Eileen Scigliano, MD
Mount Sinai School of Medicine, New York, NY
Copyright of the American Society of Hematology, 2006. ISSN: 1931-6860.
This case was reviewed and updated in March 2013 by Dr. Marc J. Kahn and members of the Teaching Cases Subcommittee.
What are the major pathophysiologic mechanisms for granulocytosis?
Elevation of the granulocyte count may result from a primary bone marrow disorder resulting in autonomous proliferation of cells, or it may be a secondary response to an underlying condition, such as an infection or inflammation.
Primary bone marrow disorders associated with an increased number of neutrophils include hematopoietic stem cell disorders. The mechanism(s) leading to excessive proliferation of cells in these disorders are not always clear, but they may be related to molecular events (gene mutations and translocations) that induce cell proliferation or suppress apoptosis (programmed cell death).
Disorders associated with increased neutrophils:
- The myeloproliferative disorders
The myeloproliferative disorders are a group of acquired clonal hematopoietic stem cell disorders characterized by excessive proliferation of blood cells. Unlike acute leukemia, the myeloproliferative disorders are not associated with an arrest in maturation which results in a profound increase in the number of the most immature granulocytes called “blasts.”
- Chronic myelogenous leukemia (CML)
Chronic myelogenous leukemia is a clonal disorder of the hematopoietic stem cell, associated with marked expansion of progenitor, precursor and mature hematopoietic cells and their premature release into the peripheral blood. Clinically, the disease is characterized by granulocytosis, thrombocytosis, basophilia and splenomegaly, and typically evolves from an indolent, chronic phase of variable duration to acute leukemia. In CML the hematopoietic cells contain a reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in two derivative chromosomes, 9q+ and 22q-, the latter referred to as the Philadelphia (Ph1) chromosome.
- Polycythemia vera (PV)
Polycythemia vera is a clonal disorder of the hematopoietic stem cell in which the dominant feature is autonomous red cell proliferation resulting in an elevated red cell mass. Granulocytosis, thrombocytosis and splenomegaly are also commonly seen. Symptoms, including dizziness, headaches and tinnitus, result from hyperviscosity secondary to the increased hematocrit. Patients are at increased risk for thrombosis (etiology unknown) and bleeding (in part, secondary to platelet dysfunction). In about 1-2% of patients, the disease evolves into acute leukemia. PV is associated with a mutation in the JAK2 signaling molecule in over 95% of cases.
- Primary myelofibrosis
Primary myelofibrosis, also known as agnogenic myeloid metaplasia (AMM), is a clonal, hematopoietic stem cell disorder characterized by progressive fibrosis of the bone marrow, extramedullary hematopoiesis (blood production outside the bone marrow, usually in the liver and spleen, sites of hematopoiesis during fetal life) and massive splenomegaly. Patients may have elevated granulocyte and platelet counts, but they eventually develop bone marrow failure (from fibrosis) and pancytopenia. Acute leukemia develops in up to 20% of patients. As in PV, AMM is associated with a JAK2 mutation in about 30% of cases.
- Essential thrombocythemia (ET)
Essential thrombocythemia is a clonal hematopoietic stem cell disorder characterized by marked thrombocytosis, platelet dysfunction and an increased risk of thrombosis and bleeding. Granulocytosis and splenomegaly may be present as well. ET rarely progresses to acute leukemia. ET is associated with a JAK2 mutation in over 50% of cases.
An increased number of neutrophils is the hallmark of CML, but it is also commonly seen in PV. It is a less constant feature of primary myelofibrosis and ET.
Granulocytosis as a secondary response
The majority of cases of increased neutrophils seen in clinical practice are secondary to processes other than the myeloproliferative disorders. The mechanisms of secondary or reactive neutrophilia include:
- Increased bone marrow production of granulocytes
- Increased bone marrow release of granulocytes
- Demargination of granulocytes – a shift of granulocytes from the marginal pool (the population of granulocytes that roll along the endothelial lining of blood vessels) to the circulating pool. This is commonly seen in patients taking glucocorticoids.
- Decreased egress of granulocytes from the circulating pool to the tissues
Cytokines and chemotactic factors elicited during infection, inflammation and tissue damage are the mediators of these events. When the reactive granulocytosis is dramatic (leukocytosis >50,000/µL) and associated with an increase in early neutrophil precursors (bands, metamyelocytes, myelocytes), it is referred to as a leukemoid reaction.
Causes of reactive neutrophilia:
- Infection: Inflammatory cytokines (IL-2, TNF) released by lymphocytes and neutrophils, as well as endotoxin, result in increased bone marrow production and release of granulocytes from storage pools, as well as demargination.
- Chronic Inflammation
- Stress: hypoxemia, exercise, epinephrine
- Smoking: generally associated with a mild increase in neutrophils
- Steroids: increased release of neutrophils from marrow, demargination and decreased egress to tissue pool
- Granulocyte colony stimulating factor
- Lithium: increased production of granulocyte colony-stimulating factors
- Non-hematologic malignancy such as non-small cell lung cancer or bladder cancer: paraneoplastic syndrome; increased neutrophils, secondary to release of G-CSF from tumor; or with metastatic disease, may result from inflammation and necrosis
- Asplenia/hyposplenism: loss of site of pooling/sequestration of WBCs
- Chronic marrow stimulation: chronic hemolytic anemias, immune thrombocytopenia
- "Rebound leukocytosis" following recovery from marrow suppression
Rare syndromes associated with neutrophilia:
- Chronic Idiopathic Neutrophilia: a syndrome of chronic leukocytosis (WBC counts between 10,000 and 40,000/µL) of unknown etiology in patients who are otherwise well.
- Leukocyte Adhesion Factor Deficiency: impaired neutrophil chemotaxis and inability to phagocytose opsonized particles; defect in adherence; neutrophils lack surface receptor for C3bi; clinically: leukocytosis, recurrent infections.
- Familial Cold Urticaria and leukocytosis: leukocytosis, fever, urticaria, rash, muscle and skin tenderness on exposure to cold.
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