Page 1021 - Williams Hematology ( PDFDrive )

996 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 65: Neutropenia and Neutrophilia 997

tocilizumab. 116,117 Results with these therapies are unpredictable. 122,127
Many specialists prefer weekly methotrexate because of its ease of
administration, efficacy, and low toxicity. G-CSF or GM-CSF can
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increase neutrophils but may exacerbate arthralgias. Combinations
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of these agents is another good alternative. Splenectomy is followed
by a rapid increase in counts in approximately two-thirds of cases, but
approximately two-thirds of patients who respond to splenectomy have
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recurrence of neutropenia. A subset of patients with Felty syndrome
have a high blood concentration of large granular lymphocytes with
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a phenotype characteristic of immature natural killer cells. These
patients tend to respond poorly to therapies directed toward increas-
ing neutrophil levels but may respond to combinations of methotrexate
and G-CSF. Several factors in addition to neutropenia predispose these
patients to infections, including monocytopenia, hypocomplemen-
temia, circulating immune complexes, and treatment with glucocorti-
coids or cytotoxic drugs. In general, treatments to correct neutropenia
should be reserved for patients with documented infections.
Figure 65–3. Morphology of a marrow sample from a patient with Other Causes of Neutropenia Associated with Splenomegaly In
autoimmune neutropenia, demonstrating a normal maturation of neu- 1942, Wiseman and Doan described a disorder they called primary
122
trophil precursors. splenic neutropenia. Since then, a variety of diseases have been rec-
ognized as also possibly causing this type of neutropenia, or pseudo-
Systemic Lupus Erythematosus Total leukocyte counts usually neutropenia. Diseases associated with splenomegaly and neutropenia
are between 2 and 5 × 10 /L and neutrophils are less than 1.8 × 10 /L in include sarcoidosis, lymphoma, tuberculosis, malaria, kala azar, and
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approximately 50 percent of patients with systemic lupus erythemato- Gaucher disease. Usually thrombocytopenia and anemia are present
sus. 108–110,123 Mild neutropenia often is accompanied by monocytopenia as well. Immune mechanisms in patients with inflammatory diseases
and lymphocytopenia, anemia, thrombocytopenia, and mild degrees are similar to the mechanisms observed in patients with systemic lupus
of splenomegaly. Marrow cellularity and maturation of cells usually erythematosus and Felty syndrome may be operative. In other patients,
are normal. An increased amount of IgG is present on the surface of sluggish blood flow through the spleen with passive trapping of neu-
neutrophils, and immune complexes are increased within the neu- trophils in the congested red pulp probably is the primary cause. For the
trophils. Fas and tumor necrosis factor-related apoptosis-inducing most part, the neutropenia in these patients is not sufficiently severe to
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ligand (TRAIL) mediate many of the clinical features of autoimmune be of clinical consequence. Removal of the spleen to raise the neutrophil
diseases, including apoptosis of neutrophils in systemic lupus erythe- count is rarely indicated.
matosus. Glucocorticoids, G-CSF, and GM-CSF elevate neutrophils in
most patients with lupus, including patients on immunosuppressive
therapies, but the mild neutropenia of these patients usually does not DRUG-INDUCED NEUTROPENIA
require treatment. 110 Idiosyncratic drug reactions cause neutropenia with an estimated
Rheumatoid Arthritis, Sjögren Syndrome, and Felty Syn- annual frequency of three to 12 cases per 1 million population. 123–125 In
drome Leukopenia in association with rheumatoid arthritis is unusual, 1922, Schultz reported six cases of severe sore throat and prostration
128
occurring in less than 3 percent of large series of patients. Approx- with absent blood neutrophils, which led rapidly to sepsis and death. A
124
imately 1 percent of patients with rheumatoid arthritis develop addi- few years later, this syndrome was associated with the coal tar–derived
tional features of Felty syndrome (splenomegaly, deforming rheumatoid drug aminopyrine. Over the past 50 years, scores of other drugs have
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arthritis, and leukopenia). Usually, these patients have had active, been recognized to cause this syndrome.
deforming arthritis and very high rheumatoid factor titers. The neutro- Two main types of idiosyncratic drug-induced neutropenia are
penia may be moderate to severe; occasionally patients are seen with no recognized. 128,129 One type is a dose-related toxicity resulting from
circulating neutrophils. The marrow usually is normal or hypercellular interference of the drug with protein synthesis or cell replication. This
but occasionally is hypocellular. Granulopoiesis usually is marked by effect often is nonselective. It can involve the hematopoietic stem cell
sufficient precursors but few band or segmented neutrophils. No clear and highly proliferative cells in other organs, such as the epithelial cells
relationship between spleen size and the neutrophil count is evident. of the gastrointestinal tract. Prototype drugs for this type of reaction
The incidence of bacterial infections in patients with Felty syn- include phenothiazines, antithyroid drugs, chloramphenicol, and clo-
drome is low until the neutrophil count is less than 0.2 × 10 /L, which zapine. 130,131 Similar effects on marrow cells may be mediated through
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has long suggested that neutrophils are made but that their blood kinet- free radicals and drug metabolites. Patients receiving multiple drugs
ics are altered. The altered kinetics may result from high levels of circu- and patients having high plasma concentration of drugs as a result of
lating and intracellular immune complexes and IgG on the surface of the dose administered, slow metabolism, or renal excretory impairment
neutrophils. Cellular injury via Fas-mediated apoptosis is an additional are more prone to these reactions. 130
mechanism for cell loss from the marrow and blood. 125 A second type of drug-induced neutropenia may not be dose
In Sjögren syndrome, approximately 30 percent of patients have related. The neutropenia is thought to be allergic or immunologic in
moderate leukopenia. The total leukocyte count usually is 2 to 5 × 10 /L origin, similar to drug-induced skin reactions and drug-initiated, anti-
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with a normal differential count. 115,126 Rarely, severe neutropenia occurs body-mediated erythrocyte destruction. Many drugs can trigger this
in association with recurrent bacterial infections. form of neutropenia. Women are affected more often than men. Older
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Therapeutic options for management of neutropenia in these patients are affected more frequently than younger patients. Patients
autoimmune disorders include methotrexate, glucocorticoids, G-CSF, with a history of allergies, including allergies to other drugs, are affected
GM-CSF, splenectomy, and biologic agents such as rituximab and more often than individuals without allergies. Neutropenia may occur

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