Hemolytic mechanisms

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        The normal mature red blood cell is a pliable biconcave disc composed of hemoglobin (25 per cent), stroma (3.5 per cent) and water (70 per cent). The arrangement of these elements in the cell is not well understood. Ordinarily, the life of an erythron is approximately 120 days and about 10,000,000 red cells are destroyed every second. Hemolysis may be said to exist when the normal rate of red blood cell destruction is increased. Although many agents may be responsible for hemolysis it is probable that, like saponins, all depend upon disruption of the cell membrane for their effect.
        When hemolysis occurs rapidly, particularly if it be intravascular, free hemoglobin appears in the plasma above the normal concentration of 3 mg. per cent. Above levels of 135 mg. per cent, it appears in the urine. If tubular reabsorption is impaired hemoglobinuria may exist with considerably lower plasma levels. Usually, however, red cell destruction occurs in the reticuloendothelial system with the conversion of the hemoglobin to bilirubin and, when excessive, with the production of acholuric jaundice.
        The breakdown of hemoglobin begins with oxidative ring rupture at the α-methene group of the porphyrin fraction of the molecule, resulting in a green compound called verdohemoglobin. This loses its iron, which is stored in the form of hepatic and splenic ferritin, and becomes biliverdin which on reduction is called bilirubin. Bilirubin exists normally in concentrations of less than 1 mg. per cent in the serum and may be subdivided into two fractions: hemobilirubin and cholebilirubin. The former retains its globin, is non-dialyzable, does not pass the glomerular filter, produces the indirect van den Bergh reaction and represents the larger fraction. The latter is free of globin but is associated with plasma albumin and appears in urine when its concentration in the plasma exceeds 2 mg. per cent. In the intestinal tract bilirubin is further reduced to urobilinogen, part of which is absorbed into the portal circulation where it is almost entirely cleared by the liver and re-introduced into the bile. In the presence of impaired liver function, however, more than the usual 2 per cent of the portal bilirubin may elude the liver and gain access to the general circulation and so appear in the urine in increased amount.
        Table I summarizes the usually recognized causes of red blood cell destruction while Table II attempts to classify these mechanisms as they occur in disease states.
        How incomplete is our understanding, however, of the basic mechanisms of hemolysis is well illustrated in the case of sickle-cell anemia where a clear-cut abnormality of the red cell exists without obvious relation to the hemolytic process and where a rational form of therapy appears to have no effect. On the other hand, the excellent results obtained by splenectomy in congenital hemolytic icterus are seen to have some experimental foundation.
        The clinical picture of chronic hemolysis is characterized by icterus, frequent enlargement of the spleen, anemia, leukocytosis and increase in reticulocytes. The urine is ordinarily free of bile although this is not invariable. The serum bilirubin is increased and classically gives an indirect van den Bergh reaction. Urobilin is increased in the stool and urobilinogen is usually present in the urine in abnormal amounts. If the liver is damaged, however, many of these points in differential diagnosis are of no value. Therapy is often disappointing unless some specific infection can be treated, some harmful agent be removed or splenectomy be advised. The success of the latter procedure is largely limited to familial hemolytic jaundice although occasional excellent results are obtained in acquired hemolytic icterus and localized disease of the spleen.
        Acute hemolysis presents quite a different and more serious prospect. The sudden onset is distinguished by headache, backache and leg pains. Pain in the abdomen may be severe and mimic an acute surgical abdomen. Chills and fever are common; shock, with anuria, may supervene. Anemia and hemoglobinemia are found. Hemoglobinuria may be present in severe cases or when tubular re-absorption is defective. Transfusion is the treatment of choice since it tends to overcome the anemia, correct the shock and so increase renal blood flow. In some instances it apparently arrests the hemolytic process as well. Alkalinization of the urine remains good therapy though perhaps of secondary importance in preventing anuria.
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