The finite life span of most mature blood cells requires their continuous replacement, a process termed hematopoiesis. New cell production must respond to basal needs and states of increased demand. Red blood cell production can increase >20-fold in response to anemia or hypoxemia, white blood cell production increases dramatically in response to a systemic infection, and platelet production can increase 10- to 20-fold when platelet consumption results in thrombocytopenia.
The regulation of blood cell production is complex. Hematopoietic stem cells are rare bone marrow cells that manifest self-renewal and lineage commitment, resulting in cells destined to differentiate into the 9 distinct blood-cell lineages. For the most part, this process occurs in the marrow cavities of the skull, vertebral bodies, pelvis, and proximal long bones; it involves interactions among hematopoietic stem and progenitor cells and the cells and complex macromolecules of the marrow stroma, and is influenced by a number of soluble and membrane-bound hematopoietic growth factors. Some of these hormones and cytokines have been identified and cloned, permitting their production in quantities sufficient for therapeutic use. Clinical applications range from the treatment of primary hematologic diseases to use as adjuncts in the treatment of severe infections and in the management of patients who are undergoing cancer chemotherapy or marrow transplantation.
Hematopoiesis also requires an adequate supply of minerals (e.g., iron, cobalt, and copper) and vitamins (e.g., folic acid, vitamin B12, pyridoxine, ascorbic acid, and riboflavin); deficiencies generally result in characteristic anemias or, less frequently, a general failure of hematopoiesis. Therapeutic correction of a specific deficiency state depends on the accurate diagnosis of the anemic state, and on knowledge about the correct dose, the use of these agents in appropriate combinations, and the expected response.
HEMATOPOIETIC GROWTH FACTORS
GROWTH FACTOR PHYSIOLOGY. Steady-state hematopoiesis encompasses the production of >400 billion blood cells each day. This production is tightly regulated and can be increased several-fold with increased demand. The hematopoietic organ also is unique in adult physiology in that several mature cell types are derived from a much smaller number of multipotent progenitors, which develop from a more limited number of pluripotent hematopoietic stem cells. Such cells are capable of maintaining their own number and differentiating under the influence of cellular and humoral factors to produce the large and diverse number of mature blood cells.
Stem cell differentiation can be described as a series of steps that produce so-called burst-forming units (BFUs) and colony-forming units (CFUs) for each of the major cell lines. These early progenitors (BFU and CFU) are capable of further proliferation and differentiation, increasing their number by some 30-fold. Subsequently, colonies of morphologically distinct cells form under the control of an overlapping set of additional growth factors (granulocyte colony-stimulating factor [G-CSF], macrophage colony-stimulating factor [M-CSF], erythropoietin, and thrombopoietin). Proliferation and maturation of the CFU for each cell line can amplify the resulting mature cell ...