C h a p t e r 1 1
Disorders of White Blood Cells and Lymphoid Tissues
247
Recent genetic studies in people of African descent
have highlighted the role of the gene encoding the
Duffy antigen receptor for chemokines (DARC). This
genetic trait is strongly associated with protection
against malaria.
11
Pathogenesis
The reduction in the number of granulocytes in the
blood (neutropenia) can be seen in a wide variety of
conditions, including neoplasms, autoimmune disor-
ders, and drug effect (Chart 11-1). Neutropenia is also
a feature of a group of rare inherited disorders, such as
Kostmann syndrome.
8
Congenital Neutropenia.
A decreased production
of granulocytes is a feature of a group of hereditary
hematologic disorders, including cyclic neutropenia and
Kostmann syndrome.
9–11
Periodic
or
cyclic neutropenia
is an autosomal dominant disorder with variable expres-
sion that begins in infancy and persists for decades. It
is characterized by periodic neutropenia that develops
approximately every 21 days and lasts approximately
2 or 3 days.
8
Although the cause is undetermined, it is
thought to result from impaired feedback regulation
of granulocyte production and release. Severe congeni-
tal neutropenia, also known as
Kostmann syndrome,
is a rare inherited form of neutropenia.
9–11
The condi-
tion occurs sporadically or as an autosomal recessive
disorder, causing severe neutropenia while preserving the
erythroid and megakaryocyte cell lineages that result in
red blood cell and platelet production. The syndrome is
usually recognized at birth or shortly thereafter. Infants
with the syndrome have almost no neutrophils that
develop beyond the promyelocyte stage (see Fig. 11-3).
Treatment includes the administration of G-CSF. Before
the advent of effective therapy, almost all patients died
in early childhood.
Acquired Neutropenia.
A number of conditions,
including aplastic anemia and treatment with cancer
chemotherapeutic drugs and irradiation, may cause
suppression of bone marrow stem cells, with decreased
production of all blood cell types.
8–10
Overgrowth of
neoplastic cells in cases of nonmyelogenous leukemia
and lymphoma also may suppress the function of neu-
trophil precursors. In splenomegaly, neutrophils may
be trapped in the spleen along with other blood cells.
Autoimmune disorders or idiosyncratic drug reactions
may cause increased and premature destruction of neu-
trophils. In Felty syndrome, a variant of rheumatoid
arthritis, there is increased destruction of neutrophils in
the spleen. Infections by viruses or bacteria may drain
neutrophils from the blood faster than they can be
replaced, thereby depleting the neutrophil storage pool
in the bone marrow.
8
Many cases of neutropenia are drug related. Chem
otherapeutic agents used in the treatment of cancer
(e.g., alkylating agents, antimetabolites) cause pre-
dictable dose-dependent suppression of bone marrow
function. The term
idiosyncratic
is used to describe
drug reactions that are different from the effects
observed in most persons and that cannot be explained
in terms of allergy. A number of drugs, such as chlor-
amphenicol (an antibiotic), phenothiazines (antipsy-
chotic agents), propylthiouracil (used in the treatment
of hyperthyroidism), and phenylbutazone (used in the
treatment of arthritis), may cause idiosyncratic depres-
sion of bone marrow function.
7,8,10
Many idiosyncratic
cases of drug-induced neutropenia are thought to be
caused by immunologic mechanisms, with the drug
or its metabolites acting as antigens (i.e., haptens) to
incite the production of antibodies reactive against the
neutrophils.
Clinical Course
The clinical features of neutropenia usually depend on
the cause and severity of the disorder. Neutropenia from
any cause places persons at risk for infection by gram-
positive and gram-negative bacteria and by fungi. The
risk of infection is related to the severity of the neu-
tropenia. Persons with chronic benign neutropenia are
often free of infection despite low neutrophil counts.
Neutrophils provide the first line of defense against
organisms that inhabit the skin and gastrointestinal
tract. Thus, skin infections and ulcerative necrotizing
lesions of the mouth are common types of infection in
neutropenia. The most frequent site of serious infection
CHART 11-1
Principal Causes of Neutropenia
Congenital
Alloimmune neonatal neutropenia (transfer of
maternal antibodies)
Cyclic neutropenia
Kostmann syndrome (severe congenital neutropenia)
Acquired
Autoimmune
Primary (rare, usually occurs in children and runs a
benign course)
Secondary
Systemic lupus erythematosus
Felty syndrome in persons with rheumatoid arthritis
Infection related
Various infectious agents (most commonly viruses)
Mechanisms include increased consumption of
neutrophils, production of autoantibodies, direct
infiltration of hematopoietic cells, bone marrow
suppression
Drug related
Immune-mediated reactions in which drugs act
as haptens (e.g., penicillin, propylthiouracil,
aminopyrine)
Accelerated apoptosis (clozapine [antipsychotic
agent])
Bone marrow depression (i.e., vinblastine and other
cancer chemotherapeutic agents)
Radiation therapy to bone marrow
Hematologic malignancies
