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White Blood Cells
Reference Range: 3.8–9.8 × 103/μL or 3.8–9.8 × 109/L
Leukocytes or WBCs comprise five different types of cells.
Neutrophils are the most abundant of the circulating WBCs, followed
in order of frequency by lymphocytes, monocytes, eosinophils, and
basophils. The neutrophils, eosinophils, basophils, and monocytes
are formed from stem cells in the bone marrow. Lymphocytes are
formed primarily in the lymph nodes, thymus, spleen, and, to a lesser
extent, in the bone marrow (Fig. 2-2). Each WBC type has a unique
function, and it is best to consider them independently rather than
collectively as “leukocytes.”71 Ultimately, all WBCs contribute to host
defense mechanisms.
NEUTROPHILS
Reference Range: 40%–70% of WBCs
The terms polys, segs, polymorphonuclear neutrophils, and
granulocytes are synonymous with the term neutrophil in clinical
practice. The number of neutrophils is commonly increased during
bacterial or fungal infections because these cells are essential in
killing invading microorganisms. Although the bone marrow
increases the production of new leukocytes, there is also an increase
in the number of circulating immature neutrophils (eg, bands); this
phenomenon is commonly referred to as a left shift, which suggests
acute bacterial infection.
However, neutrophils are also important in the pathogenesis of
tissue damage in some noninfectious diseases, such as rheumatoid
arthritis, inflammatory bowel disease, asthma, MI, or gout.
72
Increased neutrophils or neutrophilia can also be encountered during
metabolic toxic states (eg, diabetic ketoacidosis, uremia, and
eclampsia) and during physiologic response to stress (eg, physical
exercise and childbirth). Drugs (eg, epinephrine and corticosteroids)
can also cause significant neutrophilia, primarily caused by
demargination from blood vessel walls.
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Agranulocytosis and absolute neutrophil count
The condition involving decreased neutrophils, or neutropenia, is
defined as a neutrophil count of <2000 cells/μL; agranulocytosis
refers to severe neutropenia. The most common causes of
neutropenia are metastatic carcinoma, lymphoma, and
chemotherapeutic agents. The degree of neutropenia is often
expressed by the absolute neutrophil count (ANC). The ANC is
defined as the total number of granulocytes (polymorphonuclear
leukocytes and band forms) present in the circulating pool of WBCs
and can be calculated as WBC × (% neutrophils + % bands)/100.
Generally, the risk of infection is low when the ANC exceeds 1000/
μL; however, the risk of infection increases significantly when the
ANC is <500/μL. The risk of developing bacteremia is increased
further as the ANC decreases to <100/μL, a condition commonly
referred to as profound neutropenia. The most common causes of
neutropenia are metastatic carcinoma, lymphoma, and
chemotherapeutic agents. The reader is referred to Chapter 75,
Prevention and Treatment of Infections in Neutropenic Cancer
Patients, for a more detailed explanation.
LYMPHOCYTES
Reference Range: 22%–44% of WBCs
Lymphocytes constitute the second most common WBC in
circulating blood. These leukocytes respond to foreign antigens by
initiating the immune defense system. The vast majority of
lymphocytes are located in the spleen, lymph nodes, and other
organized lymphatic tissue. The lymphocytes circulating in blood
represent <5% of the total amount in the body.
There are two major types of lymphocytes. T lymphocytes (thymic
dependent) participate in cell-mediated immune responses, and B
lymphocytes (bone marrow derived) are responsible for humoral
antibody responses. Therefore, diseases affecting lymphocytes
primarily manifest themselves as immune deficiency disorders that
render the patient unable to defend against normal pathogens (see
Chapter 76, Pharmacotherapy of Human Immunodeficiency Virus
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Infection) or as autoimmune diseases in which immune responses
are directed against the body’s own cells.
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Increased numbers of lymphocytes on a white count differential
sometimes accompany lymphoma (see Chapter 96, Adult
Hematologic Malignancies) and viral infections. A relative
lymphocytosis is sometimes encountered when the total
lymphocytes have remained constant despite a decline in the total
neutrophils.
MONOCYTES
Reference Range: 4%–11% of WBCs
Monocytes are formed in the bone marrow and are the precursors to
macrophages and antigen-presenting cells (dendritic cells), which
are found in the body’s tissues.73 Macrophages and dendritic cells
are phagocytic cells that engulf foreign antigens or dead or dying
cells. Dendritic cells also present fragments of antigens to T and B
lymphocytes. Monocytosis may be observed in mononucleosis,
subacute bacterial endocarditis, malaria, and tuberculosis, as well as
during the recovery phase of some infections.
EOSINOPHILS
Reference Range: 0%–8% of WBCs
Because eosinophils have surface receptors that bind IgG and IgE,
they can modify reactions associated with IgG- and IgE-mediated
degranulation of mast cells. Primary lysosomal granules, small
dense granules, and specific or secondary granules are the three
types of granules found within eosinophils. The latter granules
account for most of the biologic activity of eosinophils and are toxic
to parasites, tumor cells, and some epithelial cells.
74
Eosinophils have phagocytic activity, catalyze the oxidation of
many substances, facilitate killing of microorganisms, initiate mast
cell secretion, protect against various parasites, and play some role
in host defense. Eosinophilia is probably most commonly associated
with allergic reactions to drugs, allergic disorders (eg, hay fever,
asthma, and eczema), invasive parasitic infections (eg, hookworm,
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schistosomiasis, and trichinosis), collagen vascular diseases (eg,
rheumatoid arthritis, eosinophilic fasciitis, and eosinophilia–myalgia
syndrome), and malignancies (eg, Hodgkin lymphoma).
74–77
BASOPHILS
Reference Range: 0%–3% of WBCs
During infection or inflammation, basophils leave the blood and
mobilize as mast cells to the affected site and release granules.
These granules contain histamine, serotonin, prostaglandins, and
leukotrienes. Degranulation results in an increased blood flow to the
site and may compound inflammatory processes. An increase in
basophils commonly accompanies allergic and anaphylactic
responses, chronic myeloid leukemia, myelofibrosis, and
polycythemia vera. A decrease in the number of basophils is
generally not readily apparent because of the small number of these
cells in the blood.
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CASE 2-5
QUESTION 1: K.T., a 50-year-old female, is hospitalized with a sustained high
fever of 102.56 °F (39.2 °C) and severe back pain. The results of the CBC and
leukocyte differential are as follows:
Total WBC count: 21,000/μL
Neutrophils: 74%
Bands: 6%
Lymphocytes: 14.6%
Monocytes: 8%
Eosinophils: 1%
Basophils: 0%
Imaging and other blood work were ordered. K.T. is diagnosed with an
abscess in her lower back and Staphylococcus aureus bacteremia.
How is K.T.’s laboratory report consistent with a systemic bacterial infection?
WBCs are the host’s chief defense system, and the neutrophil is
the main component of that system. During bacterial infections, the
leukocyte count and the neutrophils are generally increased, and a
left shift (increase in bands) may be noticeable. The percentage of
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other types of WBCs is decreased proportionately because the
number of neutrophils is increased.
As the infection progresses, the percentage of band cells may
decrease as a result of an increase in the number of neutrophils that
have a longer half-life. This decrease in bands does not necessarily
indicate improvement. A decrease in the percentage of neutrophils
with a decrease in the total WBC count is characteristic of effective
antibiotic therapy.
CASE 2-5, QUESTION 2: The S. aureus causing K.T.’s bacteremia is found to be
methicillin sensitive, and she is started on oxacillin 2 million units IV every 4
hours for treatment. After about a week of therapy, K.T. develops a fine red rash
all over her body, mild lymphadenopathy, low-grade fever, and generalized
swelling. The CBC shows a total WBC count of 8600/μL with 11% eosinophils.
What is the significance of this eosinophil count?
In the clinical setting, absolute leukocyte counts may be used in
conjunction with normal reference values. Absolute counts are
calculated by multiplying the percentage of each individual cell by
the total leukocyte count. Eosinophils are usually increased in
allergic reactions; therefore, a drug-induced hypersensitivity reaction
is a strong probability in K.T., with an absolute count of 946
eosinophils/μL (ie, 11% of 8600 leukocytes). The clinician should be
suspicious of an allergic drug reaction when absolute eosinophil
counts exceed 300 cells/μL. Eosinophils may increase before, after,
or concurrent with other evidence of allergy (eg, rash). Eosinophilia
without evidence of allergy is not sufficient cause to discontinue a
suspected medication unless the eosinophilia is significant (ie,
>2000 cells/μL). In addition, the absence of eosinophilia certainly
does not rule out an allergic diagnosis in a patient exhibiting clear
clinical manifestations of an apparent allergic reaction.
Thrombocytes
Reference Range: 150–450 × 103/μL or 150–450 × 109/L
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Thrombocytes, commonly referred to as platelets, are tiny fragments
of cells that assist with normal blood clotting. Platelet testing is
included as part of a CBC and is often ordered along with other
coagulation studies to evaluate bleeding and/or clotting disorders.
Decreased platelet counts or thrombocytopenia may lead to
petechiae, ecchymosis, and spontaneous hemorrhage.
Causes include decreased platelet production, accelerated
destruction, loss from excessive bleeding or trauma, dilution of blood
samples secondary to blood transfusion, sequestration secondary to
hypersplenism, disseminated intravascular coagulation, infection, or
systemic lupus erythematosus. Malignancy, rheumatoid arthritis, iron
deficiency anemia, polycythemia vera, and post splenectomy
syndromes are the most common causes of elevated platelet counts
or thrombocytosis.
Coagulation Studies
The control of bleeding depends on the formation of a platelet plug
and the formation of a stable fibrin clot. The formation of this clot
depends on the complex interactions of plasma proteins and clotting
factors. The prothrombin time (PT), international normalized ratio
(INR), and activated partial thromboplastin time (aPTT) are used to
diagnose coagulation abnormalities or to monitor the effectiveness of
patients receiving anticoagulation therapy. When used to assess
drug therapy, achieving a value outside the reference range is in fact
a therapeutically desirable outcome.
ACTIVATED PARTIAL THROMBOPLASTIN TIME
Reference Range: 22–37 seconds
aPTT measures the time it takes the body to form a clot. aPTT
depends on the activity of factors VIII, IX, XI, and XII (intrinsic
pathway) and the factors involved in the final common pathway of
the clotting cascade (II, X, and V). aPTT is commonly measured to
detect bleeding disorders and coagulation deficiencies and monitor
unfractionated heparin therapy. The reader is referred to Chapter 11,
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Thrombosis, for more detailed information regarding the use of
coagulation parameters in treating and monitoring thrombotic
disorders.
PROTHROMBIN TIME
Reference Range: 10–13 seconds
Prothrombin is synthesized in the liver, and is converted to thrombin
during the blood clotting process. Thrombin formation is the critical
event in the hemostatic process because thrombin creates fibrin
monomers that ultimately assemble into a clot and stimulates platelet
activation. The PT test evaluates the integrity of the extrinsic and
common pathways and directly measures the activity of clotting
factors V, VII, and X, prothrombin (factor II), and fibrinogen (factor I).
Automated laboratory instruments measure PT by recording the time
required for the blood to clot after a reagent (ie, tissue
thromboplastin) has been added to the patient’s blood sample. It is
recorded in seconds and is compared to a normal range that reflects
PT values in healthy individuals. An abnormal PT is often caused by
liver injury and/or by treatment with systemic blood thinners.
INTERNATIONAL NORMALIZED RATIO
Because different labs use different reagents, the PT results
obtained from one reagent cannot be reliably compared with another
reagent. Therefore, the INR is used as a standard unit to report the
result of a PT test. The INR is the recommended method to monitor
both the initiation and maintenance of anticoagulant therapy, most
notably warfarin. Individuals who have normal blood clotting and are
not on anticoagulation therapy should have an INR of 1. For patients
on anticoagulation therapy, the target INR (ie, therapeutic range) is
usually between 2.0 and 4.0 depending on the clinical indication and
other patient-specific factors. Outside of the therapeutic range, the
higher the INR, the higher the likelihood of bleeding because the
blood is taking longer to clot. Conversely, if the INR is lower, there is
an increased risk of developing a clot. Many factors including
medications (eg, metronidazole, trimethoprim–sulfamethoxazole,
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(Eq. 2-12)
amiodarone, and azole antifungals), vitamin K intake, alcohol use,
and certain medical conditions (eg, HF, cancer, and thyroid
disorders) can influence the INR.
The INR is calculated using Eq. 2-12, where the prothrombin ratio
(PTR) is the ratio between the patient’s PT and the laboratory’s
control PT, and the ISI is the international sensitivity index.
Commercial manufacturers quantify the ISI for the specific
thromboplastin reagent used in each lot and report this information in
the product package insert:
URINALYSIS
A standard urinalysis includes physical, chemical, and microscopic
evaluations to assist with diagnosis of various urologic conditions. It
begins with a simple observation of the color and the gross general
appearance of the urine specimen. The urine pH and specific gravity
are then recorded. Formed elements in the urine are examined
microscopically, and the urine is searched routinely for pathologically
significant substances that are normally not present (eg, glucose,
blood, ketones, and bile pigments). Urine specimens should be
evaluated quickly after collection to minimize unreliable results. The
reader is referred to Chapter 71, Urinary Tract Infections, for a more
detailed description of the use of urinalysis in the detection and
monitoring of urinary tract infections (UTIs).
Gross Appearance of the Specimen
The concentrated, first-morning urine specimen is usually analyzed
to eliminate effects of undue dilution as a result of water intake. The
color should be slightly yellow, depending on the degree of dilution,
and the appearance should be clear. The appearance of the urine
may reveal clouds of crystals, bilirubin, blood, porphyrins, proteins,
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food or drug colorings, or melanin. Discolored urine is abnormal. A
red coloration of the urine may be imparted by blood, porphyria, or
ingestion of phenolphthalein. A brown urine color may be caused by
the acid hematin of blood or from melanin pigments. Medications
such as nitrofurantoin and/or metronidazole can also contribute to
this color change. Excessive excretion of urobilinogen or the effects
of drugs such as rifampin or phenazopyridine may cause a dark
orange urine color. A blue to blue-green color of the urine may result
from the systemic administration of methylene blue.
Specimen pH
When freshly produced, urinary pH can range from 4.5 to 8 but is
mostly acidic because of metabolic activity. Alkaline urine may
indicate an aged specimen, systemic alkalosis, failure of renal
acidifying mechanisms, or infection in the urinary tract.
Specific Gravity
Urinary specific gravity provides information regarding a patient’s
hydration status. A normal morning urine specimen should have a
specific gravity of 1.003 to 1.030. The upper end of this range is
close to the maximal concentrating ability of the kidney. A value of
≤1.010 supports relative hydration, whereas a value >1.020 indicates
relative dehydration.
Protein
Proteinuria is a classic sign of renal injury. If proteinuria is found
during the evaluation of a patient with a nonrenal illness, it suggests
that the disease may also involve the kidneys (ie, hypertension and
diabetes).78 A healthy adult generally excretes 30 to 130 mg/day of
protein into the urine.
Protein in a urine sample is generally tested qualitatively on a
random urine sample by a dipstick method and is usually reported on
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a scale of 0 (<30 mg/dL), 1+ (30–100 mg/dL), 2+ (100–300 mg/dL),
3+ (300–1000 mg/dL), and 4+ (>1000 mg/dL). A positive qualitative
test result for urine protein should be repeated after a few days
because transient proteinuria can accompany various physiologic
and pathologic states, even when kidney function is normal.
Therefore, patients with HF, seizures, or febrile illnesses and normal
renal function need not undergo invasive renal function tests if the
proteinuria is modest and likely to be transient. Another qualitative
evaluation of proteinuria can be performed in about 2 weeks to
confirm the diagnosis of transient proteinuria.79 If subsequent
qualitative test results are positive, a 24-hour urine sample should be
collected to quantitatively test for protein and creatinine (see the
section on Creatinine Clearance). In patients with a normal 24-hour
urinary protein concentration, previous positive qualitative test
results probably represent either false-positive results or a transient
phenomenon.78 A laboratory parameter being used with increased
frequency to assess proteinuria is the urine albumin to urine
creatinine ratio (UACR). This measurement tends to be less
influenced by fluctuations in urine concentration and may offer a
more reliable indication of proteinuria. The reference range for
UACR is <30 mg/g.
MICROSCOPIC EXAMINATION
The urine sediment is examined for RBCs, WBCs, casts, yeast,
crystals, and epithelial cells.
RBCs should be absent in normal urine, although <4 to 6 RBCs
per high-power field (HPF) would still be considered in the normal
range. Bleeding or clotting disorders, some collagen diseases, and
various bladder, urethral, and prostatic conditions may cause
microscopic hematuria. In females, vaginal blood occasionally
contaminates the urine specimen, but the presence of numerous
squamous epithelial cells should be sufficient to alert clinicians to
this artifact.
WBCs should be virtually absent in normal urine, although up to 5
WBCs/HPF would still be within the reference range. Similarly,
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