Porth's Essentials of Pathophysiology, 4e

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Disorders of Red Blood Cells

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react with antigens on the red cell membrane, causing destructive changes that lead to spherocytosis, with sub- sequent phagocytic destruction in the spleen or reticulo- endothelial system. The antibodies lack specificity for the ABO antigens but may react with the Rh antigens. The hemolytic reactions usually have a rapid onset and may be severe and life-threatening. There are varied causes for this anemia: approximately 50% are idiopathic, and 50% are related to predisposing conditions such as lym- phoid neoplasms, autoimmune disorders (particularly systemic lupus erythematosus), and exposure to drugs such as penicillin and the cephalosporins. 5,6 Some drugs, of which the antihypertensive drug α -methyldopa is the prototype, induce the production of antibodies against red cell antigens, particularly Rh antigens. About 10% of persons taking α -methyldopa develop antibodies, and about 10% develop clinically significant hemolysis. 5 In the cold-reacting agglutinin type of hemolytic ane- mia, which is less common than the warm-reacting type, IgM antibodies bind red cells and cause agglutination and activate complement. Cold agglutinin antibodies sometimes appear transiently following certain infec- tions (e.g., Epstein-Barr, influenza), in which case the condition is relatively benign. The condition may also develop as a chronic complication of B-cell neoplasms and as an idiopathic entity. Symptoms are variable and occur in parts of the body, such as the ears, fingers, and toes, where the temperature may fall below 30°C. They manifest due to vascular obstruction caused by aggluti- nated red cells resulting in pallor, cyanosis, and Raynaud phenomenon. The diagnosis of immunohemolytic anemia requires use of the Coombs test to detect the presence of antibody or complement on the surface of red blood cells. The direct Coombs test uses antibodies specific for human immunoglobulins or complement to detect antibodies on red blood cells. It is positive in cases of autoimmune hemolytic anemia, Rh disease of the newborn, transfu- sion reactions, and drug-induced hemolysis. The indi- rect Coombs test uses commercially available red cells with known antigens to characterize the antigen target and temperature dependence of the responsible antigen. Anemia may result from the decreased production of erythrocytes by the bone marrow. This category includes anemias caused by a deficiency of substances that are needed for hematopoiesis, particularly iron, vitamin B 12 , and folic acid. Other disorders that suppress erythropoi- esis include those associated with bone marrow failure or replacement of the bone marrow by tumor or inflam- matory cells. Iron-Deficiency Anemia Iron deficiency is a common worldwide cause of ane- mia affecting persons of all ages. 16 The anemia results from dietary deficiency, loss of iron through bleeding, Anemias of Deficient Red Cell Production

body’s principal means of preventing oxidative damage. Abnormalities of glutathione metabolism resulting from impaired enzyme function reduce the ability of red cells to protect against oxidative stress. The most common inherited enzyme defect that results in hemolytic anemia is a deficiency of glucose-6-phosphate dehydrogenase (G6PD). The gene that determines this enzyme is located on the X chromosome, and the defect is expressed only in males and homozygous females. There are several hundred variants of this gene, but only the G6PD A- variant, found in 10% to 15% of African Americans, and the G6PD Mediterranean variant are known to cause clinically significant hemolytic anemia. 5,6 The disorders are also associated with favism, a disorder of hemolysis due to consumption of fava beans. Glucose-6-phosphate dehydrogenase deficiencymakes red cells more vulnerable to oxidants. The disorder fea- tures direct oxidation of hemoglobin to methemoglobin, which cannot transport oxygen, and denaturing of the hemoglobin molecule to form Heinz bodies, which are precipitated in the red blood cell. Hemolysis usually occurs as the damaged red blood cells move through the narrow vessels of the spleen, causing hemoglobinemia, hemoglobinuria, and jaundice. The hemolysis is short- lived, occurring 2 to 3 days after the triggering event. In African Americans, the defect is mildly expressed and is not associated with chronic hemolytic anemia unless triggered by oxidant drugs, acidosis, or infection. In affected persons, the hemolysis can be triggered by expo- sure to oxidant drugs such as the antimalarial drug pri- maquine, quinine, the sulfonamides, and nitrofurantoin. Severe G6PD deficiency (as in Mediterranean variants) may produce a chronic hemolytic anemia. The disorder can be diagnosed through the use of a G6PD assay and other screening blood tests (complete blood count, bili- rubin, and reticulocyte count). No treatment is necessary except to avoid known oxidant drugs. Acquired Hemolytic Anemias Several acquired factors exogenous to the red blood cell produce hemolysis by direct membrane destruction or antibody-mediated lysis. Various drugs, chemicals, toxins, venoms, and infections such as malaria destroy red cell membranes. Hemolysis can also be caused by mechanical factors such as prosthetic heart valves, vas- culitis, and severe burns. Obstructions in the microcir- culation, as in disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and renal dis- ease, may traumatize the red cells by producing turbu- lence and changing pressure gradients. Although commonly referred to as autoantibody ane- mia, the currently preferred designation is immunohe- molytic anemia, since it may be initiated by an ingested drug. The antibodies that cause hemolysis are of two types: warm-reacting antibodies of the immunoglobu- lin G (IgG) class, which are maximally active at 37°C, and cold-reacting antibodies of the IgM type, which are optimally active at about 4°C. In the warm-reacting antibody type, the most com- mon form of immunohemolytic anemia, the antibodies