who abstain from all animal food,
including milk and eggs.
sic factor is a common cause of the deciency.
15,16
Defective production of intrin-
14-16
e gastric
mucosa can fail to secrete intrinsic factor because of atrophy,
especially in elderly persons, due to autoimmune diseases or
due to surgical removal of the stomach. Disorders that aect the
ileum, such as Crohn disease, also may impair B12 absorption.
Clinical and laboratory diagnosis. Vitamin B12 is neces-
sary for deoxyribonucleic acid (DNA) synthesis in all cells,
for the synthesis of neurotransmitters, and for metabolism
12
of homocysteine. erefore, B
deciency leads to signs and
12
symptoms involving many organ systems.14 e most notable
symptoms involve the following systems:
• Gastrointestinal (GI) tract (eg, loss of appetite, smooth and
sore tongue, and diarrhea or constipation)
• Central nervous system (eg, paresthesias in ngers and toes,
loss of coordination of legs and feet, tremors, irritability, somnolence, abnormalities of taste and smell and dementia)
• Hematopoietic system (anemia)
Nuclear maturation retardation occurs in the developing cells
in the bone marrow due to slowed DNA synthesis. e morphologic result— cells with an immature and enlarged nuclei (megaloblasts) but a cytoplasm that matures normally— causes mature
cells to be larger than normal. e resulting anemia is called
a macrocytic, megaloblastic anemia, which has both morphologic characteristics of nuclear maturation retardation.14 Visual
inspection of smears of both peripheral blood and bone marrow
reveals characteristic megaloblastic changes in the appearance
of erythrocytes and WBCs. e development of neutrophils is
also aected, which results in large cells with hypersegmentation (more than three nuclear lobes).17 A mild pancytopenia
(decreased numbers of all blood elements) also occurs. e
usual laboratory test results associated with vitamin B12 deciency are listed in Tab le 16-2.
In the past, vitamin B12 concentrations were measured using
a microbiologic assay and a cobalamin- dependent organism.
e assay has largely been replaced by a competitive displacement assay using radioactive cobalamin and intrinsic factor.
Unfortunately, because of cross- reactivity with other cobamides, approximately 5% of patients have cobalamin concentrations that appear to be within the normal range yet can be shown
to have hematologic/neurologic signs of deciency. Metabolic
intermediates homocysteine and methylmalonate may be more
sensitive indicators of B12 deciency. In the presence of inadequate B12, these two compounds accumulate because of the
cobalamin dependence of their metabolizing enzymes, methionine synthase and methylmalonyl-CoA- mutase, respectively.
An elevated methylmalonate and homocysteine concentration
in the presence of normal RBC folate is strongly indicative of a
pure deciency of B12.
Historically, the Schilling test, which involves oral administration of radiolabeled B12, was used to determine if impaired
absorption is the reason for the cobalamin deciency. However,
with the advent of assays to measure autoantibodies targeting
intrinsic factor and/or gastric parietal cells, this test is now rarely
used. e availability of intramuscular injections of vitamin B12
obviates the need to specify the defect in B12 absorption, and
such injections are favored in patients with impaired B12 absorption, regardless of the cause.
Pernicious anemia is a specic disease associated with B12
deciency characterized by atrophic gastritis associated with
antibodies against intrinsic factor and gastric parietal cells. In
addition to causing B12 deciency, pernicious anemia is associated with gastric cancer. Gastrectomy (removal of all or part of
the stomach) can also lead to vitamin B12 deciency because
the procedure removes the production site of intrinsic factor.
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Achlorhydria from gastrectomy or drugs such as proton pump
inhibitors can decrease the release of B12 from food. Defective or decient absorption of the intrinsic factor–vitamin B12
complex can be caused by inammatory disease of the small
bowel, ileal resection, and bacterial overgrowth in the small
14-16
bowel.
Administration of colchicine, neomycin, and paraaminosalicylic acid can also lead to impaired absorption of vitamin B12 (Table16-3).
15,16,18
Folic Acid Deficiency
Folic acid is also called pteroylglutamic acid. Folates refer to folic
acid or reduced forms of folic acid that may have variable numbers of glutamic acid residues attached to the folic acid molecule.
e folates present in food are mainly in a polyglutamic acid
form and must be hydrolyzed in the intestine to the monoglutamate form to be absorbed eciently. e liver is the chief storage site. Adult daily requirements are approximately 50 mcg of
folic acid, equivalent to about 400 mcg of food folates. Folate
stores are limited, and anemia arising from a folate- decient
diet occurs in 4 to 5 months.
Inadequate dietary intake is the major cause of folate deciency. Folates are found in green, leafy vegetables such as spinach, lettuce, and broccoli. Inadequate intake can have numerous
causes: alcoholics oen have poor nutritional intake of folic acid;
certain physiologic states such as pregnancy require an increase
in folic acid; malabsorption syndromes (mentioned in the section on vitamin B12) can lead to defective absorption of folic acid;
and celiac sprue can lead to folate malabsorption. Patients with
chronic hemolysis, such as in sickle cell disease, and patients
undergoing hemodialysis also may develop folate deciency
Certain medications (eg, methotrexate, trimethoprim–sulfamethoxazole, and triamterene) can act as folic acid antagonists
by interfering with the conversion of folic acid into its metabolically active form, tetrahydrofolic acid. Phenytoin and phenobarbital administration can interfere with the intestinal absorption
or use of folic acid (Tabl e16-3).
Folic acid is required as the intermediate for one- carbon
transfers in several biochemical pathways, including the thymidine required for DNA synthesis. Aer absorption, folate
is reduced to tetrahydrofolate, and a carbon in one of several oxidation states is attached for transfer. e formation of
methyltetrahydrofolate requires vitamin B12 as a cofactor for
the methyl group transfer. Methyltetrahydrofolate is required
for the conversion of homocysteine to methionine, which is
subsequently used as a methyl donor in many synthetic pathways that include the production of critical neurotransmitters
and amino acids.
Clinical and laboratory diagnosis. Because folic acid is nec-
essary for DNA synthesis, a deciency causes a maturation
retardation in the bone marrow similar to that caused by vitamin B12 deciency. Folic acid deciency is also characterized
by a macrocytic, megaloblastic anemia.
acid deciency, pancytopenia does not develop as consistently
as it does with vitamin B12 deciency.
Folate supplementation in patients with a folate deciency
provides folate for the nonmethyl transfer steps that do not
require vitamin B12. High doses of folic acid can oen, at least
14-16
15,16,18
14-16
However, with folic
15,16
partially, reverse megaloblastic anemia in patients with B12 deciency but do not reverse the neurologic sequelae. Although
folate deciency is more common and easily treated, it is critical
to correctly identify the cause of a megaloblastic anemia so that
any vitamin B12 deciency is appropriately treated.
Folate Concentration
Normal range: serum folate 5 to 25 mcg/L (11.33 to 56.65
nmol/L); RBC folate 166 to 640 mcg/L (376.16 to 1450.24
nmol/L)
e folate concentration in both serum and in RBCs is used to
assess folate homeostasis. A low serum folate indicates negative folate balance and can be expected to lead to folate deciency when hepatic folate stores are depleted. Although in most
patients the serum folate alone is adequate for assessment, in
patients who were recently administered folate supplementation, the RBC folate concentration may be more indicative of
folate status.
Microcytic Anemia
Iron Deficiency
Microcytic anemia, or anemia with abnormally small erythrocytes, is most commonly caused by iron deciency. Decreased
MCV is a late indicator of the deciency (Figure16-2). Daily
requirements are approximately 1 mg of elemental iron for each
1 mL of RBCs produced, so daily iron requirements are approximately 20 to 25 mg for erythropoeisis.
within the body is obtained by recycling metabolized Hgb. RBCs
have an average lifespan of approximately 120 days. When old or
damaged erythrocytes are taken up by macrophages in the liver,
spleen, and bone marrow, the Hgb molecule is broken down and
iron is extracted and stored with proteins. Only about 5% of the
daily requirement (1 mg) is newly absorbed to compensate for
losses caused by fecal and urinary excretion, sweat, and desquamated skin (Minicase 2).
Menstruating women require more iron because of increased
blood losses. Iron requirements vary among women but average
2 mg/day. Orally ingested iron is absorbed in the GI tract, which
should permit just enough iron absorption to prevent excess or
deciency. Typically, 5% to 10% of oral intake is absorbed (normal daily dietary intake: 10 to 20 mg).
Dietary iron exists primarily in the ferric state. Because ferrous iron is more bioavailable, dietary ferric iron is reduced by
gastric acid to ferrous iron. Patients with inadequate gastric
acid secretion due to underlying diseases or medications such
as proton pump inhibitor may develop iron deciency due to
decreased absorption.
21
Recent research indicates that hepatic hepcidin22 is the primary controller of GI iron absorption, with an inverse relationship between hepcidin level and iron absorption. Hepcidin
blocks the transmembrane iron transporter ferroportin. Hepcidin levels are low in the presence of iron deciency and increase
with iron therapy. Hepcidin levels are increased in the presence
of inammatory states. Hepcidin is being studied as a biomarker
for the diagnosis of iron deciency to optimize oral iron replacement therapy and predict failure of oral iron therapy.
19-21
Most iron needed
21
364 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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MINICASE 2
Anemia and Iron Stores
Denise T. is a 25- year- old woman seen in a community health clinic
for a routine checkup. Her family history includes a sister with sickle
cell disease. She has not been affected personally but has not been
tested to determine her sickling genotype. She describes painful
menstrual periods and takes aspirin for them. She also admits to
a pica of ingesting cornstarch throughout the day. The following
laboratory test results are obtained:
TEST NAME RESULT REFERENCE RANGE
RBC 3.3 × 10
WBC 5.1 × 10
Hgb 8.3 g/dL 12.3–15.3 g/dL for
Hct 26% 36% to 45% for
MCV 78 fL/cell 80–96 fL/cell
RDW 16.1% 11.5% to 14.5%
Platelets 195,000 cells/μL 150,000–450,000
Neutrophils 52% 45% to 73%
Bands 3% 3% to 5%
Monocytes 2% 2% to 8%
Eosinophils 1% 0% to 4%
Basophils 0% 0% to 1%
6
cells/μL 4.1–5.1 × 106 cells/μL
for women
3
cells/μL 4.4–11.3 × 103 cells/μL
women
women
cells/μL
TEST NAME RESULT REFERENCE RANGE
Lymphocytes 42% 20% to 40%
Serum iron 44 mcg/dL 50–150 mcg/dL
TIBC 451 mcg/dL 250–410 mcg/dL
Transferrin
saturation
Serum ferritin 5.2 mcg/L 10–20 mcg/L
QUESTION: What hematologic abnormalities are apparent from
these results?
DISCUSSION: This patient demonstrates an anemia as manifested
by the decreased RBC, Hgb, and Hct. Her WBC and platelet counts
are normal. The RDW is elevated, indicating increased variability
of erythrocyte size (anisocytosis). Because the MCV is low, this
microcytic, hypochromic form of anemia is most likely due to iron
deficiency. This is corroborated by the iron studies, which indicate
a low serum iron and transferrin saturation. Serum ferritin is also
decreased, indicating that her iron stores are markedly reduced. The
TIBC is increased both because of increased transferrin production
and decreased iron available to bind to the protein.
There may be multiple causes of her iron deficiency. Most commonly,
the combination of low dietary iron and blood loss from menstruation
increases the frequency of iron deficiency anemia in women.
An additional possibility is occult blood loss from GI ulcerations
caused by aspirin. An exacerbating factor for this woman is her
starch pica (craving for unusual food). In addition to the high caloric
intake associated with this particular pica, the starch decreases the
bioavailability of ingested iron, decreasing the ability of the patient
to absorb dietary or supplemental iron. Given the pica, parenteral
iron may be considered.
14% 20% to 50%
Iron deciency is usually due to inadequate dietary intake in
children and increased iron requirements in adults. Poor dietary
intake, especially in situations that require increased iron (eg,
pregnancy), is a common cause. Other causes of iron deciency
include the following factors:
• Blood loss due to excessive menstrual discharge
• Peptic ulcer disease
• Hiatal hernia
• Gastrectomy
•
Gastritis due to the ingestion of alcohol, aspirin, and nonste-
roidal antiinammatory drugs
• Bacterial overgrowth of the small bowel
• Inammatory bowel disease
• Occult bleeding from GI cancers
• Starch or clay pica
Ionized, soluble iron is toxic because of its ability to mediate
the formation of oxidative species. Iron is therefore bound to
proteins both in and outside of cells. Ferritin is the iron- protein
storage complex (Figure16-3). In the normal adult, approximately 500 to 1,500 mg of total body iron is stored as ferritin
and 2,500 mg is contained in Hgb.19 When the total quantity of
extracted iron exceeds the amount that can be stored as ferritin,
the excess iron is stored in an insoluble form called hemosiderin.
e serum ferritin concentration reects total body iron
stores and is the most clinically useful method to evaluate
patients for iron deciency. Because ferritin is an acute phase
CHAPTER 16 • HEmATology: REd And WHiTE BloodCEll TEsTs 365
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Gut
Diet
10–15 mg/day
Iron Loss
1 mg/day
(epithelial cells
blood loss)
Intestinal Mucosa
Absorption
1 mg/day
Functional iron
Tissues
Myoglobin Enzymes
500 mg
Blood
Transferrin
5 mg
Red Blood Cells
2500 mg
Storage iron
20 mg
Hemosiderin
Ferritin
1000 mg
FIGURE 16-3. Intake, loss, and recycling of iron and iron
storage forms.
critical illness, chronic infections, fever, and inammatory disorders such as rheumatoid arthritis, hepatitis, and malignancies.
e transport of iron in plasma and extracellular uid occurs
with two ferric ions bound to the protein transferrin, which
when not binding iron or other metals, is termed apotransfer-
rin. Transferrin binds to specic membrane transferrin receptors
where the complex enters the cell and releases the iron. Apotransferrin is released when the apotransferrin- receptor complex returns to the surface of the cell.
e tendency of ferritin to be falsely elevated with inammatory processes has led to recent interest in using soluble transferrin receptor concentrations as an alternative marker of iron
deciency. e circulating receptor fragment is considered to
reect total body receptor expression and is elevated in times
of increased erythropoiesis such as sickle cell anemia, thalassemias, and chronic hemolysis. If such causes of increased erythropoiesis can be excluded, elevated concentrations of circulating
transferrin receptor are thought to reect iron deciency. e
use of transferrin receptor concentrations may help determine
if decreased ferritin concentrations are due to iron deciency or
anemia of chronic (inammatory) disease.
Clinical and laboratory diagnosis. e rst change observed
in the development of iron deciency anemia is a loss of storage iron (hemosiderin). If the deciency continues, a loss of
plasma iron occurs. e decrease in plasma iron stimulates an
increase in transferrin synthesis. When enough iron has been
depleted such that supplies for erythropoiesis are inadequate,
anemia develops. e RDW rises, oen before the MCV
decreases, to a notable degree. If the iron deciency persists,
the RBCs become smaller than usual (microcytic— low MCV)
and not as heavily pigmented as normal RBCs because they
contain less Hgb than normal erythrocytes (hypochromic- low
mean hemoglobin content and MCHC). Patients present with
progressively worsening weakness, fatigue, pallor, shortness
of breath, tachycardia, and palpitations. Numbness, tingling,
and glossitis also may exist.
13,21
Laboratory results for iron
deciency anemia are listed in Tab l e16-2. With adequate iron
therapy, the maximal daily rate of Hgb regeneration is 0.3 g/dL,
or approximately 1%/day in Hct.
19
Serum Ferritin
Normal range: >10 to 200 ng/mL (>10 to 200 mcg/L)
Loss of storage iron (hemosiderin) was traditionally evaluated by iron- stained bone marrow aspirate. Serum ferritin has
largely replaced these invasive tests as an indirect measure of
iron stores. Serum ferritin concentrations are markedly reduced
in iron deciency anemia (3 to 6 mcg/L) and elevated in the setting of inammation.
Serum Iron and Total Iron-Binding Capacity
Serum iron normal range: 50 to 150 mcg/dL (9 to 26.9 mmol/L);
TIBC normal range: 250 to 410 mcg/dL (44.8 to 73.4 mmol/L);
transferrin saturation 20% to 50%
e serum iron concentration measures iron bound to transferrin. is value represents about one- third of the total iron-
binding capacity (TIBC) of transferrin.20 e TIBC measures
the iron- binding capacity of transferrin protein and is an indirect indicator of iron stores. In iron deciency anemia, TIBC
isincreased due to a compensatory increase in transferrin synthesis. is increase leads to a corresponding decrease in the
percent transferrin saturation that can be calculated by dividingthe serum iron by the TIBC and then multiplying by 100.
Forexample, a person with a serum iron concentration of
100mcg/dL and a TIBC of 300 mcg/dL has a transferrin saturation of 33%. Iron decient erythropoiesis exists whenever the
percent transferrin saturation is 15% or less.
Other disease states besides iron deciency that can alter
serum iron and TIBC are critical illness, infections, cancers,
and inammatory diseases
7,23
. Anemia from these diseases is
sometimes called anemia of chronic disease or anemia of inam-
mation. Serum iron and TIBC both decrease in these disorders,
unlike in iron deciency anemia in which serum iron decreases
but TIBC increases (Minicase 2).
Patients with renal failure oen have anemia because of inad
equate renal production of erythropoietin.24 ese patients, particularly those receiving hemodialysis, may have iron deciency
in addition to the anemia caused by their renal disease. In these
patients, the transferrin saturation (TSat) is used to determine
if the patient has iron deciency.
Normochromic, Normocytic Anemia
is classication encompasses numerous etiologies. ree
causes are discussed: acute blood loss anemia, hemolytic anemia, and anemia of chronic disease.
Acute Blood Loss Anemia
Patients who suer from acute hemorrhage may experience a
dramatic drop in their whole blood volume. In this situation,
the Hct is not a reliable indicator of the extent of anemia. It is
a measure of the amount of packed RBCs per unit volume of
the blood, not the total body amount of RBCs. e total whole
blood volume may be markedly reduced, but in the acute phase
of the hemorrhage, the Hct may be normal or even slightly
increased. Usually, the Hgb and Hct are decreased by the time a
CBC is obtained. Also, patients with hemorrhage oen receive
-
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