Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 3)

Figure 101-1RBC metabolism. The Embden-Meyerhof pathway (glycolysis) generates ATP for energy and membrane maintenance. The generation of NADPH maintains hemoglobin in a reduced state. The hexose monophosphate shunt generates NADPH that is used to reduce glutathione, which protects the red cellagainst oxidant stress. Regulation of 2,3-bisphosphoglycerate levels is a critical determinant of oxygen affinity of hemoglobin. Enzyme deficiency states in order of prevalence: glucose-6-phosphate dehydrogenase (G6PD) pyruvate kinase glucose-6-phosphate isomerase rare deficiencies of other enzymes in the pathway. The more common enzyme deficiencies are encircled. ...
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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 3) Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 3)Figure 101-1 RBC metabolism. The Embden-Meyerhof pathway (glycolysis) generatesATP for energy and membrane maintenance. The generation of NADPHmaintains hemoglobin in a reduced state. The hexose monophosphate shuntgenerates NADPH that is used to reduce glutathione, which protects the red cellagainst oxidant stress. Regulation of 2,3-bisphosphoglycerate levels is a criticaldeterminant of oxygen affinity of hemoglobin. Enzyme deficiency states in orderof prevalence: glucose-6-phosphate dehydrogenase (G6PD) >>> pyruvate kinase> glucose-6-phosphate isomerase > rare deficiencies of other enzymes in thepathway. The more common enzyme deficiencies are encircled. Thus, the essential pathophysiologic process common to all HAs is anincreased red cell turnover. The gold standard for proving that the life span of redcells is reduced (compared to the normal value of about 120 days) is a red cell 51survival study, which can be carried out by labeling the red cells with Cr andmeasuring residual radioactivity over several days or weeks; however, this classictest is now available in very few centers and is rarely necessary. If the hemolyticevent is transient, it does not usually cause any long-term consequences. However,if hemolysis is recurrent or persistent, the increased bilirubin production favors theformation of gallstones. If a considerable proportion of hemolysis takes place inthe spleen, as is often the case, splenomegaly may become a prominent feature andhypersplenism may develop, with consequent neutropenia and/orthrombocytopenia. The increased red cell turnover also has metabolic consequences. In normalsubjects, the iron from effete red cells is very efficiently recycled by the body;however, with chronic intravascular hemolysis, the persistent hemoglobinuria willcause considerable iron loss, needing replacement. With chronic extravascularhemolysis, the opposite problem, iron overload, is more common, especially if thepatient needs frequent blood transfusions. Chronic iron overload will causesecondary hemochromatosis; this will cause damage, particularly to the liver,eventually leading to cirrhosis, and to the heart muscle, eventually causing heartfailure. The increased activity of the bone marrow also entails an increasedrequirement for erythropoietic factors, particularly folic acid. Compensated Hemolysis versus HA Red cell destruction is a potent stimulus for erythropoiesis, which ismediated by erythropoietin (EPO) produced by the kidney. This mechanism is soeffective that in many cases the increased output of red cells from the bonemarrow can fully balance an increased destruction of red cells. In such cases wesay that hemolysis is compensated. The pathophysiology of compensatedhemolysis is similar to that just described, except there is no anemia. This notion isimportant from the diagnostic point of view, because a patient with a hemolyticcondition, even an inherited one, may present without anemia. It is also importantfrom the point of view of management because compensated hemolysis maybecome decompensated—i.e., anemia may suddenly appear—in certaincircumstances—for instance, pregnancy, folate deficiency, renal failure interferingwith adequate EPO production, or an acute infection depressing erythropoiesis.Another general feature of chronic HA is seen when any intercurrent conditiondepresses erythropoiesis. When this happens, in view of the increased rate of redcell turnover, the effect will be predictably much more marked than in a personwho does not have hemolysis. The most dramatic example is infection byparvovirus B19, which may cause a rather precipitous fall in hemoglobin, anoccurrence sometimes referred to as aplastic crisis. Inherited Hemolytic Anemias There are three essential components in the red cell: (1) hemoglobin, (2) themembrane-cytoskeleton complex, and (3) the metabolic machinery necessary tokeep (1) and (2) in working order. Here we will discuss diseases of the latter twocomponents. Diseases caused by abnormalities of hemoglobin are discussed inChap. 99.