Porth's Essentials of Pathophysiology, 4e

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Disorders of White Blood Cells and Lymphoid Tissues

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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

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- 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