Blood neutrophil levels are maintained in a normal steady state by hematopoiesis in the marrow, the distribution of neutrophils between the marginated pool in the microvasculature and the freely circulating pool in the blood, and the rate of egress from blood to tissues. Marrow production of neutrophils is regulated by three principal glycoprotein hormones, or cytokines: interleukin-3, granulocyte-monocyte colony-stimulating factor, and granulocyte colony-stimulating factor (G-CSF), but only the genetic elimination of G-CSF has a measurable effect on blood neutrophil levels. The latter two cytokines are available as recombinant pharmaceutical products that can be administered therapeutically to ameliorate certain causes of neutropenia. Neutrophil interaction with endothelium is mediated by selectins, glycoproteins with sugar-binding sites that support shear-dependent rolling on endothelium, and by integrins on the neutrophil binding to ligands on the endothelial cells, permitting firm attachment to endothelium and emigration into tissues. Neutrophils have a short life span in blood, with a disappearance half-time of approximately 7 hours. The process can be accelerated when inflammation is present and highlights the need for a sustained rate of production to maintain a normal blood neutrophil count. The pathogenesis of neutropenia is more complex to analyze kinetically than anemia or thrombocytopenia because at least four compartments are involved: marrow storage pool, circulating pool, marginated pool, and tissue pool. The latter is particularly difficult to assay. Measurements can be further complicated in the nonsteady state, when dramatic increases in turnover rates and distribution among the four principal pools are in disequilibrium, as occurs during acute inflammatory states.
Acronyms and Abbreviations:
β2-Integrin, a member of family of receptors that mediate attachment between a cell and the tissues surrounding it; C5a, chemotactic fragment of complement component C5; CD, one of the cluster of differentiation antigens; CSF, colony-stimulating factor; DF32P, diisopropyl fluorophosphate; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; IL, interleukin; L-selectin (and other selectins), a member of selectin family of proteins, which are leukocyte cell-adhesion molecules; Mr, relative molecular mass; NTR, neutrophil turnover rate; T1/2, half-time; TBNP, total blood neutrophil pool; TNF-α, tumor necrosis factor-α.
DEFINITION AND HISTORY
Neutrophils are produced in the marrow, where they arise from progenitor and precursor cells by a process of cellular proliferation and maturation. They differentiate from the pluripotential stem cell1,2 through a series of progressively more committed progenitor or colony-forming units, including the granulocyte-monocyte colony-forming unit and the granulocyte colony-forming unit, which give rise to neutrophils.3,4 The early progenitor cells cannot be recognized under the microscope but can be identified retrospectively by the type of colony formed in culture of marrow cells (Chap. 18). The earliest morphologically recognizable neutrophil precursor is the myeloblast. From there, the formal sequence of precursor development is myeloblast → promyelocyte → myelocyte → metamyelocyte → band neutrophil → segmented neutrophil (Chap. 60). The ...