Chapter 37

### INTRODUCTION

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 nine 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. A number 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 (Hoffbrand and Herbert, 1999; Wrighting and Andrews, 2008). Therapeutic correction of a specific deficiency state depends on the accurate diagnosis of the anemic state, knowledge about the correct dose, the use of these agents in various combinations, and the expected response. This chapter deals with the growth factors, vitamins, minerals, and drugs that affect the blood and blood-forming organs.

### HEMATOPOIETIC GROWTH FACTORS

History. Modern concepts of hematopoietic cell growth and differentiation arose in the 1950s when cells from the spleen and marrow were shown to play an important role in the restoration of hematopoietic tissue in irradiated animals. In 1961, Till and McCulloch demonstrated that individual hematopoietic cells could form macroscopic hematopoietic colonies in the spleens of irradiated mice. Their work established the concept of discrete hematopoietic stem cells, which can be experimentally identified, albeit in retrospect (i.e., the presence of a multilineage clonal splenic colony appearing 11 days after transplantation implied that a single cell lodged and expanded into several cell lineages). This concept now has been expanded to include normal human marrow cells. Moreover, such cells now can be prospectively identified.

The basis for identifying soluble growth factors was provided by Sachs and independently by Metcalf, who developed clonal, in vitro assays for hematopoietic progenitor cells. Initially, such hematopoietic colonies developed only in the presence of conditioned culture medium from leukocytes or tumor ...

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