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992 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 65: Neutropenia and Neutrophilia 993

Basic in neutrophils when an alcoholic patient develops pneumococcal pneu-
Marrow pools Blood pools mechanism monia. Alcohol suppresses the marrow, and the infection consumes
Stem Mitotic Maturation- Marginal & the available neutrophil supply. After myelotoxic cancer chemotherapy,
cell storage circulating the abrupt fall in blood neutrophils at the onset of infections reflects
a similar mechanism: high demand and limited supply. With idiosyn-
MGP
Mi MSP Normal cratic drug-induced neutropenia, the counts may fall abruptly because
CGP both blood and marrow cells are simultaneously damaged. Acute neu-
tropenia that develops because of a shift of blood neutrophils from the
circulating to the marginal blood pools, that is, increased margination
(e.g., after injection of endotoxin, with exposure of blood to dialysis
Proliferation
membranes, or after intravenous granulocyte colony-stimulating fac-
tor [G-CSF] or granulocyte-macrophage colony-stimulating factor
Ineffective [GM-CSF]) usually is a transient event. The marginated cells reenter the
proliferation circulating pool, and the blood supply of neutrophils is rapidly restored
from the large reserves of marrow neutrophils entering the blood.
Cellular and Molecular Mechanisms of Neutropenia
Peripheral Our understanding of the mechanisms of neutropenia at the cellular
destruction and molecular levels is increasing rapidly because of advances in molec-
or ular genetics and cell biology. For many inherited forms of neutrope-
utilization nia, the genetic mutations causing these diseases are now known, and
the mutant protein products have been identified. Some mutations
and acquired defects shorten the survival of the precursor cells, that
Proliferation is, they accelerate apoptosis. This form of cell loss now is thought to
+
Peripheral loss be the mechanism for “maturation arrest” in several diseases. Exam-
or ples of increased apoptosis causing neutropenia include vitamin B
12
4
3
Ineffective or transcobalamin deficiency, clonal cytopenias (myelodysplasia),
6,7
5
proliferation myelokathexis, congenital and cyclic neutropenia, and the Shwach-
+ man-Diamond syndrome. Neutrophils also can be depleted from the
8
Peripheral loss blood and the marrow as a result of extrinsic factors such as antineu-
trophil antibodies and toxic cytokines generated by other cells. Some
9,10
disorders that cause neutropenia also perturb neutrophil function, such
as glycogen storage disease type 1b, Chédiak-Higashi syndrome, and
12
11
Marginal HIV infection. Susceptibility to infection in these conditions relates to
13
pool shift
the combination of defects.
or
Storage CAUSES OF NEUTROPENIA
pool egress Causes of neutropenia are classified physiologically as disorders of
production, distribution, or turnover. Not every condition fits neatly
Figure 65–1. Mechanisms of neutropenia are shown schematically. into this scheme, but it provides a framework for understanding these
The size of each pool is represented by the size of the cross-hatched diverse disorders.
areas. The rate of flow of cells through each compartment is represented
by the size of the arrows. CGP, circulating granulocyte (neutrophil) pool; Disorders of Production
MGP, marginated granulocyte (neutrophil) pool; Mi, mitotic; MSP, matu- Cytotoxic drugs given for cancer chemotherapy and as immunosup-
ration (marrow storage) pool.
pressive agents regularly cause neutropenia by decreasing cell produc-
tion (Chap. 22). These drugs now are probably the most frequent cause
of neutropenia in the United States. Neutropenia as a result of impaired
Myelotoxic chemotherapeutic drugs commonly cause neutropenia production is a common feature of several diseases affecting hemato-
because of the high proliferative activity of neutrophil precursors in the poietic stem cells, such as acute leukemia (Chaps. 88 and 91), the myel-
marrow and short half-life (4 to 8 hours) of neutrophils in the blood. odysplastic syndromes (Chap. 87), and aplastic anemia (Chap. 35). The
Production of neutrophils is defined as ineffective when, under a steady selective causes of impaired production, progressing from disorders of
state of hematopoiesis, a relative abundance of early neutrophil precur- early precursors to disorders presumed to involve defective maturation
sors, a paucity of late-maturing cells, and neutropenia occur. This con- (ineffective production), are described briefly as follows.
dition has often been referred to as “maturation arrest,” but it is almost Congenital Neutropenias (Kostmann Syndrome and Related
always explained by either the apoptotic loss of late precursors in the Disorders In 1956, Kostmann described congenital neutropenia
marrow as an intrinsic defect in cell maturation or rapid release of seg- (agranulocytosis) as an autosomal recessive disease occurring in an
14
mented neutrophils because of exaggerated tissue demands. extended family in northern Sweden. Phenotypically similar sporadic
Accelerated neutrophil utilization occurs with autoimmune neu- cases and families with autosomal dominant congenital neutrope-
tropenia and acute bacterial infections. When rapid neutrophil utiliza- nia have been reported. 15,16 In severe congenital neutropenia, symp-
tion and impaired production occur, acute severe neutropenia often toms and signs of otitis, gingivitis, pneumonia, enteritis, peritonitis,
develops. The condition is illustrated by the abrupt and sustained fall and bacteremia usually begin in the first months of life. At diagnosis,

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