Neutropenia overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Neutropenia is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term leukopenia. However, neutropenia is more properly considered a subset of leukopenia as a whole. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression may present as a medical emergency.

Classification

Calculated based on blood count differential, neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).

- Mild Neutropenia: ANC 1,000-1500 cells/microliter

- Moderate Neutropenia: ANC 500-1000 cells/microliter

- Severe Neutropenia (Agranulocytosis): ANC <500 cells/microliter

NOTE: These ranges are based on Caucasian patients, whereas African Americans and some ethnicities have mild neutropenia without increased risk of complications. Neutropenia in African American individuals is defined as an ANC < 1200 cells/microliter. This often overlooked fact results in overdiagnosis of neutropenia in African American population.[1]

Severe chronic neutropenia may be present at birth (congenital neutropenia) or may occur at any stage in life (acquired neutropenia). There are several types of severe chronic neutropenia:

Severe congenital neutropenia — a rare inherited form of the disease usually detected soon after birth. It affects children mainly and may result in premature loss of teeth and peremptory gum infections. The most severe form of chronic congenital neutropenia is known as Kostmann’s syndrome. It is genetically heterogeneous. Most commonly, it arises as a result of new,autosomal dominant mutations in the gene, ELA2, encoding the neutrophil granule protease, neutrophil elastase, NE. The gene responsible for many cases of autosomal recessively inherited severe congenital neutropenia is HAX1. The mechanism for congenital neutropenia is not well-understood. There is evidence that mutations in neutrophil elastase, or in other genes associated with syndromic forms of neutropenia, disrupt its intracellular trafficking. Apoptosis may be a final effector for neutropenia, but the original studies from Dale and Aprikian supporting this pathway were retracted.

Cyclic neutropenia — tends to occur every three weeks and lasting three to six days at a time due to changing rates of cell production by the bone marrow. It is often present among several members of the same family. Cyclic neutropenia is also the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase.

Idiopathic neutropenia — a rare form of neutropenia which develops in children and adults usually in response to an illness. It is diagnosed when the disorder cannot be attributed to any other diseases and often causes life-threatening infections.

Myelokathexis — a rare form of inherited autosomal dominant disease associated with severe neutropenia. Some but not all patients have warts, Hypogammaglobulinemia, and recurrent Infections. Therefore myelokathexis is also known as the W.H.I.M. syndrome. In spite of severe neutropenia (low number of neutrophils) in peripheral blood of myelokathexis patients, their bone marrow is hypercellular and it is packed with mature neutrophils indicating an impaired mobilization of hematopoietic cells in this disorder. Truncating mutations in the human cytokine receptor CXCR4 gene were identified in most of the families afflicted by myelokathexis. The molecular mechanism is not yet defined. Recent reports demonstrate that CXCR4 mutations appear to result in an increased sensitivity of bone marrow hematopoietic cells to its ligand, a stromal-derived growth factor SDF-1 that provides proliferative and survival signals.

Autoimmune neutropenia — most common in infants and young children where the body identifies the neutrophils as enemies and makesantibody to destroy them. This form usually lessens in severity within two years of diagnosis.

Drug-induced neutropenia — Many drugs can cause agranulocytosis (complete absence of white cells) and neutropenia. Manyanti-neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or complement-mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About 75% of all cases of agranulocytosis in the United States are related to medication. Clozapine, File:Example.jpgprocainamide, anti-thyroid drugs (e.g. methimazole, and sulfasalazine are at the top of the list of drugs causing this problem, but many others (such as antiepileptics) have been implicated.

Pathophysiology

Neutropenia develops as a result of one of the three following mechanisms:

1) Impaired granulocyte production

- Hematologic malignancy with bone marrow infiltration

- Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow

- Nutritional deficiencies

2) Margination (process where free flowing blood cells exit circulation)

- Splenic sequestration

- Adherence to the vascular endothelium

3) Peripheral destruction

- Autoimmune hemolysis

- Drug-induced hemolysis