Hemolytic anemias

Destruction of red cells at a rate substantially greater than normal, if not compensated for by accelerated red cell production, causes a type of anemia called hemolytic. Increased red cell destruction is recognized by demonstrating increased quantities of the pigmentary products of their destruction, such as bilirubin and urobilinogen, in the blood plasma, urine, and stools and by evidence of accelerated erythropoiesis, such as an increase in the number of young corpuscles (reticulocytes) in the blood. When blood destruction is extremely rapid or occurs in the blood vessels, free hemoglobin is found in the urine (hemoglobinuria). Treatment varies with the cause of the hemolytic anemia.

There are two principal causes of hemolytic anemia: (1) inherently defective red cells and (2) an environment hostile to red cells. Abnormalities within the red cell are usually congenital and hereditary. They are exemplified by diseases in which the cell membrane is weakened, cell metabolism is defective, or hemoglobin is abnormal.

Hereditary spherocytosis is the most common disease involving the red cell membrane. It is characterized by the presence of red cells that appear small, stain densely for hemoglobin, and look nearly spherical. Such cells are mechanically fragile and readily swell up and burst in dilute salt solution. In the body they break up when deprived of free access to plasma glucose. The abnormality is aggravated by a tendency for the cells to remain longer than usual in the spleen because of their spheroidal shape. The corpuscular defect may appear if itis inherited from either parent (it is caused by a dominant gene). The anemia varies in severity. It may be so mild as to pass unnoticed for years, but it may suddenly become severe; e.g., when an incidental respiratory infection briefly suppresses the accelerated production of red cells necessary to meet the constantly increased rate of their destruction. An agent known to cause this transient cessation of erythropoiesis is the parvovirus, and the development of severe anemia under these circumstances is termed aplastic crisis. Removal of the spleen, which always is enlarged, cures the anemia by eliminating the site of sequestration and destruction of the red cells but does not prevent hereditary transmission of the disease.

Red cells metabolize glucose by breaking it down to lactic acid either via an anaerobic (oxygenless) pathway, or by oxidation through a pathway called the pentose shunt. The anaerobic pathway, the main route of metabolism, provides energy in the form of ATP. Deficiencies of enzymes, such as pyruvate kinase, in this pathway shorten red cell survival times because energy-requiring activities within the red cell are curtailed. Deficiencies of enzymes in the anaerobic pathway, also a vital pathway for red cell survival, are generally relevant only when they are homozygous (i.e., when the deficiency is inherited from each parent on an autosomal chromosome and is therefore expressed). Abnormalities also have been discovered in the alternative process of glucose metabolism, known as the phosphogluconate oxidative, or pentose shunt, glycolytic pathway. The pathway provides a reducing factor, NADPH (nicotinamide-adenine dinucleotide phosphate), which is part of a mechanism for returning glutathione to its reduced form following its oxidation by peroxides, a reaction that protects other molecules in the cell from oxidative damage by these peroxides. Deficiency of the first enzyme in the pathway, glucose-6-phosphate dehydrogenase (G6PD), is rather common. This deficiency results in a decreased capacity to detoxify peroxides and leads to oxidative damage to the red cell and hemolysis. If the deficiency is mild, there is hemolysis only when an excessive amount of peroxides is present,as may occur with the administration of some medications. The frequency of G6PD deficiencyvaries up to 36 percent among different Caucasian population groups and is especially frequent in Mediterranean peoples. Ingestion of fava beans by some of these people may induce severe destruction of red cells. The deficiency rarely is extreme and results in hemolysis without exposure to oxidants, medications, or toxins. Another variety of G6PD deficiency has been found in 10 to 14 percent of American blacks; the defect is harmless unless the person is exposed to certain drugs, such as certain antimalarial compounds (e.g., primaquine) and sulfonamides. The full effect of the deficiency is rarely observed in females because the gene is sex-linked (i.e., carried on the X chromosome), and only rarely do both X chromosomes carry the abnormal gene. Males, on the other hand, have only one X chromosome and thus only one gene available, and therefore the deficiency is fully expressed if it is inherited on the X chromosome from the mother.

Hemolytic anemia can also result as the consequence of an environment hostile to the red cell. Certain chemical agents destroy red cells whenever sufficient amounts are given (e.g., phenylhydrazine); others are harmful only to persons whose red cells are sensitive to the action of the agent. A number of the toxic drugs are oxidants or are transformed into oxidizing substances in the body. Injury may be accidental, as with moth ball (naphthalene) ingestion in children, or it may be the undesirable effect of a drug used therapeutically. Individual sensitivity is of several kinds. There is the susceptibility of certain patients to oxidant drugs such as antimalarial compounds mentioned above. This is attributable to a sex-linked, inherited deficiency of the enzyme G6PD. In other instances, sensitivity is on an immunologic basis; e.g., hemolytic anemia caused by penicillin, quinidine, or alpha-methyldopa (a drug used in the treatment of elevated blood pressure). The anemia develops rapidly over a few days and without transfusions may be fatal.

A long recognized type of hemolytic anemia is that associated with the transfusion of incompatible red cells. Antibodies to the substances alpha- and beta-isoagglutinin, which occur naturally in the blood, destroy the donor red cells when incompatible blood is given by transfusion. Besides the best-known blood groups—A, B, and O—there are other groups to which a person may develop antibodies that will cause transfusion reactions. The rhesus (Rh) and Kell groups are examples. In hemolytic disease of the newborn (erythroblastosis fetalis) the destruction of the blood of the fetus by that of the mother may be due to Rh or ABO incompatibility. The events that take place are, first, the passage of incompatible red cells from the fetus into the circulation of the mother through a break in the placental blood vessels, then development of antibodies in the mother, and, finally, passage of these antibodies into the fetus, with consequent hemolysis, anemia, and jaundice.

A form of hemolytic anemia that is relatively common depends on the formation of antibodies within the patient's body against his own red cells (autoimmune hemolytic anemia). This may occur in association with the presence of certain diseases, but it is often seen without other illness. Trapping of the red cells by the spleen is thought to depend on the fact that red cells coated with incomplete (nonhemolytic) antibody, when brought into contact with reticuloendothelial cells, adhere, become spherical, are ingested (phagocytosed), and break down.

Such anemias may be severe but often can be controlled by the administration of adrenocorticosteroids (which interfere with the destructive process) and treatment of the underlying disease, if one is present. In a number of instances, splenectomy—removal of the spleen—is necessary and is usually partially or wholly effective in relieving the anemia. The effectiveness of splenectomy is attributed to the removal of the organ in which red cells, coated with antibody, are selectively trapped and destroyed.

Other varieties of hemolytic anemia include that associated with mechanical trauma, such asthat produced by the impact of red cells on artificial heart valves, excessive heat, and infectious agents (e.g., the organism causing malaria).