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Erythrocyte Disorders Deficiency or dysfunction of the membrane proteins, includ- ing hereditary spherocytosis (HS), elliptocytosis, and stomato- U'1'.ry cltosis, can alter these properties and result in hemolysis. HS is more common in people of Northern European descent. and most cases are autosomal dominant. Mutations in o or B-spectrin, ankyrin, band 3, or protein 4.2 result in defective interaction between the cltoskeleton and the lipid bilayer and formation of a spherocyte (Figure 17), with a reduced surface-to-volume ratio. This forms the basis for the Iaboratory findings in HS, including elevated mean corpuscu- lar hemoglobin concentration, increased osmotic fragility, varying degrees of anemia, and reticulocytosis. The PBS shows

Deficiency or dysfunction of the membrane proteins, includ- ing hereditary spherocytosis (HS), elliptocytosis, and stomato- U'1'.ry cltosis, can alter these properties and result in hemolysis. HS is more common in people of Northern European descent. and most cases are autosomal dominant. Mutations in o or B-spectrin, ankyrin, band 3, or protein 4.2 result in defective interaction between the cltoskeleton and the lipid bilayer and formation of a spherocyte (Figure 17), with a reduced surface-to-volume ratio. This forms the basis for the Iaboratory findings in HS, including elevated mean corpuscu- lar hemoglobin concentration, increased osmotic fragility, varying degrees of anemia, and reticulocytosis. The PBS shows L 6 numerous spherocSrtes, and flow c).tometry showing reduced eosin-S-maleimide binding to band 3 on the erythrocyte establishes the diagnosis. Most patients experience mild disease, are often asympto !%. matic, and have normal or near normal hemoglobin levels with FIGU n E 1 8. Acanthocytes (spur cells) are erythrocytes with a small number of spicules of variable size and distribution on the cell surface typically associated compensated hemo$sis. Hemolysis can worsen at times of with severe liver disease. Acanthocytes have also been associated with hypothyroidism, oxidative stress, including active infections. Patients with severe splenectomy, and malnutrition. HS have more brisk hemolysis that is not as well compensated. Patients are at increased risk for splenomegaly, development of pigmented gallstones, and aplastic crisis with parvovirus infec- erythrocyte shape and deformability. Abnormalities in these path- tion. All patients with HS should receive folate supplementa- ways are often defined by specific en4irne deficiencies, resulting tion, and splenectomy is effective for those with severe disease. in hemo$sis. Bmrvate kinase deficienry is the most common Membrane defects can also be acquired. Acanthocytes abnormality seen in the glycolltic pathway and is more common (Figure 18) are identified by multiple irregular projections on in people ofNorthern and Eastern European descent. the erythrocyte. They can be seen in severe liver disease, often G6PD deficiency affects the hexose-monophosphate alcoholic cirrhosis, as a result ofnonesterified cholesterol dep- shunt with failure to generate nicotinamide adenine dinucleo- osition on the erythrocyte. The cholesterol deposition causes tide phosphate (NADPH). NADPH is necessary to reduce oxi- decreased deformability and increased destruction, resulting in dative stress in response to medications, infection, or other significant hemolltic anemia. When related to liver failure, it is toxins. Without NADPH, hemoglobin is subject to oxidation, sometimes called Zieve syndrome. Liver transplantation can and denatured hemoglobin aggregates (Heinz bodies) form. correct the problem. Treatment is otherwise supportive. The erythroqtes become trapped and partially destroyed in the spleen, resulting in bite cells (Figure 19) visible on the PBS Enzyme Deficiencies and Heinz bodies visible on supravital stain. The glycoly.tic pathway and the hexose-monophosphate shunt are The gene for G6PD deficiency is on the X chromosome, so the main pathways ofglucose metabolism in erythrocytes. Among it primarily affects men. Women who are homozygous can be other functions, glucose catabolism is important for maintaining affected through lyonization (inactivation of one of the two X chromosomes) or in those with Turner syndrome (XO karyo-

L 6 numerous spherocSrtes, and flow c).tometry showing reduced eosin-S-maleimide binding to band 3 on the erythrocyte establishes the diagnosis. Most patients experience mild disease, are often asympto !%. matic, and have normal or near normal hemoglobin levels with FIGU n E 1 8. Acanthocytes (spur cells) are erythrocytes with a small number of spicules of variable size and distribution on the cell surface typically associated compensated hemo$sis. Hemolysis can worsen at times of with severe liver disease. Acanthocytes have also been associated with hypothyroidism, oxidative stress, including active infections. Patients with severe splenectomy, and malnutrition. HS have more brisk hemolysis that is not as well compensated. Patients are at increased risk for splenomegaly, development of pigmented gallstones, and aplastic crisis with parvovirus infec- erythrocyte shape and deformability. Abnormalities in these path- tion. All patients with HS should receive folate supplementa- ways are often defined by specific en4irne deficiencies, resulting tion, and splenectomy is effective for those with severe disease. in hemo$sis. Bmrvate kinase deficienry is the most common Membrane defects can also be acquired. Acanthocytes abnormality seen in the glycolltic pathway and is more common (Figure 18) are identified by multiple irregular projections on in people ofNorthern and Eastern European descent. the erythrocyte. They can be seen in severe liver disease, often G6PD deficiency affects the hexose-monophosphate alcoholic cirrhosis, as a result ofnonesterified cholesterol dep- shunt with failure to generate nicotinamide adenine dinucleo- osition on the erythrocyte. The cholesterol deposition causes tide phosphate (NADPH). NADPH is necessary to reduce oxi- decreased deformability and increased destruction, resulting in dative stress in response to medications, infection, or other significant hemolltic anemia. When related to liver failure, it is toxins. Without NADPH, hemoglobin is subject to oxidation, sometimes called Zieve syndrome. Liver transplantation can and denatured hemoglobin aggregates (Heinz bodies) form. correct the problem. Treatment is otherwise supportive. The erythroqtes become trapped and partially destroyed in the spleen, resulting in bite cells (Figure 19) visible on the PBS Enzyme Deficiencies and Heinz bodies visible on supravital stain. The glycoly.tic pathway and the hexose-monophosphate shunt are The gene for G6PD deficiency is on the X chromosome, so the main pathways ofglucose metabolism in erythrocytes. Among it primarily affects men. Women who are homozygous can be other functions, glucose catabolism is important for maintaining affected through lyonization (inactivation of one of the two X chromosomes) or in those with Turner syndrome (XO karyo- : rt : {1 , type). G6PD provides a survival advantage against Plosmodium falciparum and is, therefore, more common in persons of African, Asian, Mediterranean, and Middle Eastern descent. * f *J **w ,s II Estimates are that more than 200 million persons are affected worldwide. The G6PD A variant produces mild, often asymp- tomatic, disease. G6PD Mediterranean is associated with

: rt : {1 , type). G6PD provides a survival advantage against Plosmodium falciparum and is, therefore, more common in persons of African, Asian, Mediterranean, and Middle Eastern descent. * f *J **w ,s II Estimates are that more than 200 million persons are affected worldwide. The G6PD A variant produces mild, often asymp- tomatic, disease. G6PD Mediterranean is associated with ; l"; favism, or hemolysis after eating fava beans. Adults tlpically have signs of acute hemolysis 1 to 3 days after l; I exposure to oxidative stress. Certain drugs can trigger a hemolytic I rr episode, including chloroquine, sulfonamides, rasburicase, dap- sone, nitrofurantoin, and phenazopyridine. Semiquantitative

l; I exposure to oxidative stress. Certain drugs can trigger a hemolytic I rr episode, including chloroquine, sulfonamides, rasburicase, dap- sone, nitrofurantoin, and phenazopyridine. Semiquantitative .p% @I : r*r - -" FIGUnE 17. Ihis peripheral blood smear in a patientwith hereditary I assays that evaluate reduction of NADP to NADPH are used to assess G6PD function. En4.rne function should not be tested dur- ing an acute episode because older erythroqtes are preferentially spherocytosis shows round cells of uniform density (without central pallor) destroyed, leaving younger erythrocytes with higher G6PD levels, characteristic of spherocytes. resulting in a false-negative result. 28

Erythrocyte Disorders Sickle Cell gmdromes Sickle cell disease (SCD) affects nearly every organ system and causes unpredictable and extraordinarily painful vaso- occlusive events. It is prevalent among Black patients. SCD is characterized by homozygosity for a single point mutation in the sixth position of the p globin gene resulting in abnormal hemoglobin S (Hb S) that polymerizes under hypoxic condi- tions. This causes deformed erythrocytes that can adhere to the endothelium of capillaries throughout the circulation. Free hemoglobin from hemolysis scavenges nitric oxide, and hemolyzed erythrocyes release arginase, depleting arginine, a necessary precursor to nitric oxide. This process results in vasoconstriction and platelet activation, complicating the clinical course. Hb S is more common in patients of African origin, and most patients homozygous for Hb S (Hb SS) are Black, with about 87, of Black persons in the United States having sickle cell trait (Hb S). Hb S can be coinherited with hemoglobin C (Hb SC), B-thalassemia (SB* thalassemia), or other hemo- globin types, which tend to lead to milder disease than Hb SS. t I G U R E 1 9. Bite cells seen at the center of this slide (b/ack arow) are a typical Characteristic electrophoretic patterns for sickling disorders finding in glucose-6-phosphate dehydrogenase deficiency and are characterized by are shown in Table 14. a membrane defect that appears as though a semicircular bite has been taken out ofthe erythrocyte.Ihe defect is caused by removal of denatured hemoglobin by macrophages in the spleen. A polychromatophilic macro-ovalocyte can also be seen Sickle Cell Diseose Complications ond (blue arrowl, indicating a reticulocyte response. Their Management Chronic hemolysis, vaso occlusion with acute and chronic end-organ damage, nitric oxide depletion, and immune com- Treatment involves primary prevention, with avoidance of promise from functional asplenia lead to a myriad of prob- known triggers. Removal of the offending agent and supportive lems. The only potential cure for SCD is allogeneic bone interventions are mainstays of treating an acute episode. marrow transplantation, but the timing and appropriate pop- IIY P0lXl:,. : :' ulation for transplantation have not been adequately deter o Testing for glucose 6-phosphate dehydrogenase defi, mined. Hydroxyurea modulates many of the complications of SCD and even prolongs life expectancy because ofits ability to ciency should not be performed during an acute hemo- increase fetal hemoglobin levels and generate nitric oxide. It lytic episode because of high false-negative rates. should be considered in patients with frequent pain events,

Sickle Cell gmdromes Sickle cell disease (SCD) affects nearly every organ system and causes unpredictable and extraordinarily painful vaso- occlusive events. It is prevalent among Black patients. SCD is characterized by homozygosity for a single point mutation in the sixth position of the p globin gene resulting in abnormal hemoglobin S (Hb S) that polymerizes under hypoxic condi- tions. This causes deformed erythrocytes that can adhere to the endothelium of capillaries throughout the circulation. Free hemoglobin from hemolysis scavenges nitric oxide, and hemolyzed erythrocyes release arginase, depleting arginine, a necessary precursor to nitric oxide. This process results in vasoconstriction and platelet activation, complicating the clinical course. Hb S is more common in patients of African origin, and most patients homozygous for Hb S (Hb SS) are Black, with about 87, of Black persons in the United States having sickle cell trait (Hb S). Hb S can be coinherited with hemoglobin C (Hb SC), B-thalassemia (SB* thalassemia), or other hemo- globin types, which tend to lead to milder disease than Hb SS. t I G U R E 1 9. Bite cells seen at the center of this slide (b/ack arow) are a typical Characteristic electrophoretic patterns for sickling disorders finding in glucose-6-phosphate dehydrogenase deficiency and are characterized by are shown in Table 14. a membrane defect that appears as though a semicircular bite has been taken out ofthe erythrocyte.Ihe defect is caused by removal of denatured hemoglobin by macrophages in the spleen. A polychromatophilic macro-ovalocyte can also be seen Sickle Cell Diseose Complications ond (blue arrowl, indicating a reticulocyte response. Their Management Chronic hemolysis, vaso occlusion with acute and chronic end-organ damage, nitric oxide depletion, and immune com- Treatment involves primary prevention, with avoidance of promise from functional asplenia lead to a myriad of prob- known triggers. Removal of the offending agent and supportive lems. The only potential cure for SCD is allogeneic bone interventions are mainstays of treating an acute episode. marrow transplantation, but the timing and appropriate pop- IIY P0lXl:,. : :' ulation for transplantation have not been adequately deter o Testing for glucose 6-phosphate dehydrogenase defi, mined. Hydroxyurea modulates many of the complications of SCD and even prolongs life expectancy because ofits ability to ciency should not be performed during an acute hemo- increase fetal hemoglobin levels and generate nitric oxide. It lytic episode because of high false-negative rates. should be considered in patients with frequent pain events, TAtsLE 14. Characteristics of Adult Sickle Cell Syndromes Disease Type Hb (g/dt [g/t]) MCv (fL) Hb S (%) Hb A (%) Hb A, (%) Peripheral Clinical BIood Smear Severitf O to Findings +++ Sickle trait (AS) NL NL 40 60 <3.5 NL 0 Hb SS 6-8 (60-80) NL >90 0 <3.5 Sickle cells + Sp'-thalassemia 9-12i'90-120) 70-75 >60 10-30 >3.5 Rare sickle cells +to+ Target cells SBo-thalassemia 7-9(70-90\ 65-70 >90 0 >3.5 Sickle cells # Target cells SCD 1 0-1 s (1 00-1 s0) 7s-NL 50 0 Hb42=0 Sickle cells +to+ HbC=50b Target cells

TAtsLE 14. Characteristics of Adult Sickle Cell Syndromes Disease Type Hb (g/dt [g/t]) MCv (fL) Hb S (%) Hb A (%) Hb A, (%) Peripheral Clinical BIood Smear Severitf O to Findings +++ Sickle trait (AS) NL NL 40 60 <3.5 NL 0 Hb SS 6-8 (60-80) NL >90 0 <3.5 Sickle cells + Sp'-thalassemia 9-12i'90-120) 70-75 >60 10-30 >3.5 Rare sickle cells +to+ Target cells SBo-thalassemia 7-9(70-90\ 65-70 >90 0 >3.5 Sickle cells # Target cells SCD 1 0-1 s (1 00-1 s0) 7s-NL 50 0 Hb42=0 Sickle cells +to+ HbC=50b Target cells Hb = hemoglobin; Hb SS = homozygous sickle cell anemia; MCV = mean corpuscular volume; NL = normal; S0'= sickle 0.; S00 = sickle 00; SCD = hemoglobin SC disease. 'Clinical severity is variable within each genotype. t'Note that Hb C comigrates with Hb A, on standard alkaline cellulose acetate electrophoresis but will separate on citrate agar electrophoresis. NOTE: Hb percentages may not total 1 00% because Hb F is not included in this table. 29