Page 513 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 32 Acquired Disorders of Red Cell, White Cell, and Platelet Production 433

inhibition of hematopoiesis by inflammatory cytokines, exhaustion Neutropenia and Hypersplenism
of marrow reserves, or redistribution.
Hypersplenism may be associated with neutropenia, but in most
Neutropenia Association With Nutritional Deficiency instances other cytopenias will also be present. However, hypersplen-
ism may be a sign of diseases that can result in neutropenia, such as
and Nutritional Excess in T-LGL leukemia 212–214 and Felty syndrome. Other than direct
sequestration, another potential mechanism leading to neutropenia
Malnutrition, dietary restrictions, malabsorptive states, and con- may be increased neutrophil apoptosis that normalizes after splenec-
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comitant intake of inhibitory drugs are just a few common causes tomy. A high incidence of Helicobacter pylori infection has also been
of nutritional deficiencies that may lead to neutropenia. Vitamin noted among individuals with neutropenia and splenomegaly. Sple-
B 12 and folate deficiency, frequently associated with megaloblastic nectomy either laparoscopically or through laparotomy may be
anemia, can also be associated with neutropenia. Lack of these effective in most cases, although in situations precluding splenectomy,
essential vitamin cofactors results in the impairment of normal intraoperative splenic artery embolization is also effective.
DNA synthesis, leading to abnormal granulopoiesis. A frequently
observed morphologic feature is the presence of hypersegmented
neutrophils. Pure White Cell Aplasia
Copper deficiency may also be associated with neutropenia. Pos-
sible mechanisms may include arrest in maturation of neutrophil PWCA is a rare condition with pathophysiologic overlap with some
development as shown in studies in mice and increased antineutro- forms of AIN associated with myeloid suppression. Similar to PRCA,
phil antibody formation. Most cases have been found in malnour- the pathogenesis may vary and includes antibody-mediated suppres-
ished infants, in patients with zinc intoxication and malabsorption sion of granulopoiesis, T cell–mediated suppression of granulopoiesis,
states, and in persons receiving total parenteral nutrition without direct myelotoxicity as seen with certain drugs, opsonization of
adequate copper supplementation. Copper deficiency is often neutrophil precursors in the bone marrow leading to its destruction
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accompanied by a normocytic anemia, whereas platelet counts are by macrophages within the bone marrow, and formation of an
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invariably normal. Other clinical and laboratory manifestations antibody-drug complex that may damage myeloid progenitors. A
associated with copper deficiency include the presence of ringed bone marrow examination reveals either a total absence of myeloid
sideroblasts in the bone marrow, macrocytic anemia, low ceruloplas- precursors or arrest at the promyelocyte stage, with megakaryocytes
min levels, myeloneuropathy, and skeletal abnormalities. Zinc and the erythroid series remaining quantitatively and qualitatively
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intoxication in the absence of concomitant copper deficiency has normal. In many cases, a thymoma is present. PWCA, if associated
also been associated with neutropenia generally in conjunction with with thymoma, has a variable clinical outcome. The complete absence
severe anemia. of granulocytic precursors portends a poor response to both immu-
nosuppression and thymectomy and is often fatal, whereas the pres-
ence of a maturation arrest at the promyelocyte stage may respond
Neutropenia Associated With Metabolic Disorders to immunosuppressive therapy. PWCA has been described in con-
nection with imipenem-cilastatin, ibuprofen, mesalamine, and
Various acquired or inherited metabolic conditions may be associated chlorpropramide. The discontinuation of the offending drug leads to
with neutropenia. For example, neutropenia has been observed in rapid improvement. PWCA has also been associated with primary
patients with ketoacidosis and hyperglycemia, orotic aciduria, or biliary cirrhosis.
methylmalonic aciduria. Similarly, glycogen storage disease type IB Therapeutic options may include azathioprine, G-CSF combined
is commonly associated with neutropenia responsive to myeloid with plasmapheresis especially if the disease process is antibody-
growth factors. mediated, methylprednisolone, IV cyclophosphamide combined with
plasmapheresis and G-CSF, and thymectomy. Severe depression of
counts may require ATG therapy (see later).
Acquired Neonatal Neutropenias
Neutropenia Associated With
Neutropenia has been described in infants of hypertensive mothers.
In this syndrome, the ANC can be severely depressed for up to 1 Immunologic Abnormalities
month postpartum. This type of neutropenia is associated with an
increased risk for early-onset sepsis in neonates, a prolonged duration Acquired and inherited defects of the cellular and humoral immune
of neutropenia, and an increased risk for neonatal nosocomial infec- system may be accompanied by secondary neutropenias. In the
tions. Granulocyte kinetic investigations suggested that the neutro- inherited immunodeficiency syndromes, the initial presentation is
penia is the result of diminished neutrophil production. An inhibitor neutropenic in children and may be associated with failure to thrive.
released by the placenta and present in cord blood serum has been X-linked agammaglobulinemia is a primary immunodeficiency dis-
shown to play a role in this syndrome. order caused by mutations in the gene for Bruton tyrosine kinase
Moderate to severe neutropenia has also been observed secondary (Btk) expressed in both myeloid and B cells that result in the absence
to IgG antibodies transferred from mother to infant. This is a condi- of development of B lymphocytes and hypogammaglobulinemia.
tion called isoimmune neonatal neutropenia or neonatal alloimmune Neutropenia is seen in 15% to 26% of patients with X-linked agam-
neutropenia. In most cases, antibodies are directed against antigens maglobulinemia, and most suffer from upper respiratory tract infec-
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on neutrophil FcγRIIIb (anti-NA1, anti-NA2, and anti-SH) and tions. The exact pathogenetic mechanism is not clear but is believed
NB1, 210,211 but in rare circumstances maternal neutrophil-specific to be related to the crucial role of Btk in myeloid survival under stress.
isoantibodies are also produced when there is deficiency of the Neutropenia is also seen in 40% to 50% of patients with X-linked
FcγRIIIb gene. The incidence of this condition can be as high as hyper-IgM syndrome and has been associated with defects of myelo-
2 : 1000 live births. In both neutropenia occurring in hypertensive poiesis. The most common form of hyper IgM syndrome is caused
mothers and isoimmune neonatal neutropenia, differentiation from by mutations in the CD40 gene. This defect also leads to a decrease
congenital forms of neutropenia may be difficult. Treatment in IgG and IgA. In addition to chronic anemia, children suffer from
with G-CSF is usually effective in neutropenia of infants of various infectious complications. They typically lack ANAs and
hypertensive mothers, but higher doses may be needed because pre- show an arrest at the promyelocyte-myelocyte stage of neutrophil
eclampsia-associated inhibitor of rhG-CSF may be present. IVIg and development. Allogeneic HSCT has been curative in some instances.
G-CSF are both effective for treatment of isoimmune neonatal Common variable immunodeficiency can be associated with
neutropenia. neutropenias that can be either chronic or episodic. In addition,