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366 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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IV crystalloid uids such as normal saline or lactated Ringer’s
solution to maintain intravascular volume. e drop in these
patients’ Hgb and Hct is partly iatrogenic, caused by dilution of
the patient’s RBCs with the IV uid.
In patients with normal bone marrow, the production of
RBCs increases in response to hemorrhage, resulting in reticulocytosis. If the patient is transfused, each unit of packed RBCs
administered should increase the Hgb by 1 g/dL if the bleeding
has stopped. Table16-2 shows the usual laboratory ndings in
acute blood loss anemia (Minicase 3).
MINICASE 3
Anemia and Low Platelet Count
Michael T., a 50- year- old man with a long history of alcohol
abuse, cirrhosis, and esophageal varices, is brought to the
emergency department (ED) by concerned family members.
The family says that he suddenly began coughing up bright
red blood. As he is moved to a bed in the ED, he begins
coughing and vomiting large amounts of bright red blood.
Astat CBC reveals the following values:
TEST NAME RESULT REFERENCE RANGE
RBC 2.91 × 10
cells/μL
WBC 6.6 × 10
cells/μL
Hgb 8 g/dL 14–17.5 g/dL for men
Hct 28.2% 42% to 50% for men
MCV 92.4 fL/cell 80–96 fL/cell
RDW 14.1% 11.5% to 14.5%
Platelets 75,000
cells/μL
QUESTION: What does this CBC indicate?
DISCUSSION: The presence of bright blood (as opposed
to dark, “coffee ground” material) in the emesis indicates
an acute and active bleed— either from a gastric ulcer or
from esophageal varices. The CBC is consistent with acute
blood loss. At the onset of bleeding, the RBC, Hgb, and
Hct may show minimal changes. Here, the RBC, Hgb, and
Hct are all moderately decreased, and the red cell indices
are within normal limits, supporting a recent history of
significant blood loss. The platelet count is also decreased,
which may have led to the increasing risk of bleeding.
Esophagogastroduoedenoscopy revealed that the bleeding
was caused by ruptured esophageal varices.
6
4.5–5.9 × 106 cells/μL
for men
3
4.4–11.3 × 103 cells/μL
150,000–450,000
cells/μL
Hemolytic Anemia
Hemolysis, the lysis of RBCs, oen leads to irregularly shaped
or fragmented erythrocytes, termed poikilocytosis. If hemolysis
is rapid and extensive, severe anemia can develop, yet RBC indices (MCV and MCHC) remain unchanged in the short term.
Patients with normal bone marrow respond with an increase in
erythrocyte production to replace the lysed cells, and reticulocytosis is present. Specialized tests, called antiglobulin tests, can
be useful in determining immune causes of hemolytic anemia.
Plasma (free) Hgb measures the concentration of Hgb circulating in the plasma unattached to RBCs. It is almost always
elevated in the presence of intravascular hemolysis. Haptoglobin, an acute- phase reactant, binds free Hgb and carries it to
the reticuloendothelial system. In the presence of intravascular
hemolysis, the serum haptoglobin concentration is decreased.
Concomitant corticosteroid therapy may confound interpretation because many diseases associated with in vivo hemolysis are
treated with corticosteroids. Serum haptoglobin may be normal
or elevated in hemolysis if the patient is receiving steroids. If
the increase in serum haptoglobin is from steroids, other acutephase reactants, such as hepcidin or ferritin, will also be elevated. Serum haptoglobin is also elevated in patients with biliary
obstruction and nephrotic syndrome. It is variably decreased in
folate deciency, sickle cell anemia, thalassemia, hypersplenism,
liver disease, estrogen therapy, and pregnancy.
Immune hemolytic anemias are caused by the binding of
antibodies and complement components to the erythrocyte cell
membrane with subsequent lysis.
25,26
e method used to detect
autoantibodies already bound to erythrocytes is a direct antiglobulin test (DAT), sometimes referred to as the direct Coombs
test. e DAT is performed by combining a patient’s RBCs with
rabbit or goat antihuman globulin serum, which contains antibodies against human immunoglobulins and complement.23 If
the patient’s RBCs are coated with antibody or complement,
the antibodies in the antiglobulin serum bind to the immunoglobulins coating the RBCs, leading to the agglutination of the
RBCs. e DAT is the only test that provides denitive evidence
of immune hemolysis.25 e DAT can also be used to investigate
possible blood transfusion reactions.
e method used to detect antibodies present in serum is an
indirect antiglobulin test (IAT, indirect Coombs). Patient serum
is combined with several types of normal erythrocytes of known
antigenic expression. Any antibodies able to bind to the antigens expressed on these sample RBCs adhere aer the serum is
washed away. Antihuman immune globulin is then added and
binds to any of the patient’s immune globulin that is present on
the erythrocytes, followed by agglutination.
e antiglobulin tests are sensitive, but a negative result does
not eliminate the possibility of antibodies bound to erythrocytes.
A low concentration of antibodies may give a false- negative
reaction. Numerous conditions and medications can be associated with immune hemolytic anemia (Tab l e 16-4).
tions can induce antibody formation by three mechanisms
that result in a hemolytic anemia.
Autoimmune type. Methyldopa and procainamide are
infrequently used cardiovascular drugs that may induce the
8
25
26,27
Medica-
25-27
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TABLE 16-4. Causes of Immune Hemolytic Anemia
Neoplasm
Chronic lymphocytic leukemia
Lymphoma
Multiple myeloma
Rheumatologic disorders
Systemic lupus erythematosus
Rheumatoid arthritis
Medication
Autoimmune type
Levodopa, mefenamic acid, methyldopa, procainamide
Innocent bystander type
Cefotaxime, ceftazidime, ceftriaxone, chlorpromazine,
doxepin, uorouracil, isoniazid, quinidine, quinine,
rifampin, sulfonamides, thiazides, chlorpropamide
Hapten type 1
Cephalosporins, penicillins
Infections
Mycoplasma
Viruses
Source: Adapted with permission from References 25–29.
formation of antibodies directed specically against normal
RBC proteins. is autoimmune state can persist for up to
1month aer drug administration has been discontinued. is
mechanism is known as a true autoimmune type of antibody
formation and is detected using the DAT.
Innocent bystander type. Antibodies to the drugs quinine and
quinidine are examples of the immune complex (innocent
bystander) mechanism. Each drug forms a drug–protein complex with plasma proteins to which antibodies are formed. is
drug–plasma protein–antibody complex attaches to RBCs and
xes complement, which leads to lysis of the cells.
situation, the RBC is an innocent bystander. Examples of other
drugs implicated in causing this type of hemolytic anemia are
listed in Table16-4.
Hapten type 1. e hapten (penicillin) type 1 mechanism is
involved when a patient has produced antibodies to penicillin.
If the patient receives penicillin at a future date, some penicillin can bind to the RBC membrane. e antipenicillin antibodies, in turn, bind to the penicillin bound to the RBC, and
hemolysis can result.
Glucose-6-Phosphate Dehydrogenase
Deficiency Anemia
Glucose-6- phosphate dehydrogenase (G6PD) is an intracellular enzyme that forms the nicotinamide adenine dinucleotide
phosphate needed by the erythrocyte to synthesize the antioxidant glutathione. Variants of this enzyme are more commonly
found in African Black (GdA-), Mediterranean, and Asian populations (Gd
Med
) than in white populations. ese variants have
25,26
In this
an impaired ability to resist the oxidizing eect of drugs and
collateral oxidative exposure to the granulocytic response to
infections. us, exposure of patients with G6PD deciency to
oxidizing drugs or an infection can lead to a dramatic, nonimmunologic hemolysis.28 Examples of drugs that can lead to
hemolysis in G6PD- decient patients include dapsone, primaquine, rasburicase, phenazopyridine, methylene blue, and nitrofurantoin. A more complete list of oending medications and
their relative risk can be found at https://www.g6pd.org/G6PD
Deciency/SafeUnsafe.aspx.
Assessment of at- risk patients for signs of hemolysis (anemia, hemoglobinemia, dark urine, and back pain) is appropriate. Routine genotyping of patients aids in drug selection and
monitoring; for example, it aids before prescribing dapsone
for Pneumocystis juroveci prophylaxis in a patient with human
immunodeciency virus (HIV) infection.
Anemia of Inflammation (Anemia of Chronic Disease)
Mild- to- moderate anemia oen accompanies various infections, inammatory illnesses, or neoplastic diseases that last
more than 1 to 2 months.
monary abscesses, tuberculosis, endocarditis, pelvic inammatory disease, and osteomyelitis. Chronic inammatory illnesses
(eg, rheumatoid arthritis and systemic lupus erythematosus),
solid tumors, and hematologic malignancies (eg, Hodgkin disease, leukemia, and multiple myeloma) are also associated with
anemia. Because these disorders as a group are common, anemia
due to chronic disease (also called anemia of chronic inammation) is also common. Although anemia of chronic disease
is more commonly associated with normocytic, normochromic
anemia, it can also cause microcytic anemia. Tabl e16-2 shows
the usual laboratory results found in anemia of inammation.
e pathogenesis of this anemia is not totally understood.
Various investigations have found that the erythrocyte lifespan is shortened and that the bone marrow does not increase
erythrocyte production to compensate for the decreased longevity. While iron stores are normal or even elevated, iron use
is impaired. Although erythrocytes are frequently normal size,
microcytosis can develop. One distinguishing feature between
early iron deciency anemia and microcytic anemia of chronic
disease is the normal serum ferritin that is present in the
23,30
latter.
In patients with chronic kidney disease (CKD), anemia is
associated with decreased renal production of erythropoietin, decreased RBC lifespan, impaired RBC production, and,
in patients receiving hemodialysis, blood loss with subsequent
iron deciency and folate deciency.
cient iron stores, erythrocyte- stimulating agents (ESA), such
as epoetin alfa and darbepoetin, may be used to decrease a
patient’s need for blood cell transfusions. In patients with CKD
and anemia, a trial of IV or oral iron is recommended regardless of whether they are receiving an ESA, particularly if the TSat
is ≤30% and the ferritin is ≤500 ng/mL. In pediatric patients,
thresholds of TSat ≤20% and ferritin ≤ 100 ng/mL are used to
determine the need for a trial of iron replacement.24 More conservative use and dosing of ESAs is recommended by recent
guidelines based on evidence that ESAs increase the risk for
23,30
Chronic infections include pul-
24,30
In the presence of suf-
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serious adverse cardiovascular events. ESA use should be individualized to use the lowest dose of ESA sucient to reduce the
need for transfusion. Patients with CKD who are not on dialysis should consider starting ESA treatment only when the Hgb
level is <10 g/dL and reduce or stop the ESA dose if the Hgb level
exceeds 10 g/dL. For patients on dialysis, ESA treatment should
be initiated when the Hgb level is <10 g/dL, and the ESA dose
should be reduced or interrupted if the Hgb level approaches
or exceeds 11 g/dL. Monitoring of Hgb levels should be done at
least weekly until stable and then monitored monthly.
24
Use of ESA therapy in patients with cancer has become controversial because of the increased risk of thromboembolism
and mortality. Recent guidelines recommend use of ESA therapy only with great caution in patients with malignancy, such as
in patients with incurable malignancies and Hgb <10 g/dL.
24,31
As with patients with CKD, dosing should be individualized
to use the lowest dose of ESA sucient to reduce the need for
transfusion.
Anemia of critical illness32 is common in critically ill patients
and is similar to anemia of inammation, but in a compressed
time frame. Critically ill patients have decreased RBC life span
and production, with the additional problem of blood loss due
to frequent phelobotomies and potential hemorrhagic losses in
surgical and trauma patients. Anemia of critical illness is associated with adverse patient outcomes, and it is not clear if transfusion and/or ESA therapy improves outcomes.
Hemoglobinopathies
Several diseases arise from abnormal synthesis of the α or
β subunits of Hgb. e most common types of anemias related
to these hemoglobinopathies include sickle cell trait/disease and
thalassemias. Sickle cell disease is caused by the substitution of
a valine amino acid for glutamate on the β chain of Hgb. e
heterozygous (trait) carrier state involving valine substitution on
one β chain is thought to provide a resistance to clinical manifestations and sequelae of malaria. Homozygous persons with
both β chains carrying the valine substitution are at increased
risk of developing a sickling of RBCs. is occurs most commonly under circumstances of hypoxia, infection, dehydration, or acidosis. Deoxygenated Hgb molecules polymerize into
rod- like structures within the RBC, deforming the cell into an
arched, rigid sickle- shaped cell. ese erythrocytes are not able
to deform and pass through the capillaries or reticuloendothelial
system. Hypoxia, ischemia, and even infarction occur in tissues
downstream of these sites of impaired blood ow. Severe pain
is usually present during these “sickle crises,” and pain management is oen needed in addition to hydration, transfusion, and
other treatments. Diagnosis is made by inspection of the peripheral blood smear and by electrophoresis of the patient’s Hgb.
alassemias are a more diverse group of hemoglobinopathies most commonly associated with persons of ancestry arising in the Mediterranean, Middle East, South Asia, and Asia
regions. Unlike the chemical change caused by the valine substitution in sickle cell patients, thalassemias are characterized
by a deciency or absence of one of the subunits of the Hgb.
Because there are two α and two β Hgb subunits in the normal
Hgb tetramer, an inability to produce adequate amounts of one
33
of the subunits would clearly lead to diculty in synthesizing
intact, complete Hgb molecules.
34
alassemias are oen diagnosed by a peripheral blood
smear, which shows small, pale erythrocytes, sometimes in very
high numbers. Some of the RBCs are nucleated, reecting the
intense pressure on erythropoiesis in the bone marrow to provide oxygen- carrying capacity to the body even if it requires
releasing immature, nucleated erythrocyte precursors. e type
of thalassemia present is determined using electrophoresis.
WHITE BLOOD CELL COUNT
AND DIFFERENTIAL
White blood cells are divided into two general classications:
1.
Granulocytes or phagocytes (leukocytes that engulf and
digest other cells)
2.
Lymphocytes (leukocytes involved in the recognition of non-
self cells or substances)
e functions of these general leukocyte classes are interrelated. For example, immunoglobulins produced by B lymphocytes are needed to coat or opsonize encapsulated bacteria so
that T cells and neutrophils can more eectively identify, adhere,
and destroy them.
When a WBC count and dierential is ordered for a patient,
the resulting laboratory report provides the total WBCs in a
given volume of blood plus the relative percentages each cell
type that contribute to the total. erefore, the percentages of the
WBC subtypes must add up to 100%. If one cell type increases
or decreases, percentages of all other types change in the opposite direction. Tab l e16-5 is a general breakdown of the dierent
types of WBCs and their usual percentages in peripheral blood.
e WBC count and dierential is one of the most widely
performed clinical laboratory tests. Large, clinical laboratories
commonly use automated methods for determining the WBC
dierential, but manual dierential counts may still be used.
Automated instruments count thousands of cells and can report
not only the relative percentages of the various WBC types but
also the absolute numbers, Hgb, RBC, platelets, and RBC indices. When reviewing a WBC dierential, one must be aware of
not only the relative percentages of cell types but also the absolute numbers. e percentages viewed in isolation can lead to
incorrect conclusions.
Numerous cluster of dierentiation (CD) surface markers
have been characterized on leukocytes and their precursors. CD
molecules are surface proteins or glycoproteins that are typically immunologically characterized by their unique epitopes.
e function of only a minority of the hundreds of CD molecules identied on human cells have been determined; however,
their expression on specic cell types can permit identication
of abnormal cell types and allow targeted treatment at cells
expressing the CD molecule.
Granulocytes
Granulocytes are phagocytic cells and derive their name from
the presence of granules within the cytoplasm. e granules
store lysozymes and other chemicals needed to oxidize and
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TABLE 16-5. Normal WBC Count and Differential
CELL TYPE NORMAL RANGE
Total WBC count
Polymorphonuclear neutrophils
4.4–11.3 × 10
45% to 73%
(“polys,” “segs,” PMN)
Band neutrophils (“bands,” “stabs”) 3% to 5%
Lymphocytes 20% to 40%
Monocytes 2% to 8%
Eosinophils 0% to 4%
Basophils 0% to 1%
PMN = polymorphonuclear cells.
enzymatically destroy foreign cells. Granulocytic leukocytes
include neutrophils, eosinophils, and basophils. Monocytes are
phagocytic cells that mature into macrophages, which are predominantly found in tissue rather than in the circulation. When
a peripheral smear of blood is prepared, three types of granulocytes are named by the staining characteristics of their cytoplasmic granules
1.
Neutrophils, which retain neutral stains and appear light tan
2.
Eosinophils, which retain acidic dyes and appear red- orange
3.
Basophils, which retain basic dyes and appear dark blue to
8,35
:
purple
Granulocytes are formed in large numbers from the pluripotential stem cells in the bone marrow. ey undergo numerous
dierentiation and proliferation steps in the marrow and are
usually released into the peripheral blood in their mature form.
A common exception is the appearance of banded neutrophil
during an infection, as discussed later. Neutrophils, eosinophils,
and basophils die in the course of destroying ingested organisms
or particles, forming purulent material or pus. On the other
hand, monocytes and macrophages do not usually need to sacrice themselves when destroying target cells.
Neutrophils
Normal range: PMN leukocytes 45% to 73% or 0.45 to 0.73;
bands 3% to 5% or 0.03 to 0.05
Neutrophils are also termed segmented neutrophils (“segs”) or
polymorphonuclear cells (PMNs, “polys”). e less mature form
of the neutrophil with a crescent- shaped nucleus is a band cell.
Bands derive their name from the morphology of their nucleus,
which has not yet segmented into multiple lobes. Less mature
forms of the neutrophil, such as the metamyelocyte and myelocyte, are normally found in the bone marrow but not in the
peripheral blood. e neutrophil is a phagocytic cell that exists
to ingest and digest foreign cells and proteins (eg, bacteria and
fungi).
e absolute segmented neutrophil count is the percentage
of neutrophils and bands multiplied by the WBC count. e
3
cells/µL
reference range for absolute counts can be estimated by multiplying the normal range of percentages for the particular type
of WBC by the upper and lower limits of the total WBC count.
Absolute neutrophil counts of <1,000/µL represent neutropenia, with counts of <500/µL and 100/µL considered severe and
absolute neutropenia, respectively. Because of the risk of rapidly
progressing, life- threatening infection, antimicrobials may be
started aer cytotoxic chemotherapy if the absolute neutrophil
count is <500/µL and the patient develops a fever.
36
Under normal conditions, about 90% of the neutrophils are
stored in the bone marrow. When released, neutrophils normally circulate for several hours before eventually marginating
by the adhering to vascular endothelium in the spleen and other
organs. is dynamic process of margination, with the potential
for demargination, causes large shis in the measured neutrophil count because only the granulocytes that are circulating at
the time are measured by a venipuncture. Neutrophils spend
only about 6 to 8 hours in the circulation, aer which they move
through the endothelium into the tissue. Unless used to engage
a foreign body or sustained by the cytokine milieu, neutrophils
then undergo programmed cell death, a noninammatory process termed apoptosis.
During an acute infection, there is an increase in the percentage of neutrophils because they initially demarginate from
the endothelium and are released from the bone marrow.
37,38
Demarginated neutrophils are mature, so initially the percent of band neutrophils will remain normal. However, as less
mature neutrophils are released from the marrow, usually in
response to bacterial infection, the percent of band neutrophils increases. e increase percent of band cells in infections
is termed a le shi. is term may be due to the traditional
order in which the manual dierential count was reported. It
may also arise from the use of a le- to- right sequence in gures describing the process of neutrophil dierentiation from
the stem cell (Figure16-1).
When the neutrophils and bands are elevated, the percentage
of lymphocytes decreases. Ratios of only 10% to 15% lymphocytes may appear in these patients, but this relative lymphopenia
arises from the concomitant increase in total WBCs and likely
does not reect an absolute lymphopenia. An exception is a neutrophilia caused by glucocorticoid treatment, which will cause
a drop in the absolute lymphocyte count because of its lymphotoxic eect while increasing the absolute neutrophil count due
to demargination.
Eosinophils and Basophils
Normal range: eosinophils 0% to 4% or 0 to 0.04; basophils 0%
to 1% or 0 to 0.01
e functions of eosinophils and basophils are not completely
known. Eosinophils are present in large numbers in the intestinal mucosa and lungs, two locations in which foreign proteins
enter the body. Eosinophils can phagocytize, kill, and digest bacteria and yeast. Elevations of eosinophils counts are highly suggestive of parasitic infections and allergic diseases, including
some forms of asthma.
Basophils are present in small numbers in the peripheral
blood and are the most long- lasting granulocyte in blood, with
370 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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a circulating lifespan of approximately 2 weeks.2 ey contain
heparin, histamine, and leukotriene B4.39 Many signs and symptoms of allergic responses can be attributed to specic mast
cell and basophil products. Basophils are probably involved in
immediate hypersensitivity reactions (eg, extrinsic, or allergic,
and asthma) in addition to delayed hypersensitivity reactions.
Basophils may be increased in chronic inammation and in
some types of leukemia.
Monocytes/Macrophages
Normal range: monocytes 2% to 8% or 0.02 to 0.08
Monocytes leave the circulation in 16 to 36 hours and enter
the tissues, where they mature into macrophages. Macrophages
are present in lymph nodes, alveoli of the lungs, spleen, liver,
and bone marrow, comprising the reticuloendothelial system.40 Macrophages, both those circulating and those that have
migrated out of the blood, participate in the removal of foreign
substances from the body. In addition to attacking foreign cells,
they are involved in the destruction of old erythrocytes, denatured plasma proteins, and plasma lipids. Tissue macrophages
also salvage iron from the Hgb of old erythrocytes and return
the iron to transferrin for delivery to the bone marrow. Under
appropriate stimuli, monocytes/macrophages are transformed
into antigen- presenting cells (also termed dendritic cells). ese
transformed macrophages are an important component of both
cell- mediated (T lymphocytes) and soluble (B lymphocyte)
immune activity against antigens.40 Macrophages express a
variety of chemokine receptors and secrete a variety of substances, including enzymes, a variety of interleukins, tumor
necrosis factor-α, interferons, and a variety of tissue and vascular growth factors.
Lymphocytes and Plasma Cells
Normal range: lymphocytes 20% to 40% or 0.2 to 0.4
Lymphocytes make up the second major group of leukocytes.
ey are characterized by a far less granular cytoplasm and relatively large, smooth nuclei. ese cells give specicity and memory to the body’s defense against foreign invaders.41 ere are
three subgroups of lymphocytes:
1. T lymphocytes (T cells)
2. B lymphocytes (B cells)
3. Natural killer cells (NK cells)
Lymphocytes are not phagocytic, but the NK and T- cell
subtypes are cytotoxic by virtue of complement activation and
antibody- dependent cell- mediated cytotoxicity. Morphologic
dierentiation of lymphocytes is dicult; visual inspection of a
blood smear cannot uniformly distinguish between T, B, and NK
cells. Fortunately, lymphocytes can be distinguished by the presence of CD lineage- specic membrane markers. us, mature
T cells have CD3 and CD5, B cells have CD20, and NK cells
have CD56 membrane markers.41 Individual CD moieties may
be surface proteins, enzymes, or adhesion molecules, to name
a few. Labeled antibodies to specic CD molecules identify the
lineage of the lymphocyte, either in blood or in tissue.
Identication of the subtype of lymphocytes is not a rou-
tine clinical hematology test at present; they are reported simply
as lymphocytes by automated counting instruments. However,
in research applications and for the diagnosis and guidance of
targeted treatment of leukemias and lymphomas, subtypes can
be both counted and sorted by an automated process termed
uorescence- activated cell sorting. e WBC layer is separated
by centrifugation and exposed to one or more CD antibodies
tagged with uorescent dyes. e labeled cells are given an electrostatic charge and then ow individually past one or more
lasers that induce the labeled cells to glow at wavelengths specic
to the dye staining each cell. is method is general and can be
used to count and sort virtually any cell that can be labeled with
a uorescent tag.
42
With the help of T cells, B cells recognize foreign substances
and are transformed into plasma cells, capable of producing
antibodies (discussed later). Tab le16-6 lists the types of disorders in which lymphocytes are increased or decreased.
T Lymphocytes
T lymphocytes are responsible for cell- mediated immunity and
are the predominant lymphocytes in circulation and in tissue. ey require partial maturation in the embryonic thymus,
hence, the name T cell. In addition to identifying infections,
they oversee delayed hypersensitivity (seen with the skin test for
tuberculosis) and rejection of transplanted organs.
eign antigen to be recognized by T cells, it must be “presented”
by macrophages or dendritic cells on one of two complex, individualized molecules termed major histocompatibility complexes
(MHC1 and MHC2).
T cells can be further divided into helper and cytotoxic (or
suppressor) cells, which, respectively, express the CD4 and CD8
markers. CD4 helper cells are not cytotoxic but on recognizing an antigen will activate and produce cytokines such as IL-2,
which stimulate nearby immune cells, including macrophages
and CD8 T cells, B cells, and NK cells.
CD4 T- helper cells can again be divided into T
types. e T
1
subtype mediates the activation of macrophages
H
and the delayed hypersensitivity response, while the TH2 subtype
appears primarily responsible for B- cell activation. e cellular
specicity of these subtypes appears to arise primarily from their
distinct pattern of cytokine production.
Human immunodeciency virus binds specically to the
CD4 receptor but does not elicit the desired antiviral response
in most patients. is infection leads to destruction of this subset of T cells and a reversal of the CD4/CD8 ratio (normally >1).
e CD4 lymphocyte count and viral load measured by viral
RNA are inversely related and correlate with overall prognosis.
Although the CD4 count remains a useful surrogate marker in
monitoring the course and treatment of patients infected with
HIV, viral loads are routinely measured. e lack of adequate
numbers of active T- helper cells that activates other immune
cells leads to an increased susceptibility to numerous opportunistic infections, cancer, and progression to acquired immune
deciency syndrome.
44,45
T cells are the primary mediator for
host rejection of transplanted solid organs,47 such as heart, lung,
kidney, liver, and pancreas gras. e perioperative and postoperative treatment of solid organ gra recipients is directed
toward minimizing the antigra T- cell response, while not ablating the T- cell population to the point of causing life- threatening
infections. In practice, this is a narrow path plagued by viral and
41,43
For a for-
1
and TH2 sub
H
-
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TABLE 16-6. Quantitative Disorders of White Blood Cells
35,41,43,47,50,51,34
WBC ABNORMALITY TYPICAL THRESHOLD (CELLS/μL) POSSIBLE CAUSES
Neutrophilia
>12,000
Acute bacterial infection
Trauma
Myocardial infarction
Chronic bacterial infection
Epinephrine, lithium, G-CSF, GM-CSF, glucocorticosteroids
Neutropenia
<1,500
Radiation exposure
Medications:
Antineoplastic cytotoxic agents
Captopril Carbamazepine
Cephalosporins Chloramphenicol
Clozapine Diclofenac
Ganciclovir Levamisole
Methimazole Penicillins
Phenothiazines Procainamide
Propylthiouracil Ticlopidine
Vancomycin Zidovudine
Tricyclic antidepressants
Sulfamethoxazole–trimethoprim
Overwhelming acute bacterial infection
Vitamin B
or folate deciency
12
Salmonellosis
Pertussis
Eosinophilia
>350
Allergic disorders/asthma
Parasitic infections
Leukemia
Medications
Angiotensin- converting enzyme inhibitors
Antibiotics (or any allergic reaction to a drug)
Eosinopenia
Basophilia
<50
>300
Acute infection
Chronic inammation
Leukemia
Monocytosis
>800
Recovery state of acute bacterial infection
Tuberculosis (disseminated)
Endocarditis
Protozoal or rickettsial infection
Leukemia
Lymphocytosis
>4,000
Infectious mononucleosis
Viral infections (eg, rubella, varicella, mumps, cytomegalovirus)
Pertussis
Tuberculosis
Syphilis
Lymphoma
Lymphopenia
<1,000
HIV type 1
Radiation exposure
Corticosteroids
Lymphoma (Hodgkin disease)
Aplastic anemia
G-CSF = granulocyte- colony stimulating factor; GM-CSF = granulocyte- macrophage colony- stimulating factor.
Source: Adapted with permission from references 34,35,41,43,47,50,51.
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fungal infections that cause substantial morbidity and mortality
in gra recipients.
Typically, T- cell populations in gra recipients46 are not measured, and drug titration is based on biopsies of the transplanted
organ, drug concentrations of the immunosuppressants, and
blood counts. Anti–T- cell treatments employed in transplant
recipients include corticosteroids; Muromonab-CD3 (OKT3),
an anti-CD3 antibody directed against the CD3 marker found on
T cells; antihuman lymphocyte immunoglobulin; and inhibitors
of T- cell activation such as cyclosporine, tacrolimus, or mycophenolate. Because these immunoglobulin products are typically
obtained from nonhuman species, they can cause severe allergic
reactions and are usually eective for only a short period.
B Lymphocytes
B cells are named aer similar avian lymphocytes that required
maturation in an organ termed the Bursa of Fabricius. ere is
no equivalent organ in humans, and maturation of B lymphocytes occurs in the bone marrow. Quiescent, circulating B cells
express one form of antibody, immunoglobulin M (IgM). When
stimulated by activated T cells or antigen- presenting cells, B cells
are transformed into plasma cells that will produce one of ve
immunoglobulin types: IgA, IgD, IgE, IgG, or IgM.
47
e two antibodies most commonly associated with the
development of immunity to foreign proteins, viruses, and bacteria are IgM and IgG. IgE is associated with the development
of immediate hypersensitivity reactions, such as anaphylaxis
and allergic diseases, including asthma. IgA is secreted into the
lumen of the GI tract and helps avoid sensitization to foods,
and IgD is bound to the lymphocyte cell membrane.47 Abnormal immunoglobulins can typically be detected using serum
and/or urine protein electrophoretic gels and urine immunoxation. Monoclonal hyperimmunoglobulinemias are identied
by single electrophoretic peaks and are typically associated with
plasma(B) cell premalignant or malignant disorders. Polyclonal
hyperimmunoglobulinemias can be associated with infections
and inammatory reactions.
Lymphopenia and hypogammaglobulinemia (a decrease
in the total quantity of immunoglobulin) are seen as a consequence of corticosteroid treatment, transplant rejection prophylaxis, and anticancer treatment, but they can also paradoxically
arise from leukemias. In general, lymphopenia is more common in chemotherapy regimens that include high doses of corticosteroids, which bind to a receptor on lymphocytes and are
lymphotoxic, even to the point of initiating cellular apoptosis.47
Interestingly, although HIV-1 infections lead to lymphopenia,
other viral infections (eg, infectious mononucleosis, hepatitis,
mumps, varicella, rubella, herpes simplex, herpes zoster, and
inuenza) oen increase the number of circulating lymphocytes
(lymphocytosis)
48,49
(Minicase 4). Severe malnutrition also may
result in lymphopenia.
Natural Killer Cells
Natural killer cells (NK) are derived from T- cell lineage but are
not as restricted in requiring MHC identication of the target
cell. NK cells are thought to be particularly important for cytotoxic eects on virally infected cells and cancer cells.
Leukocyte Disorders
Patients can suer from three major classes of leukocyte disorders: functional, quantitative, and myeloproliferative. Functional
disorders involve defects in recognition, metabolism, cytotoxic
eects, signaling, and other related activities. Routine laboratory
values are not intended to evaluate these abnormalities and are
not discussed further here.
Quantitative disorders involve too few or too many leuko-
cytes. Possible causes are listed in Table16-6. Neutropenia is
usually considered to exist when the neutrophil count is <1,500
or 1,000 cells/µL.
36,50
When the neutrophil count is <500 cells/
µL, normal defense mechanisms are signicantly impaired, and
the patient is at increased risk of bacterial and fungal infections.
A neutrophil count <100/µL is termed absolute neutropenia or
agranulocytosis. is is oen encountered aer cytotoxic chemotherapy is administered and aer regimens intended to ablate
the bone marrow in preparation for a stem cell transplant. An
infection is probable if agranulocytosis is prolonged or severe, so
patients at risk are monitored closely for infection and administered broad spectrum antimicrobials when fever or other signs
of infection are seen. When infections do occur in such patients,
they can be dicult to successfully treat— even with normally
eective antibiotics— because the number and phagocytic activity of the neutrophils are impaired.
Agranulocytosis51 may be seen as a specic toxic drug eect
(such as seen with propylthiouracil) or as part of a broader
myelopoietic disorder (such as aplastic anemia). Aplastic anemias (inadequate production of blood cells by the bone marrow) have multiple causes including drug, toxin, or radiation
exposure; congenital defect; or age- related fatty or brotic bone
marrow replacement. e word anemia in this term is misleading because production of other blood cell types can also be
decreased resulting in pancytopenia. Because some cases of
aplastic anemia are autoimmune in nature, some patients are
treated with immunosuppressive therapy.
Myelodysplastic anemias are characterized by abnormal mat
uration of RBCs and WBCs. ese are typically classied by
the World Health Organization system52 based on the marrow
morphology identied from a bone marrow aspirate. e usual
treatment course is supportive care (ie, transfusions or stem cell
transplant in patients for whom this is feasible).
Neutrophilia (increased circulating neutrophils) is caused
by both an increased release from the bone marrow and a shi
of marginated cells into the circulation. is rapid rise in the
number of circulating cells can be caused by acute infections,
trauma, or administration of epinephrine or corticosteroids.
Neutrophilia exceeding 50,000 cells/µL is termed “leukemoid
reaction” and can be seen with a variety of underlying inammatory conditions. While sometimes mistaken for leukemia,
the neutrophils in leukemoid reactions typically are mature cells
rather than the highly immature cells seen in leukemias.
Myeloproliferative Disorders
Leukemias
Neoplasms of the bone marrow cells most commonly involve
a leukocyte line and are termed leukemias. Leukemias are
-
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MINICASE 4
Anemia and Lymphopenia
Donna L. is a 55- year- old woman with a history of rheumatoid
arthritis and type 2 diabetes mellitus who presents to her physician
for a routine physical examination. She is feeling well and has no
complaints, other than the soreness routinely associated with the
arthritis in her hands. She has normal vital signs, and other than the
stigmata of her moderate rheumatoid arthritis, she has a normal
physical examination. She takes the following oral medications
routinely:
• Prednisone 5 mg once daily with dinner
• Metformin 750 mg once daily with dinner
• Methotrexate 10 mg weekly
• Acetaminophen 650 mg q 6hr PRN for hand pain
The physician draws a comprehensive metabolic panel and a CBC
with differential and platelet count. The results of the CBC with
differential and platelet count are as follows:
TEST NAME RESULT REFERENCE RANGE
RBC 4 × 10
WBC 9.6 × 10
Hgb 13.3 g/dL 12.3–15.3 g/dL for
Hct 37.9% 36% to 45% for women
MCV 105.5 fL/cell 80–96 fL/cell
MCH 39.2 pg/cell 27–33 pg/cell
RDW 15% 11.5% to 14.5%
Platelets 304,000 cells/μL 150,000–450,000 cells/μL
6
cells/μL 4.1–5.1 × 106 cells/μL for
women
3
cells/μL 4.4–11.3 × 103 cells/μL
women
TEST NAME RESULT REFERENCE RANGE
Neutrophils 76% 45% to 73%
Bands 5% 3% to 5%
Monocytes 7% 2% to 8%
Eosinophils 2% 0% to 4%
Basophils 1% 0% to 1%
Lymphocytes 9% 20% to 40%
QUESTION: What abnormalities are present, and what is their cause
and resolution?
DISCUSSION: This patient has somewhat low RBC count and
Hgb as well as elevated MCV and MCH, indicating a macrocytic
anemia. She also has a high WBC count with increased neutrophil
and decreased lymphocyte counts. She is not showing signs of
infection. The macrocytic anemia could be caused by vitamin B12 or
folate deficiency. Treatment with methotrexate, an antifolate drug, is
the likely cause. The differential diagnosis can be made by obtaining
blood assays for vitamin B12 and folate. Many clinicians prescribe
5mg oral folate daily except for methotrexate dosing days, and this
would be an appropriate recommendation for this patient as well.
The lymphopenia and neutrophilia are likely caused by the prednisone
therapy. Glucocorticoids are known to cause demargination of
neutrophils from the vascular endothelium, leading to a relative
neutrophilia. Glucocorticoids are also lymphotoxic, typified in their
use for treatment of lymphocytic malignancies. No treatment is
indicated in this patient, but monitoring for opportunistic infections,
such as candidiasis, needs to be ongoing. The corticosteroidinduced changes in lymphocyte and neutrophil counts are expected
to return to normal after the cessation of the steroid dosing.
broadly classied as being acute or chronic, and leukemias are
either of myeloblastic (granulocytic lineage) or lymphoblastic
( lymphocytic) lineage.
52;53
e clinical course and biology of
various leukemias varies. Almost all leukemias fall within one
of four categories:
1. Acute myelogenous
2. Acute lymphoblastic
3. Chronic myelogenous
4. Chronic lymphocytic
Although the clinical course varies among these neoplasms, a
common denominator is the proliferation of the neoplastic cell
line and displacement of normal hematopoiesis. e neoplastic cells may arise from cells of varying levels of dierentiation
of either a granulocytic or lymphocytic lineage. Morphology
and CD membrane markers vary among individuals but are
fairly uniform throughout the disease course in a given patient.
e morphology and CD membrane markers of cells obtained
from the diagnostic bone marrow aspirate and ow cytometry, respectively, are used to assign a French-American-British
(FAB) classication of M0 through M7 to subtype acute myelogenous leukemia or to diagnose acute lymphoblastic leukemia.
Other morphologic features and surface marker combinations
are used to characterize the other leukemias.
Multiple (plasma cell) myeloma is notable in that it is a
plasma cell neoplasm of the bone marrow. e monoclonal
neoplastic plasma cells produce a single immunoglobulin isotype (IgG, IgA, light chain only, IgD, IgE, or rarely IgM). is
single, monoclonal protein is referred to as the M- protein. e
M- protein is usually identied using serum protein electrophoresis. e specic immunoglobulin type can be dened with a
subsequent step of serum immunoxation with protein- specic
374 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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antibody (eg, anti-IgG). Other laboratory ndings associated
with multiple myeloma include Bence Jones protein (light chain)
in urine, hypercalcemia, increased ESR, normochromic, normocytic anemia, and coagulopathy.
54
Chronic myeloproliferative disorders55 involve an abnormal
proliferation of more mature bone marrow cells. Excessive or
uncontrolled proliferation of all cell lines leads to polycythemia
vera, a malignancy when erythrocyte overproduction is the most
prominent abnormality. Chronic myelogenous leukemia is characterized by a chromosomal translocation [t(9:22), “Philadelphia
chromosome”] that creates a fusion product (BCR/ABL) resulting in autonomous tyrosine kinase activity, a growth- signaling
enzyme. Patients with chronic lymphocytic leukemia present
with increased numbers of circulating mature B lymphocytes,
which are monoclonal.
Patients with chronic leukemias may live for several years
with minimal treatment because of the indolent nature of the
disease. At some point, a patient typically develops a transformation of the disease into a life- threatening accelerated phase
or blast crisis. Fortunately, with the development of tyrosine
kinase inhibitors and other targeted medications, this fatal complication can now oen be substantially delayed. Although the
chronic leukemias are less aggressive than the acute leukemias,
they are less curable with chemotherapy, and stem cell transplantation is appropriate in selected patients.
Lymphomas
A lymphoma is a neoplasm of lymphocytic lineage, which
typically predominates in lymph nodes forming tissue masses
rather than being primarily located in the bone marrow. e
lymphomas are classied into two main groups: (1) nonHodgkin lymphoma (NHL), and (2) Hodgkin lymphoma. e
pattern of tissue involvement— termed either diuse or follicular
(nodular)— and the cytology of the neoplastic lymphoid cells
(primarily the size and appearance of the cell nucleus) are used
to morphologically subclassify non-Hodgkin lymphoma.56 e
World Health Organization classication57 of NHL also uses CD
surface markers, cytogenetics, and molecular and genetic studies
to further dene subcategories of NHL. Non-Hodgkin lymphomas can also be practically divided into aggressive and indolent
forms. e aggressive lymphomas grow and spread quickly but
are generally more likely to be eradicated with current, intensive chemotherapy. In contrast, the slower- growing, indolent
lymphomas are not as responsive and are more dicult to cure,
but these oen have a long disease course. Hodgkin lymphoma
is generally a more treatable lymphoma. e neoplastic cellular
element is termed the Reed-Sternberg cell. is is a large cell with
a lobulated nucleus and prominent nucleoli. It is typically surrounded by a nonneoplastic population of lymphocytes, eosinophils, neutrophils, plasma cells, and macrophages.
Lymphomas predictably involve T- lymphocyte or
B- lymphocyte precursors, and many express CD marker characteristics of mature lymphocytes. Identication of the CD20
marker on B- cell lymphomas provides an opportunity to treat
these patients with recombinant antibodies specic to this surface marker. Dierentiation between a T- cell leukemia and a
peripheral T- cell lymphoma likely requires the identication of
CD phenotypes.
SUMMARY
is chapter presents a brief characterization of the lineage and
function of RBCs and WBCs. Normal laboratory values have
been presented, but it is important to realize that normal ranges
vary slightly depending on the laboratory conducting the analysis and the population being studied. Hematologic conditions
are common, resulting in widespread use of hematologic tests
such as the CBC in all patient care settings. Proper interpretation of these commonly used tests is important for the clinician to provide a correct assessment of the patient’s condition,
choose the most appropriate therapy, and monitor the outcomes
of that therapy.
ACKNOWLEDGMENTS
e authors and editors would like to acknowledge the contributions of Dr. Paul R. Hutson, who authored this chapter in previous editions of this textbook.
LEARNING POINTS
1.
How do iron d eciency and nutrient deciency (folate
and vitamin B12) differ in their presentation in a CBC?
ANSWER: As expressed by the term anemia, in each of these
circumstances, the Hgb and Hct are low. Iron deciency is characterized by small (microcytic, low MCV) and pale (hypochromic) RBCs. In contrast, both folate and vitamin B12 deciency
classically present with larger (macrocytic, elevated MCV) erythrocytes. Patients with vitamin B12 deciency may also have
abnormalities in WBC and platelets.
2. What are the roles of transferrin, ferritin, TIBC, and TSat,
and how are these laboratory values interpreted?
ANSWER: Transferrin’s primary role is to transport iron to the
bone marrow for erythrocyte synthesis, while in the process protecting intervening tissue from the reactivity of the metal ion. Ferritin serves as the storage form of iron. Ferritin protein not bound
to iron is termed apoferritin. Most of the iron- binding protein in
the plasma is transferrin, and the serum TIBC is an indirect mea-
sure of the transferrin concentration. With iron deciency, the
liver synthesizes more transferrin. Thus, the residual, unbound
capacity of the transferrin (and thus TIBC) is increased, while the
percentage saturation of receptors on the transferrin molecules
(transferrin saturation, TSat) is decreased. With less tissue stores
of iron, the ferritin level is decreased in iron deciency. In anemia
of chronic disease, the plasma iron and transferrin concentrations
are both low, and the TSat may be decreased or normal. Liver dis
ease or malnutrition can also slow the production of transferrin,
which may complicate the interpretation of the TIBC.
3.
What are typical reasons why WBC counts are elevated,
and how can the differential cell count help clarify the
cause?
ANSWER: A sustained elevation of the WBC count is typi-
cally due to metabolic stress, infections, certain medications,
-
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8.
or leukemias. Infections, corticosteroids, epinephrine, and exercise cause a demargination of neutrophils from the endothelium,
causing a transient, increased percentage of neutrophils, but in
most cases a normal absolute lymphocyte count. Corticosteroids cause neutrophil demargination but are also lymphotoxic,
so the absolute lymphocyte count decreases. Bacterial infections
are associated with an increase in the percentage and absolute
number of neutrophils and to the release of less mature neutrophils (band cells) from the bone marrow.
4.
What are common, unintended drug- induced alterations
in RBC and WBC counts and function?
ANSWER: RBC counts can be reduced by nonsteroidal antiin-
ammatory drug–induced GI bleeding or by hemolytic anemia
in patients with G6PD deciency treated with various oxidiz-
ing drugs. RBC and WBC (and platelet) counts are commonly
decreased following cytotoxic chemotherapy, but the impact
on WBCs is greater, especially for neutrophils, because of
their faster turnover and shorter lifespan. Macrocytic, hypochromic anemia can be caused by treatment with antifolates
such as methotrexate, or chronic treatment with antibiotics
inhibiting DNA synthesis such as trimethoprim. Corticosteroids are lymphotoxic and decrease the lymphocyte count
but also lead to a higher apparent neutrophil count due to
their drug- induced demargination from the endothelium.
Some medications, such as propylthiouracil and clozapine, can
cause a sudden, dramatic reduction in neutrophils, resulting
in agranulocytosis.
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