The anemias. Derangement of function in anemia

Red cells are formed within the marrow cavities of the central bones of the adult human skeleton (skull, spine, ribs, breastbone, pelvic bones). The marrow contains nucleated red cells (normoblasts), as well as white cells of all stages of development and megakaryocytes, the source of blood platelets. The normoblasts are present in various stages of development toward the mature, adult, nonnucleated, hemoglobin-containing red cells that will be releasedinto the circulating blood.

The newly arrived red cells in the circulation remain as reticulocytes, young red cells with a characteristic threadlike network, for two or three days. Each day's output of new red cells survives an average of 120 days before succumbing to old age. The red cells are able to withstand the vicissitudes of the circulation because glucose absorbed from the plasma is metabolized within the cell to supply energy in the form of adenosine triphosphate (ATP) as well as to provide reducing systems that protect against the products of oxidation (oxidation-reduction systems).

Ultimately the aged red cells are broken down by specialized reticuloendothelial cells that are found throughout the body and especially in the spleen and liver. The hemoglobin is digested into its components: iron, a red pigment with a ring-shaped structural formula (porphyrin), and a protein (globin). The iron remains within the body to be used over and over again in the formation of new hemoglobin. The porphyrin ring opens and is changed chemically to become the yellow pigment of the blood plasma, bilirubin. This is then excreted by the liver and gives the bile its characteristic colour. The globin is metabolized. In a healthy person, red cell production (erythropoiesis) is so well adjusted to red cell destruction that the levels of red cells and hemoglobin remain constant.

The circulation is a closed system from which there normally is no loss of blood except that which occurs physiologically in menstruation. Anemia results when (1) the production of red cells and hemoglobin lags behind the normal rate of their destruction, (2) excessive destruction exceeds production, or (3) blood loss occurs. The bone marrow normally is capable of increasing production as much as sixfold to eightfold through an increased rate of development from the primitive precursors. Anemia ensues when the normal fine balance between production, destruction, and physiological loss is upset and erythropoiesis has not been accelerated to a degree sufficient to reestablish normal blood values.

The rate of production of red cells by the bone marrow normally is controlled by a physiological feedback mechanism analogous to the thermostatic control of temperature in aroom. The mechanism is triggered by a reduction of oxygen in the tissues (hypoxia) and operates through the action of a hormone, erythropoietin, in the formation of which the kidney plays an important role. Erythropoietin is released and stimulates further erythropoiesis. When oxygen needs are satisfied, erythropoietin production is reduced and red cell production diminishes.

Failure of production of red cells may be caused by deficiency of certain essential materials, such as iron, folic acid, or vitamin B12. It may be due to other causes, such as the presence of certain types of disease—e.g., infection; damage of the bone marrow by ionizing radiation or by drugs or other chemical agents; or anatomical alterations in the bone marrow, as by leukemia or tumour metastases (migration of tumour cells to the marrow from distant sites oforigin). Accelerated destruction of red cells may occur for any one of a large variety of causes(see below Hemolytic anemias). Finally, blood loss may result from trauma or may be associated with a variety of diseases.

Persons whose anemia is due to increased destruction of red cells have excessive amounts of bilirubin in the plasma. They appear to be slightly jaundiced, and the excess pigments darken the excreta. Certain laboratory tests measure the degree of excessive pigment production. The bone marrow responds to increased destruction of red cells by increasing the rate of their production, thereby increasing the number of reticulocytes in the blood. These cells, in addition to their unique staining characteristics, are larger than fully mature red cells.If their number is increased sufficiently, the mean corpuscular volume of the cells in the circulation is increased. The anemia is then characterized as macrocytic.

Macrocytic anemia also is produced when the anemia results from impaired production of red cells, e.g., when vitamin B12 or folic acid is lacking. In other circumstances, as for example when there is a deficiency of iron, the circulating red cells are smaller than normal and poorly filled with hemoglobin—this is termed hypochromic microcytic anemia. In still other forms of anemia there is no significant alteration in the size, shape, or coloration of the red cells—normocytic anemias.

Anemias may be classified according to the underlying abnormality in the basic physiologicalmechanism (decreased production, increased destruction, blood loss) or on morphological grounds (macrocytic, normocytic, or microcytic hypochromic) or according to their cause (e.g.,vitamin B12 deficiency). In practice it is by a combination of clinical, morphological, and physiological studies that the cause is determined. Accurate diagnosis is essential before treatment is attempted because, just as the causes differ widely, so the treatment of anemia differs from one patient to another. Indiscriminate treatment by the use of hematinics (drugs that stimulate production of red cells or hemoglobin) is wasteful and can be dangerous.