Hematopoiesis is the process of blood cell formation. In normal, healthy adults, blood cells are manufactured in the red marrow of relatively few bones, notably the sternum, ribs, vertebral bodies, pelvic bones, and proximal portions of the humerus and the femur. This production is in contrast to that taking place in the embryo, in which blood cells are derived from the yolk sac mesenchyme. As the fetus develops, the liver, the spleen, and the marrow cavities of nearly all bones become active hematopoietic sites (Fig. 1—1). In the newborn, hematopoiesis occurs primarily in the red marrow, which is found in most bones at that stage of development. Beginning at about age 5 years, the red marrow is gradually replaced by yellowish fat-storage cells (yellow marrow), which are inactive in the hematopoietic process. By adulthood, blood cell production normally occurs in only those bones that retain red marrow activity.5
Adult reticuloendothelial cells retain the potential for hematopoiesis, although in the healthy state reserve sites are not activated. Under conditions of hematopoietic stress in later life, the liver, the spleen, and an expanded bone marrow may resume the production of blood cells.
All blood cells are believed to be derived from the pluripotential stem cell,6 an immature cell with the capability of becoming an erythrocyte, a leukocyte, or a thrombocyte. In the adult, stem cells in hematopoietic sites undergo a series of divisions and maturational changes to form the mature cells found in the blood (Fig. 1-2). As they achieve the "blast" stage, stem cells are committed to becoming a specific type of blood cell. This theory also explains the origin of the several types of white blood cells (neutrophils, monocytes, eosinophils, basophils, and lymphocytes). As the cells mature, they lose their ability to reproduce and cannot further divide to replace themselves. Thus, there is a need for continuous hematopoietic activity to replenish worn-out or damaged blood cells.
Erythropoiesis, the production of red blood cells (RBCs), and leukopoiesis, the production of white blood cells (WBCs), are components of the hematopoietic process. Erythropoiesis maintains a population of approximately 25 × 1012 circulating RBCs, or an average of 5 million erythrocytes per cubic millimeter of blood. The production rate is about 2 million cells per second, or 35 trillion cells per day. With maximum stimulation, this rate can be increased sixfold to eightfold, or one volume per day equivalent to the cells contained in 0.5 pt of whole blood.
The level of tissue oxygenation regulates the production of RBCs; that is, erythropoiesis occurs in response to tissue hypoxia. Hypoxia does not, however, directly stimulate the bone marrow. Instead, RBC production occurs in response to erythropoietin, precursors of which are found primarily in the kidney and to a lesser extent in the liver. When the renal oxygen level falls, an enzyme, renal erythropoietic factor, is secreted. This enzyme reacts with a plasma protein to form erythropoietin, which subsequently stimulates the bone marrow to produce more RBCs. Specifically, erythropoietin (1) accelerates production, differentiation, and maturation of erythrocytes; (2) reduces the time required for cells to enter the circulation, thereby increasing the number of circulating immature erythrocytes such as reticulocytes (see Fig. 1-2); and (3) facilitates the incorporation of iron into RBCs. When the number of produced erythrocytes meets the body's tissue oxygenation needs, erythropoietin release and RBC production are reduced. Table 1-1 lists causes of tissue hypoxia that may stimulate the release of erythropoietin.
Threats to normal erythropoiesis occur if sufficient amounts of erythropoietin cannot be produced or if the bone marrow is unable to respond to erythropoietic stimulation. People without kidneys or with severe impairment of renal function are unable to produce adequate amounts of renal erythropoietic factor. In these individuals, the liver is the source of erythropoietic factor. The quantity produced, however, is sufficient to maintain only a fairly stable state of severe anemia that responds minimally to hypoxemia.
Inadequate erythropoiesis may occur also if the bone marrow is depressed because of drugs, toxic chemicals, ionizing radiation, malignancies, or other disorders such as hypothyroidism. Also, in certain anemias and hemoglobinopathies, the bone marrow is unable to produce sufficient normal erythrocytes.
Other substances needed for erythropoiesis are vitamin B12, folic acid, and iron. Vitamin B12 and folic acid are required for DNA synthesis and are needed by all cells for growth and reproduction; because cellular reproduction occurs at such a high rate in erythropoietic tissue, formation of RBCs is particularly affected by a deficiency of either of these substances. Iron is needed for hemoglobin synthesis and normal RBC production. In addition to dietary sources, iron from worn-out or damaged RBCs is available for reuse in erythropoiesis.7
Leukopoiesis, the production of WBCs, maintains a population of 5,000 to 10,000 leukocytes per cubic millimeter of blood, with the capability for rapid and dramatic change in response to a variety of stimuli. No leukopoietic substance comparable to erythropoietic factor has been identified, but many factors are known to influence WBC production, with a resultant excess (leukocytosis) or deficiency (leukopenia) in leukocytes (Table 1-2).
Note that WBC levels vary in relation to diurnal rhythms; thus, the time at which the sample is obtained may influence the results. Overall, leukocytes may increase by as many as 2000 cells per milliliter from morning to evening, with a corresponding overnight decrease. Eosinophils decrease until about noon and then rise to peak between midnight and 3 AM. This variation may be related to adrenocortical hormone levels, which peak between 4 and 8 AM, because an increase in these hormones can cause circulating lymphocytes and eosinophils to disappear in a few hours.