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Disorders of Granulopoiesis

Neutrophils are the principal effector cells in host defenses against bacterial and fungal pathogens. These cells do not constitute a latent system of host defense. Rather, continuous turnover and resupply of neutrophils to tissues and to certain regions of the integument (in particular, the mucosal surfaces of the GI tract) are critical for maintaining health.

Unlike other blood cells, neutrophils (and the precursor cells committed to become neutrophils) spend most of their relatively brief lifespan (about 15 days) in the bone marrow. Under normal conditions only a small proportion of the body's supply of neutrophils is in the intravascular space (about 8%), and only half of these are circulating at any given time.

Normal granulopoiesis must support a cell population which is turning over very rapidly in the marrow, blood, and tissue compartments; approximately 2-3 times the number of neutrophils present in the intravascular space at any given time are used up and resupplied every day.

Monocytes are closely related to neutrophils. Not only are they derived from the same committed stern cell, but they share many of the same functional capacities as wandering phagocytes. Both cell types normally arrive at an acute P inflammatory site in a coordinated fashion (monocytes following neutrophils and, in a self-limited inflammatory process, replacing neutrophils within 12-24 hours). Monocytes, however, are not stored in the marrow.

The proliferation and maturation of myeloid progenitor cells is known to be regulated in part by specific hematopoietic hormones or "cytokines," including "colony stimulating factors" (CSFs; so-called because they stimulate primitive hematopoietic progenitor cells to proliferate and form colonies of cells in semisolid tissue culture media) or "interleukins" (ILs). Certain of these humoral factors, such as IL-6 and Stem Cell Factor (SCF) appear to "recruit" primitive.

Disturbed neutrophil production and turnover

Disturbances of granulopoiesis are revealed by abnormalities in absolute blood neutrophil counts. However, it should be kept in mind that only the circulating blood pool of neutrophils (< 4% of total neutrophil supplies) is measured by a CBC and differential. Normal ranges for blood neutrophil counts (95% confidence limits for a healthy Caucasian population) are shown below. In such a population, neutropenia is defined by an absolute neutrophil count of less than 1800/mm³ and neutrophilia by counts greater than 7300/mm^3. Among healthy African-Americans, the lower limit of normal for neutrophil counts is somewhat lower (-1300-1500/mm3). In assessing neutropenias it is important to consider the absolute monocyte count as well, for monocytopenia with neutropenia implies a reduction in the numbers.

The marrow storage and proliferative compartments are not readily quantified. However, inferences about these compartments may be drawn from nucleated cell differentials of marrow.

Neutrophilia

Neutrophilia may be caused by a chronic stimulation and expansion of the proliferative compartment, as occurs with infections, certain tumors, endocrinopathies, primary inflammatory diseases, or myeloproliferative diseases. Rapidly developing neutrophilias may, on the other hand, be caused by acute pool shifts from the marginated blood pool to the circulating pool.

Neutrophilia

Neutropenia

Neutropenia-like neutrophilia may be caused by transient or chronic pool shifts from the circulating to marginated blood compartments. However, for practical purposes neutropenia confirmed by successive CBCs almost always implies some degree of impairment in the production of mature neutrophils.

Neutropenias should be stratified. Mild neutropenias (absolute neutrophil counts of 1000-1500/ram3) and moderate neutropenias (500-1000/mm³⁾ are of clinical interest primarily because they demand diagnostic considerations of associated diseases or drug reactions. However, unless neutrophil counts are rapidly falling, they are not indicative of a significant host defense defect and specific interventions aimed at correcting the neutropenia are inappropriate. On the other hand, severe neutropenias (0-500/mm3) are regularly associated with an increased risk of infection. These risks, however, are highly variable and dependent.

Numbers (1+ - 4+) reflect the approximate frequencies of drug reactions associated with neutropenia that are encountered in clinical practice.

Underlying diseases associated with otherwise unexplained neutropenia are outlined below in their approximate order of frequency.