Leukocytosis

Production, Maturation and Survival of Leukocytes

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.2 An abnormal elevation 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.3 Approximately 90 percent of white blood cells remain in storage in the bone marrow, 2 to 3 percent are circulating and 7 to 8 percent are located in tissue compartments.

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.

Etiology of Leukocytosis

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 (2) the effect of a primary bone marrow disorder. Physiologic mechanisms of leukocytosis are listed in Table 1.

TABLE 1

Pathophysiologic Mechanisms of Leukocytosis

Normally responding bone marrow

Infection

Inflammation: tissue necrosis, infarction, burns, arthritis

Stress: overexertion, seizures, anxiety, anesthesia

Drugs: corticosteroids, lithium, beta agonists

Trauma: splenectomy

Hemolytic anemia

Leukemoid malignancy

Abnormal bone marrow

Acute leukemias

Chronic leukemias

Myeloproliferative disorders

Leukocytosis with Normal Bone Marrow

In most instances, increased white blood cell counts are 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.

In hemolytic anemia, non-specific increases in leukocyte production and release occur in association with increased red blood cell production; marrow growth factors are likely contributors.