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NEIL ABRAMSON, M.D., and BECKY MELTON, M.D.


Baptist Regional Cancer Institute, Jacksonville, Florida
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Leukocytosis, defined as a white blood cell count greater than 11,000 per mm (11 X 10 per L), is
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frequently found in the course of routine laboratory testing. An elevated white blood cell count typically
reflects the normal response of bone marrow to an infectious or inflammatory process. Occasionally,
leukocytosis is the sign of a primary bone marrow abnormality in white blood cell production, maturation
or death (apoptosis) related to a leukemia or myeloproliferative disorder. Often, the family physician can
identify the cause of an elevated white blood cell count based on the findings of the history and physical
examination coupled with basic data from the complete blood count.

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Common progenitor cells, referred to as "stem cells," are located in the bone marrow and give rise to
erythroblasts, myeloblasts and megakaryoblasts. Three quarters of the nucleated cells in the bone marrow
are committed to the production of leukocytes. These stem cells proliferate and differentiate into
granulocytes (neutrophils, eosinophils and basophils), monocytes and lymphocytes, which together
comprise the absolute white blood cell count. Approximately 1.6 billion granulocytes per kg of body
weight are produced each day, and 50 to 75 percent of these cells are neutrophils. An abnormal elevation
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in the neutrophil count (neutrophilia) occurs much more commonly than an increase in eosinophils or
basophils.
The maturation of white blood cells in the bone marrow and their release into the circulation are
influenced by colony-stimulating factors, interleukins, tumor necrosis factor and complement
components. Approximately 90 percent of white blood cells remain in storage in the bone marrow, 2 to 3
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percent are circulating and 7 to 8 percent are located in tissue


compartments.

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The cells within the bone marrow compartment are classified  

   
  

into two populations: those that are in the process of DNA

synthesis and maturation and those that are in a storage phase awaiting release into the circulating pool.
The storage of maturing cells allows for rapid response to the demand for increased white blood cells,
with a two- to threefold increase in circulating leukocytes possible in just four to five hours.

The circulating pool of neutrophils is divided into two classes. One pool of cells is circulating freely, and
the second pool is deposited along the margins of blood vessel walls. When stimulated by infection,
inflammation, drugs or metabolic toxins, the deposited cells "demarginate" and enter the freely circulating
pool.

Once a leukocyte is released into circulation and tissue, it remains there only a few hours, at which time
cell death occurs. The estimated life span of a white blood cell is 11 to 16 days, with bone marrow
maturation and storage comprising the majority of the
cell's life.

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The investigation of leukocytosis begins with an

understanding of its two basic causes: (1) the appropriate   




 

response of normal bone marrow to external stimuli and !  

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(2) the effect of a primary bone marrow disorder.   


 


Physiologic mechanisms of leukocytosis are listed in 0 -


  
  

 
 

Table 1. 1-
 

 

 

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In most instances, increased white blood cell counts are (


   

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the result of normal bone marrow reacting to


   
 

inflammation or infection. Most of these cells are

polymorphonuclear leukocytes (PML). Circulating PML and less mature forms (e.g., band cells and
metamyelocytes) move to a site of injury or infection. This is followed by the release of stored
leukocytes, commonly referred to as a "left shift." Inflammation-associated leukocytosis occurs in tissue
necrosis, infarction, burns and arthritis.
Leukocytosis may also occur as a result of physical and emotional stress. This is a transient process that
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is not related to marrow production or the release of band cells or other immature cells. Causes of stress
leukocytosis include overexertion, seizures, anxiety, anesthesia and epinephrine administration. Stress
leukocytosis reverses within hours of elimination of the inciting factor.

Other causes of leukocytosis include medications, splenectomy, hemolytic anemia and malignancy.
Medications commonly associated with leukocytosis include corticosteroids, lithium and beta agonists. 1,6,7

Splenectomy causes a transient leukocytosis that lasts for weeks to months. In hemolytic anemia,
nonspecific increases in leukocyte production and release occur in association with increased red blood
cell production; marrow growth factors are likely contributors. Malignancy is another recognized cause of
leukocytosis (and, occasionally, thrombocytosis); the tumor nonspecifically stimulates the marrow to
produce leukocytosis.

An excessive white blood cell response (i.e., more than 50,000 white blood cells per cm [50 X 10 per L])
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associated with a cause outside the bone marrow is termed a "leukemoid reaction." Even this exaggerated
white blood cell count is usually caused by relatively benign processes (i.e., infection or inflammation).
An underlying malignancy is the most serious but least common cause of a leukemoid reaction.

As mentioned previously, an increase in neutrophils is the most common cause of an elevated white blood
cell count, but other subpopulations of cells (eosinophils, basophils, lymphocytes and monocytes) can
also give rise to increased leukocyte numbers.

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Eosinophils are white blood cells that participate in immunologic and allergic events. Common causes of
eosinophilia are listed in Table 2. The relative frequency of each cause usually relates to the clinical
setting. For example, parasitic infections are often responsible for eosinophilia in pediatric patients, and
drug reactions commonly cause an increased eosinophil count in hospitalized patients. Dermatologists
frequently find eosinophilia in patients with skin rashes, and pulmonologists often see elevated numbers
of eosinophils in conjunction with pulmonary infiltrates and bronchoallergic reactions.

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Other causes of eosinophilia include malignancies, especially those affecting the immune system
(Hodgkin's disease and non-Hodgkin's lymphoma), and immunologic disorders such as rheumatoid
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arthritis and periarteritis. Eosinophilia-myalgia syndrome, a recently described disorder associated with
dietary supplements of tryptophan, resembles a connective tissue disease with fibrosis of muscle fascial
tissue and peripheral eosinophilia. 9

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Basophilia is an uncommon cause of leukocytosis. Basophils are inflammatory mediators of substances
such as histamine. These cells, along with similar tissue-based cells (mast cells), have receptors for IgE
and participate in the degranulation of white blood cells that occurs during allergic reactions, including
anaphylaxis. Causes of basophilia, some of uncertain origin,
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are listed in Table 3.

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Lymphocytes normally represent 20 to 40 percent of   


 

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circulating white blood cells. Hence, the occurrence of

lymphocytosis often translates into an increase in the overall white blood cell count. Increased numbers of
lymphocytes occur with certain acute and chronic infections (Table 4). Malignancies of the lymphoid
system may also cause lymphocytosis.

Relative, rather than absolute, leukocytosis occurs in a number of clinical situations, such as infancy, viral
infections, connective tissue diseases, thyrotoxicosis and Addison's disease. Splenomegaly causes relative
lymphocytosis as a result of splenic sequestration of granulocytes.

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Clinical factors that increase suspicion of an underlying bone marrow disorder are listed in Table 5. Bone
marrow disorders are generally grouped into leukemias and myeloproliferative disorders.

Marrow abnormalities may occur with stem cells (acute leukemia) or more differentiated cells (chronic
leukemia). Delineating acute leukemias from chronic leukemias is clinically important because the acute
forms are more often associated with rapidly life-threatening complications such as bleeding, brain
infarction and infection. Differences in the clinical presentations of acute and chronic leukemias are
provided in Table 6.

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Patients with an acute leukemia often present with signs and symptoms of bone marrow failure, such as
fatigue and pallor, fever, infection and/or bleeding with purpura and petechiae. In acute leukemias, the
marrow is typically overpopulated with blast cells. These cells are indistinguishable from stem cells by
light microscopy, but the term "blast" implies an acute leukemic clone. The maturing normal marrow
cellular elements are decreased or absent. Peripheral leukemic cell counts may range from leukocytosis to
leukopenia, but, as anticipated, anemia and thrombocytopenia are common.

The acute leukemias are broadly divided into two classes based on the cell of origin: acute lymphocytic
leukemia and acute nonlymphocytic leukemia. The previous designation of "acute myeloid leukemia" has
been replaced by "acute nonlymphocytic leukemia" to appropriately encompass the full variety of
possible abnormal cells (undifferentiated, myeloid, monocytic and megakaryocytic).
Acute lymphocytic leukemia most commonly occurs in children less
than 18 years of age. Adults usually have acute nonlymphocytic
leukemia. Occasionally, patients with acute lymphocytic leukemia
have a mediastinal mass or central nervous system involvement at the
onset of illness.

Blast cells are often seen in the peripheral blood smears of patients

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with acute leukemia. Auer rods, as shown in  e 1, are a marker of  




  



acute nonlymphocytic leukemia. Because Auer rods do not appear   


   
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frequently, precise distinction between acute lymphocytic leukemia     


 
 



and acute nonlymphocytic leukemia usually cannot be accomplished   


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based on the peripheral smear alone; histochemistry, immunotyping  




 


and chromosome analysis are usually required.    


 
 
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All patients with acute leukemia require prompt attention and therapy.    
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White blood cell counts in excess of 100,000 per mm (100 X 10 per L) constitute a medical emergency
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because patients with this degree of leukocytosis are predisposed to brain infarction or hemorrhage.

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Patients with a chronic leukemia typically present with much less severe illness than those with an acute
leukemia. Chronic leukemia is usually diagnosed incidentally based on high white blood cell counts. The
chronic leukemias are divided into two groups according to the cell of origin: chronic lymphocytic
leukemia and chronic myelogenous leukemia.

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Chronic lymphocytic leukemia results from the proliferation
 

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and persistence (lack of apoptosis) of relatively mature-


   

appearing lymphocytes ( e 2). The spleen and lymph

nodes are enlarged because of the excessive accumulation of


lymphocytes. Despite the increased number of lymphocytes, this disease is associated with impaired
immunity as a result of the scarcity of normal lymphocytes.

Unless complications are present, patients with chronic lymphocytic leukemia do not require urgent
referral to a hematologist. In the absence of symptoms, such as fever, sweats, weight loss, anemia,
moderate thrombocytopenia or organ enlargement, the leukocytosis usually does not require treatment.

Chronic myelogenous leukemia, which affects myeloid cells (polymorphonuclear cells and less mature
cell forms), is frequently diagnosed after the incidental finding of a high white blood cell count. A
peripheral blood smear from a patient with this form of leukemia is shown in  e 3. In some
situations, the smear can also show increases in basophils or eosinophils.

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Middle-aged adults more commonly develop chronic myelogenous leukemia. Some patients describe
fatigue, bleeding or weight loss. Splenomegaly is frequently present, and the markedly enlarged spleen
sometimes causes abdominal discomfort, indigestion or early satiety. Lymphadenopathy is uncommon.

Platelet counts are usually normal to increased. In fact, chronic myelogenous leukemia is the only
leukemic process that is associated with thrombocytosis. Another laboratory feature that distinguishes this
disease from other leukemias and myeloproliferative disorders is the presence of the Philadelphia
chromosome, an abnormality of translocation between chromosome 22 and chromosome 9.

Chronic myelogenous leukemia eventually develops an accelerated phase and subsequently transforms
into acute leukemia. The accelerated phase is characterized by fever, sweats, weight loss, bone pain,
bruising and hepatosplenomegaly. During this time, thrombocytopenia and anemia develop. The median
time for transformation of chronic myelogenous leukemia to acute leukemia is two to five years. After the
development of acute leukemia, median survival is short.

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The myeloproliferative disorders include chronic myelogenous leukemia, polycythemia vera,
myelofibrosis and essential thrombocythemia (Table 7). Because all of these entities may present with
leukocytosis, differentiation can be difficult and usually requires special laboratory studies and bone
marrow examinations. 11

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Polycythemia vera usually presents with excessive numbers of erythroid cells, but increased white blood
cell and platelet counts may also be evident. Symptoms resulting from hypervolemia and hyperviscosity,
such as headache, dizziness, visual disturbances and paresthesias, are sometimes present. Less frequently,
patients with polycythemia vera develop myocardial infarction, stroke, venous thrombosis and congestive
heart failure. Overall survival is long (10 to 20 years).

Myelofibrosis is a bone marrow disorder in which fibroblasts replace normal elements of the marrow.
Patients with myelofibrosis are usually 50 years or older and have a median survival of less than 10 years.
As bone marrow fibrosis develops, patients can present with leukocytosis, although decreased white
blood cell, red blood cell and platelet counts are more common. Patients are asymptomatic early in the
course of the disease and are usually diagnosed incidentally based on changes in blood cell counts.
Symptomatic patients have fatigue, shortness of breath, weight loss, bleeding or abdominal discomfort
related to splenomegaly. Acute leukemia can develop over time and, when it occurs, progresses rapidly.

Leukocytosis is also found in patients with essential thrombocythemia (primary thrombocythemia).


Although elevated platelet counts occur in all myeloproliferative disorders, essential thrombocythemia is
distinguished by the singular prominence of platelets. Markers of other disorders, such as the Philadelphia
chromosome and bone marrow fibrosis, are absent. It is important to exclude secondary thrombocytosis
caused by nonmarrow disorders (e.g., iron deficiency or bleeding). Most patients with essential
thrombocythemia are asymptomatic and require little, if any, therapy, although some patients develop
thrombosis or hemorrhage secondary to increased numbers of dysfunctional platelets.

 
 

Excessive numbers of white blood cells are most often due to the response of normal bone marrow to
infection or inflammation. In some instances, leukocytosis is a sign of more serious primary bone marrow
disease (leukemias or myeloproliferative disorders). Attention to clinical factors associated with marrow
disorders, such as extremely elevated white blood cell counts, abnormalities in red blood cell or platelet
counts, weight loss, bleeding and organ enlargement, can help the family physician decide which patients
require further investigation and consultation.


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