McCance 31. PDF Alterations of Hematologic Function in Children

CHAPTER 31 Alterations of Hematologic Function in Children Lauri A. Linder, Kathryn L. McCance http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Fetal and Neonatal Hematopoiesis, 992 Postnatal Changes in the Blood, 993 Erythrocytes, 993 Leukocytes and Platelets, 995 Disorders of Erythrocytes, 995 Acquired Disorders, 995 Inherited Disorders, 999 This chapter briefly explains fetal and neonatal hematopoiesis and postnatal changes in blood as a foundation for understanding the pathophysiology of specific blood disorders in childhood. Among the diseases that affect erythrocytes are acquired disorders, such as iron deiciency anemia, hemolytic disease of the newborn, and anemia of infectious disease; and inherited disorders, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, sickle cell disease, and the thalassemias. Disorders of coagulation and platelets include inherited hemorrhagic diseases, such as the hemophilias, and antibody-mediated hemorrhagic diseases, which include immune thrombocytopenia, autoimmune neonatal thrombocytopenias, and autoimmune vascular purpuras. Finally, leukocyte disorders, such as leukemia and the lymphomas (non-Hodgkin lymphoma as well as Hodgkin lymphoma), are discussed. FETAL AND NEONATAL HEMATOPOIESIS As the developing embryo becomes too large for oxygenation of tissues by simple diffusion, the production of erythrocytes begins within the vessels of the yolk sac. Shortly after 2 weeks of gestation, circulating erythrocytes play a major role in delivering oxygen to the tissues. At approximately the eighth week of gestation, the site of erythrocyte 992 CHAPTER 31 Health Illness Liver Infant Spleen Hematopoietic tissue Child Yellow marrow Adult Sites of hematopoiesis Yellow marrow FIGURE 31.1 Sites of Hematopoiesis in Health and Illness. With normal maturation, red marrow is partly replaced by yellow marrow in the shafts of the long bones. In adults, red marrow is largely restricted to femur and humerus. In response to hemolysis, red marrow replaces yellow marrow in the long bones. In infants, whose long bones already are additional hematopoiesis takes place in the liver and spleen. red marrow can replace yellow marrow in response to hemolysis, less hematopoiesis in the liver and spleen. to occur outside the marrow cavities, especially in the liver and spleen. Extramedullary hematopoiesis is more likely to occur in children than in adults because the bony cavities of children already are illed with red marrow (Fig. 31.1). This is why hemolytic disease causes especially pronounced enlargement of the spleen and liver in children. The erythrocytes undergo striking changes during gestation, par- ticularly during the irst two trimesters, at which time they nearly double in numbers and in hemoglobin content. A proportionate increase in hematocrit level also occurs. By the end of gestation the erythrocyte count has more than tripled but the size of each erythrocyte has decreased. A biochemically distinct type of hemoglobin is synthesized during fetal life. The three embryonic hemoglobins (Gower 1, Gower 2, and Portland) and the fetal hemoglobin (HbF) are composed of two α and two γ chains of polypeptides, whereas the adult hemoglobins (HbA and HbA2) are composed of two α chains and two β chains. (The structure of an adult hemoglobin molecule is illustrated in Fig. 28.16, and types of hemoglobin are deined in Table 28.5.) Some unknown regulatory mechanism promotes γ-chain synthesis and inhibits β- and δ-chain synthesis in utero. This results in production of embryonic or fetal hemoglobin. After birth, γ-chain synthesis is inhibited, whereas β- and δ-chain synthesis is facilitated, resulting in production of adult hemoglobins. TABLE 31.1 HEMATOLOGIC VALUES DURING INFANCY AND HEMOGLOBIN HEMATOCRIT (g/dL) (%) RETICULOCYTES AGE MEAN RANGE MEAN RANGE (%) MEAN Cord blood 16.8 13.7–20.1 55 45–65 5 2 wk 16.5 13–20 50 42–66 1 3 months 12 9.5–14.5 36 31–41 1 6 months to 12 10.5–14 37 33–42 1 6 yr 7–12 yr 13 11–16 38 34–40 Adult Female 14 12–16 42 37–47 1.6 Male 16 14–18 47 42–52 *Relatively wide range. fl, Femtoliters; MCV, mean corpuscular volume; WBC, white blood From Behrman R et al, editors: Nelson textbook of pediatrics, CHAPTER 31 hemoglobin level increase continues into early puberty, at which time it stabilizes. In the male, the hemoglobin level increase keeps pace with growth and maturation and eventually surpasses that of the female. This higher value of hemoglobin level in the mature male is related to androgen secretion. Metabolic processes within the erythrocytes of neonates differ signiicantly from those of erythrocytes in the normal adult. The relatively young population of erythrocytes in the newborn consumes greater quantities of glucose than do erythrocytes in adults. Several enzymes that regulate glucose consumption are increased in the erythrocytes of neonates, with a subsequent increase in the rate of glycolysis. Leukocytes and Platelets The lymphocytes of children tend to have more cytoplasm and less compact nuclear chromatin than do the lymphocytes of adults. The signiicance of these differences is unknown. One possible explanatio is that children tend to have more frequent viral infections, which are associated with atypical lymphocytes. Even minor infections, in which the child fails to exhibit clinical manifestations of illness, or administra- tion of immunizations may result in lymphocyte changes.2 The lymphocyte count is high at birth and continues to rise in some healthy infants during the first year of life. A steady decline occurs throughout childhood and adolescence until lower adult values are reached. Whether these developmental variations are physiologic or are a pathologic response to frequent viral infections and immunizations in children is not known. In healthy neonates, the neutrophil count peaks at 6 to 12 hours after birth and then declines over the next few days of life.3 Neutrophil counts also are slightly higher in female neonates compared with males. After 2 weeks of life, neutrophil counts fall to within or below normal adult ranges. By approximately 4 years of age, the neutrophil count is similar to that of an adult. White children have slightly higher counts than black children.4 The eosinophil count is elevated in the irst year of life relative to children, teenagers, or adults.5,6 Monocyte counts are elevated through the preschool years and then decrease to adult levels. No relationship between age and basophil count has been found. Platelet counts in full-term neonates are comparable to platelet counts in adults and remain so throughout infancy and childhood.5 DISORDERS OF ERYTHROCYTES Anemia is the most common blood disorder in children. Although not a disease state in and of itself, the presence of anemia may be associated with an underlying pathophysiologic process. Like anemia in adults, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes. The most common cause of insuficient erythropoiesis is iron deiciency, which may result from insufficient dietary intake or chronic loss of iron caused by bleeding. The hemolytic anemias of childhood may be divided into two large categories. The first category consists of disorders that result from premature destruction caused by intrinsic abnormalities of the erythrocytes, and the second category consists of disorders that result from damaging extra-erythrocytic factors. The hemolytic anemias can be inherited, congenital, or both. The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the fetus and newborn (HDFN) an alloimmune disorder in which maternal blood and fetal blood are antigenically incompatible, causing the mother’s immune system to produce antibodies against fetal erythrocytes. Fetal erythrocytes that have been bound to maternal antibodies are recognized as foreign or defective by the fetal mononuclear phagocyte system and are removed from the circulation 996 UNIT VIII The Hematologic System TABLE 31.2 ANEMIAS OF CHILDHOOD CAUSE Deficient Erythropoiesis or Hemoglobin Synthesis Decreased stem cell population in marrow (congenital or acquired Decreased erythropoiesis despite normal stem cell population disease, congenital dyserythropoiesis) Deficiency of a factor or nutrient needed for erythropoiesis Cobalamin (vitamin B12), folate Iron Increased or Premature Hemolysis Alloimmune disease (maternal-fetal Rh, ABO, or minor blood Autoimmune disease (idiopathic autoimmune hemolytic anemia, lymphoma, drug-induced autoimmune processes) Inherited defects of plasma membrane structure (spherocytosis, (pyknocytosis) Infection (bacterial sepsis, congenital syphilis, malaria, herpes) Intrinsic and inherited enzymatic defects (deficiencies of 5′-nucleotidase, glucose phosphate isomerase) Inherited defects of hemoglobin synthesis Disseminated intravascular coagulation (see Chapter 29) Galactosemia Prolonged or recurrent respiratory or metabolic acidosis Blood vessel disorders (cavernous hemangioma, large vessel aorta) (see Chapter 33) PATHOPHYSIOLOGY. Regardless of the cause, a deiciency of iron produces a hypochromic-microcytic anemia.7 Progressive depletion of blood and low serum levels of ferritin and transferrin saturation eventually lead to a lowering of hemoglobin and hematocrit values. In early stages an adaptive increase in red blood cell activity in the bone marrow may prevent the development of anemia. Anemia develops when the iron stores are depleted with accompanying important laboratory indicators. (Mechanisms of iron depletion are described in Chapter 28.) CLINICAL MANIFESTATIONS. The symptoms of mild anemia— lethargy and listlessness—usually are not clearly evident in infants and young children, who are unable to describe these symptoms. Therefore parents usually do not notice any change in the child’s behavior or appearance until moderate anemia has developed. General irritability, decreased activity tolerance, weakness, and lack of interest in play are nonspecific indications of anemia. In mild to moderate IDA (hemoglobin level of 6 to 10 g/dL), compensatory mechanisms of tissue oxygenation, such as increased amounts of 2,3-DPG within erythrocytes and a shift of the oxyhemoglobin dissociation curve, may be so effective that few clinical manifestations are apparent. When the hemoglobin level falls below 5 g/dL, however, pallor, tachycardia, and systolic murmurs often occur. Clinical manifestations of chronic IDA include splenomegaly; skull sutures; decreased physical growth and developmental delays; and pica, a behavior in which non–food substances such as clay, paper, or ice are eaten. Weight is not necessarily an indicator of IDA because children may be obese, underweight, or of normal weight. CHAPTER 31 genetically: they may be type A, B, or O and may or may not include Rh antigen D. Erythrocytes that express Rh antigen D are Rh-positive; those that do not are Rh-negative. The frequency of Rh negativity is higher in whites (15%) than in blacks (5%), and is rare in Asians. Maternal-fetal incompatibility exists if mother and fetus differ in ABO blood type or if the fetus is Rh-positive and the mother is Rh-negative. (The antigenic properties of erythrocytes are described in Chapter 9.) ABO incompatibility occurs in about 20% to 25% of all pregnan- cies, but only 1 in 10 cases of ABO incompatibility results in HDFN. Rh incompatibility occurs in less than 10% of pregnancies and rarely causes HDFN in the irst incompatible fetus. Even after ive or more pregnancies, only 5% of women have babies with hemolytic disease. Typically, erythrocytes from the first incompatible fetus cause the mother’s immune system to produce antibodies that affect the fetuses of subsequent incompatible pregnancies. Most cases of HDFN are caused by ABO incompatibility, and only one in three cases is caused by Rh incompatibility. PATHOPHYSIOLOGY. HDFN will result from the following: (1) if the mother’s blood contains preformed antibodies against erythrocytes or produces antibodies on exposure to fetal erythrocytes, (2) if sufficient amounts of antibody (usually immunoglobulin G [IgG]) cross the Fetal Rh-positive erythrocyte A Agglutination of fetal Rh-positive erythrocytes leads to hemolytic disease of the newborn C FIGURE 31.2 Hemolytic Disease of the erythrocytes from the fetus enter the is sensitized to the Rh antigen and effect on the fetus in the first pregnancy. erythrocytes cross the placenta, enter against the Rh antigen. The Rh antibodies of fetal erythrocytes, and HDFN develops. ed 3, St Louis, 1995, Mosby.) 998 UNIT VIII The Hematologic System The irst Rh-incompatible pregnancy usually presents no dificulties because very few fetal erythrocytes cross the placental barrier during gestation. However, when the placenta detaches at birth, large numbers of fetal erythrocytes usually enter the mother’s bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, the mother produces anti-Rh antibodies. The capacity of the mother’s immune system to produce anti-Rh antibodies depends on many factors, including her genetic capacity to make antibodies against the Rh antigen D, the amount of fetal-to-maternal bleeding, and the occurrence of any bleeding earlier in the pregnancy. Anti-Rh antibodies persist in the bloodstream for a very long time, and if the next offspring is Rh-positive, the mother’s anti-Rh antibodies can enter the fetus’s bloodstream and destroy the erythrocytes. Antibodies against Rh antigen D are of the IgG class and easily cross the placenta. IgG-coated fetal erythrocytes are destroyed through extravascular hemolysis, primarily by mononuclear phagocytes in the spleen. As hemolysis progresses, the fetus becomes anemic. Erythropoiesis acceler- ates, particularly in the liver and spleen, and immature nucleated cells (erythroblasts) are released into the bloodstream, hence the name erythroblastosis fetalis (Fig. 31.3). The degree of anemia depends on the length of time the antibody has been in the fetal circulation, the concentration of antibody, and the ability of the fetus to compensate for increased hemolysis. Unconjugated (indirect) bilirubin, which is formed during breakdown of hemoglobin, is transported across the placental barrier into the maternal circulation and is excreted by the mother. Hyperbilirubinemia, an increase in bilirubin concentration in the blood, occurs in the neonate after birth because excretion of lipid-soluble unconjugated bilirubin through the placenta no longer is possible. The pathophysiologic effects of HDFN are more severe in Rh incompatibility than in ABO incompatibility. ABO incompatibility may resolve after birth without life-threatening complications. Maternal-fetal incompatibility in which a mother with type O blood has a child with type A or B blood usually is so mild that it does not require treatment. Rh incompatibility is more likely than ABO incompatibility to cause severe or even life-threatening anemia, death in utero, or damage to the central nervous system (CNS). Severe anemia alone can cause death as a result of cardiovascular complications (see Chapter 29). Extensive hemolysis also results in increased levels of unconjugated bilirubin in the circulation. If bilirubin levels exceed the liver’s ability to conjugate and excrete bilirubin, some of it is deposited in the brain, causing FIGURE 31.3 Rh Incompatibility in Hemolytic Disease of the Newborn. This micrograph shows immature red blood cells not normally purple cells are erythroblasts; nucleated red blood cells are red blood cells also are shown (×500). (Copyright Ed Reschke.) CHAPTER 31 Jaundice and indirect hyperbilirubinemia are reduced when the infant is exposed to high-intensity light in the visible spectrum from 460 to 490 nm.20 Bilirubin in the skin absorbs light energy, which, by photoisomerization, converts the toxic unconjugated bilirubin into conjugated isomers that are excreted in the bile. Phototherapy also causes autosensitization that results in oxidation reactions. Breakdown products from the oxidation reactions are excreted by the liver and kidney without need for conjugation. The therapeutic effect of photo- therapy depends on the light energy emitted in the effective wavelengths, the distance between the infant and the light source, and the amount of skin exposed; the rate of hemolysis and the infant’s ability to excrete bilirubin also are factors in determining the effectiveness of phototherapy in lowering serum bilirubin levels. Anemia of Infectious Disease Infections of the newborn, often initially acquired by the mother and transmitted to the fetus, may result in a hemolytic anemia with clinical manifestations similar to those of HDFN. Congenital syphilis, toxo- plasmosis, cytomegalic inclusion disease, rubella, coxsackievirus B infection, herpesvirus infection, and bacterial sepsis can cause hemolytic anemia in the neonate. The exact mechanism of anemia caused by congenital infections is unclear. In some instances, it is related to direct injury of erythrocyte membranes or erythrocyte precursors by the infectious microorganism. In other instances, it results from traumatic destruction of erythrocytes during their passage through inflamed capillaries. Anemia in Critically Ill Children Anemia is a common occurrence in critically ill children (see Chapter 50). The causes are numerous and include decreased erythropoietin activity, poor iron use by the body, and blood loss from diverse conditions and consequences of treatment. A topic of ongoing discussion is whether transfusion of blood products, particularly packed RBCs, improves outcomes in critically ill children because of problems related to blood storage. New research is ongoing and needed to understand these problems, the development of new blood transfusion strategies, and blood substitutes.21 Inherited Disorders A number of inherited and intrinsic erythrocyte defects are known to cause hemolytic disease or increased hemolysis (see Table 31.2). These defects may result from enzymatic abnormalities that disrupt metabolic processes and prevent normal biochemical balance within the cell, alterations of hemoglobin structure or synthesis, or plasma membrane defects accompanied by changes in erythrocyte size or shape. Glucose-6-Phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited disorder caused by a genetic defect in the RBC enzyme G6PD, which is involved in the normal processing of carbohydrates. The enzyme G6PD is responsible for the irst step in a pathway that converts glucose to ribose-5-phosphate. The chemical reactions usually produce nico- tinamide adenine dinucleotide phosphate (NADPH), which helps in protecting cells from oxidative stress from reactive oxygen species (ROS). G6PD deiciency is the most common disorder of RBCs, estimated to affect 200 to 400 million people worldwide. The enzyme deiciency leads to damaged RBCs that can rupture and break down prematurely, causing hemolysis. The deficiency occurs most often in tropical and subtropical regions of the Eastern Hemisphere including Europe, Africa, and Asia. G6PD deiciency is an X-linked recessive disorder, most fully expressed in homozygous males, although partial expression is possible in heterozygous females because of mosaicism resulting from X- 1000 UNIT VIII The Hematologic System transfusions and oral iron therapy. Spontaneous recovery generally follows treatment. Hereditary Spherocytosis Hereditary spherocytosis (HS) is an inherited disorder caused by defects in the membrane skeleton of RBCs. The changes cause RBCs to become spherical, less deformable, and vulnerable to destruction. HS is caused by genetic mutations in at least ive genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB). These genes provide proteins for producing RBC membranes. These proteins act as transporters for molecules in and out of the cells, attach to other proteins, and maintain cell shape. Thus these proteins help the cells to be lexible for RBC mobility from large blood vessels to capillaries. Mutations in RBC membranes result in changes in shape, becoming more spherical instead of a flattened disc shape, and rigid. The misshapen cells, or spherocytes, are removed from circulation and end in the spleen for destruction. In the spleen, the spherocytes break down and undergo hemolysis. PATHOPHYSIOLOGY. HS is transmitted as an autosomal dominant trait in about 75% of cases. The defect results from properties of its specialized membrane skeleton, which lies close to the internal surface of the plasma membrane.7 The affected proteins include spectrins and ankyrin, and their intrinsic defects in the membrane cause less deformability and increased vulnerability to splenic sequestration destruction. The spleen is intimately involved in the hemolytic process. The spherocyte is relatively rigid and passes with dificulty through the small openings between the splenic cords and sinuses initiating macrophage response. Circulation of blood to the spleen creates repeated circulation through a metabolic environment that results in sequestration and destruction of spherocytes. CLINICAL MANIFESTATIONS. The presenting signs of HS are anemia, jaundice, and splenomegaly. Anemia may be mild or absent in some cases depending on the individual’s physiologic compensation. In these cases, the reticulocyte count will be elevated. Splenomegaly is usually mild. HS can present at any age, from the neonatal period until older adulthood. If HS presents during the newborn period, it is typically more severe with the infant developing signs of hemolytic anemia and hyperbilirubinemia.23 These children, therefore, may have life-threatening anemia with clinical symptoms ranging from dificulty feeding, cir- 2 Preferential adhesion of sickled cells to endothelial cell surfaces increases with peripheral resistance and causes narrowing of the vascular lumen. Macrophage-shea capillarie 1 Retrograde obstruction by irreversibly sickled cells is a consequence of reduction in blood flow that aggravates the obstruction because oxygen tension decreases. FIGURE 31.4 Sickle Cell Hemoglobin. and cell biology: an introduction CHAPTER 31 from the Mediterranean countries, such as Greece, Turkey, and Italy; the Arabian peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean.26 Most infants with SCD born in the United States are now identiied by routine screening. Between 1 and 3 million Americans and more than 100 million individuals worldwide are estimated to be heterozygous carriers for the sickle cell trait (HbAS).27 It is estimated that between 70,000 and 100,000 Americans have SCD.28 Cycles of deoxygenation and oxygenation cause the HbS molecule to polymerize and stiffen. These polymers can damage the RBC structure, leading to sickle-shaped RBCs. This change causes a variety of pathologic consequences; the sickle-shaped RBCs die prematurely leading to hemolytic anemia, microvascular obstruction, and ischemic tissue damage. SCD is inherited in an autosomal recessive pattern parent carries one copy of the mutated gene. Sickle cell anemia HbSS), a homozygous form, is the most severe. Sickle cell trait (HbAS), in which the child inherits HbS from one parent and normal hemoglobin (HbA) from the other, is a heterozygous carrier state and not a form of SCD. The most prevalent SCD genotypes include homozygous hemoglobin SS (HbSS, or sickle cell anemia) and the compound het- erozygous conditions hemoglobin Sβ0-thalassemia (Hbβ0-thalassemia), hemoglobin Sβ-thalassemia (HbSβ+-thalassemia), and hemoglobin SC disease (HbSC).28 HbSS and HbSβ0-thalassemia are clinically similar and are, therefore, commonly referred to as sickle cell anemia (SCA); these genotypes are associated with the most severe clinical tions.28 All forms of SCD are lifelong conditions. Two effective therapies for SCD are hydroxyurea and chronic transfusion.28 a cure is use of hematopoietic stem cell transplantation (HSCT); however, it is infrequently performed and needs signiicant investigation.28 PATHOPHYSIOLOGY. Pathogenesis of sickling includes erythrocyte derangement, chronic hemolysis (hemolytic anemia), microvascular occlusions, and tissue damage. Deoxygenation is probably the most important variable in determining the occurrence of sickling. Other signiicant variables that affect sickling include interaction of HbS with other types of hemoglobin in the cell, mean cell hemoglobin concentra- tion (MCHC), intracellular pH, and transit times of erythrocytes through the microcirculation.7 In heterozygotes with sickle cell trait, the presence of other types of Hb prevents sickling except under conditions of severe hypoxia. Intracellular dehydration increases the MCHC, which increases sickling. A decrease in pH reduces the oxygen affinity of hemoglobin, resulting in an increase in the quantity of deoxygenated HbS at any oxygen tension and increasing sickling. Inflammation in the microcircula- tion will slow erythrocyte transit times because blood low is sluggish with adhesion of leukocytes to activated endothelial cells. Increased osmolality of the plasma draws water out of the erythrocytes. This promotes sickling by raising the relative HbS content in erythrocytes. Investigators are studying the optimal intravenous luid to increase erythrocyte deformability and biomechanical properties.29 To simplify, sickling as an occasional, intermittent phenomenon can be triggered or sustained by one or more of the following stressors: decreased oxygen tension (Po2) of the blood (i.e., hypoxemia), acidosis (decreased pH), increased plasma osmolality, decreased plasma volume, and low tem- perature (Fig. 31.5). Low temperatures precipitate sickle crisis, presumably because of vasoconstriction.30 Sickling causes damage to erythrocytes through several mechanisms, including (1) membrane derangements occur because as HbS units (polymers) grow they protrude through the membrane skeleton by only the lipid layer, causing changes in membrane structure: (2) membrane derangement leads to changes in ionic flow with an inlux in Ca++ ions, which induces cross-linking of membrane proteins and activation of an ion channel that induces the eflux of K+ and H2O; and (3) with time the damaged cells are converted to end-stage, nondeformable 1002 UNIT VIII The Hematologic System Sickle cell Normal anemia hemoglobin hemoglobin !-chain !-chain Valine Valine Histidine Histidine Leucine Leucine Threonine Threonine Proline Proline Glutamic Valine acid Glutamic Glutamic acid acid A FIGURE 31.6 Sickle Cell Disease Pathogenesis. Aster JC: Robbins and Cotran pathologic A Normal red blood cell FIGURE 31.7 Normal and Sickle-Shaped erythrocytes and sickled blood cell. together. The irregularly shaped cells PH, Johnson GB: Biology, ed 3, St expression of adhesion molecules on endothelial cells. These reactions further promote sickled erythrocytes to become arrested during move- ment through the microvasculature.7 The sluggish and stagnant red cells within the inlamed vascular vessels result in extended exposure to low oxygen tension, sickling, and vascular obstruction.7 Lysed sickle erythrocytes release hemoglobin and free hemoglobin can bind and CHAPTER 31 Acute manifestations Brain Thrombosis or hemorrhage causing paralysis, sensory deficits, or death Lung Atelectasis (incomplete expansion) Infarction Pneumonia Abdominal organs Acute hepatomegaly Gallstones Splenic sequestration Splenomegaly Infarction Bones and joints Hand-foot syndrome (painful swelling of hands and feet) Kidney Hematuria (blood in urine) FIGURE 31.8 Clinical Once sickling begins, it tends to continue until the Po2 returns to normal; then it ceases spontaneously. The extent, severity, and clinical manifestations of sickling depend to a great extent on the percentage of hemoglobin that is HbS. That is why homozygous inheritance of HbS produces the severest form of SCD—sickle cell anemia. Heterozygous inheritance of SCD results in less sickling because the individual’s erythrocytes contain other forms of abnormal hemoglobin that, although defective, do not contribute to sickling to any great degree. Heterozygous inheritance (sickle cell trait), in which abnormal hemoglobin is inherited from one parent and normal hemoglobin from the other, rarely results in sickling because normal HbF and HbA do not contribute to sickling at all. Anemia persists because HbF does not live 120 days. CLINICAL MANIFESTATIONS. There is much variation in the clinical manifestations of sickle cell disease. Some individuals have mild symptoms and others suffer from repeated vaso-occlusive crises.7 Clinical manifestations of SCD may irst be seen at 6 to 12 months of age as fetal hemoglobin is replaced by HbS. Two characteristics of SCD determine presentation: the first is its nature to be a chronic disease with acute exacerbations; the second is that it is a condition affecting RBCs that supply oxygen to all cells of the body. Therefore SCD can 1004 UNIT VIII The Hematologic System the penis, can lead to hypoxic damage and erectile dysfunction. Vaso- occlusion in vessels to the brain can result in stroke. Chronic vaso- occlusion in vessels to the kidneys results in end-stage renal disease. Vaso-occlusive crisis is extremely painful and may last for days or even weeks. The frequency of this type of crisis is variable and unpredictable because it may develop spontaneously or be precipitated by infection, exposure to cold, dehydration, low Po2, acidosis (low pH), or localized hypoxemia. Aplastic crisis, a transient cessation in RBC production resulting in acute anemia, occurs as a result of a viral infection, almost always infection with parvovirus B1. The virus causes temporary shutdown of RBC production in the bone marrow but hemolysis continues. The outcome is a sudden drop in hemoglobin level with an extremely low reticulocyte count. In sequestration crisis, large amounts of blood become pooled in the spleen. Massive large amounts of sickle red cells lead to a rapid splenic enlargement, hypovolemia, and sometimes shock.7 Sequestration crisis and acute chest syndrome may be fatal and can require prompt treatment with exchange transfusions. Hyperhemolytic crisis, an accelerated rate of RBC destruction, is unusual but may occur in association with certain drugs or infections. It is characterized by anemia, jaundice, and reticulocytosis. The con- comitant presence of G6PD deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency) contributes to hyperhemolytic episodes, especially when combined with infections. A significant cause of morbidity and mortality is infection, especially for those with impaired splenic function. Splenic function is severely altered in children with splenic congestion and poor blood low, and severe splenic damage in adults occurs from splenic infarction. In children, infections from Pneumococcus pneumoniae and Haemophilus influenzae are common. Glomerular disease, characterized by damage to the glomeruli allowing protein and often RBCs to leak into the urine, is caused by sickling of RBCs in the kidneys. Extensive damage to the glomeruli results in nephropathy that may progress to renal failure. The earliest manifestation of SCD in the kidney is hyposthenuria, or the inability of the tubules of the kidneys to concentrate urine. Very low urine speciic gravity occurs and in young children this often results in bed-wetting. Proteinuria also is an early manifestation of sickle nephropathy. Cholecystitis, inlammation of the gallbladder that occurs when a gallstone blocks the cystic duct, can be caused by hemolysis resulting in an increase of bilirubin concentration, which in turn causes the formation of gallstones in the gallbladder. The presence of gallstones can cause right upper quadrant pain, nausea, vomiting, and white blood cell count and alkaline phosphatase level. Cholecystectomy may be required. Sickle cell–hemoglobin C (HbC) disease is usually milder than sickle cell anemia. HbC results when lysine is substituted for glutamic acid in the amino acid chain. HbC is less soluble than HbA; however, it does not polymerize under conditions of decreased oxygen tension as does HbS. The main clinical problems are related to vaso-occlusive crises and are proposed to result from higher hematocrit values and viscosity. In older children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of the femoral heads occur along with obstructive crises. Sickle cell–thalassemia has the mildest clinical manifestations of all the SCDs. Individuals with sickle cell–thalassemia have mutations in each allele coding for hemoglobin. One mutation results in HbS formation and the other is associated with β-thalassemia and results in decreased production of hemoglobin. Even though most of the child’s hemoglobin is HbS (60% to 90%), normal hemoglobins (HbA and HbF) also are present. The normal hemoglobins, particularly HbF, inhibit sickling. In addition, the erythrocytes tend to be small (microcytic) and to contain CHAPTER 31 pattern where both copies of the HBB gene in each cell have mutations. In a small percentage of families, the HBB gene mutation is inherited in an autosomal dominant manner.43 The mutations are classified as (1) β0 mutations or absent β-globin synthesis and (2) β+ mutations with reduced amounts of β-globin synthesis. Genetic studies have identiied more than 100 different causative mutations, and most are point (missense) mutations. Clinical classiication of β-thalassemias is based on the severity of the anemia, which is dependent on the type of mutation (β0 or β+ allele) and gene dosage (homozygous or hetero- zygous).7 β-Chain production is depressed in the heterozygous form, thalassemia minor (β0 or β+ allele); and anemia, if present, is mild; however, anemia is severe in the homozygous form, β-thalassemia major. β-Thalassemia major may lack HbA (β0/β0 genotype) or contain small amounts (β+/β+ or β0/β+ genotypes). The main type of hemoglobin is HbF and sometimes HbA2 is high and often normal or low.7 Depression of β-chain synthesis results in erythrocytes having a reduced amount of hemoglobin and accumulations of free α chains. The free α chains are unstable and easily precipitate in the cell (Fig. 31.9). Most eryth- roblasts that contain precipitates are destroyed by mononuclear phagocytes in the marrow, resulting in ineffective erythropoiesis and anemia. Some of the precipitate-carrying cells do mature and enter the bloodstream, but they are destroyed prematurely in the spleen, resulting in mild hemolytic anemia. NORMAL Reduced β-globin synthesis, with relative excess of α-globin HbA (α2β2) Normal erythroblast Normal red blood cells Dietary iron Disorders of Coagulation and Platelets, 1006 Inherited Hemorrhagic Disease, 1006 Antibody-Mediated Hemorrhagic Disease, 1008 Neoplastic Disorders, 1010 Leukemia, 1010 Lymphomas, 1012 production shifts from the vessels to the liver sinusoids, and the produc- tion of leukocytes and platelets begins in the liver and spleen. Eryth- ropoiesis in the liver and, to a lesser extent, in the spleen and lymph nodes, reaches a peak at approximately 4 months. Hepatic blood forma- tion declines steadily thereafter but does not disappear entirely during the remainder of gestation. By the fifth month of gestation, hematopoiesis begins to occur in the bone marrow and increases rapidly until hema- topoietic (red) marrow ills the entire bone marrow space. By the time of delivery, the marrow is the only signiicant site of hematopoiesis. In neonates and young infants, hematopoietic marrow progressively ills the bony cavities of the entire axial skeleton (skull, vertebrae, ribs, sternum), the long bones of the limbs, and many intramembranous bones. (These structures are described in Chapter 46.) Fatty (yellow) marrow gradually replaces hematopoietic marrow in some bones. During childhood, hematopoietic tissue retreats centrally to the vertebrae, ribs, sternum, pelvis, scapulae, skull, and proximal ends of the femur and humerus. In diseases characterized by hemolysis, erythrocyte production can increase as much as eight times the normal level because erythropoietin causes hematopoietic marrow to increase in volume. Initially, hematopoi- etic marrow expands from the ends of the long bones toward the middle of the shafts, replacing fatty marrow. Next, blood cell production begins Alterations of Hematologic Function in Children 993 Fetal hemoglobin has greater afinity for oxygen than does adult hemoglobin because it interacts less readily with an enzyme Liver (2,3-diphosphoglycerate [2,3-DPG]) that inhibits hemoglobin-oxygen binding. The decreased inhibitory effects of 2,3-DPG enable fetal blood Spleen to transport oxygen despite the relative lack of oxygen in the uterine environment. The increased afinity for oxygen enables HbF to bind with maternal oxygen in the placental circulation. During the first trimester nearly all of the hemoglobin in the fetus is embryonic, but some HbA can be detected. Therefore it is possible to identify as early as 16 to 20 weeks of gestation some disorders of adult hemoglobin, such as sickle cell anemia and thalassemia major. In the 6-month fetus, HbF constitutes 90% of the total. This percentage then begins to decline. At birth, neonatal hemoglobin consists of 70% HbF, 29% HbA, and 1% HbA2. Between 6 and 12 months of age, normal adult hemoglobin percentages are established (see Chapter 28). POSTNATAL CHANGES IN THE BLOOD Blood cell counts tend to rise higher than adult levels at birth and then decline gradually throughout childhood. Table 31.1 lists normal ranges during infancy and childhood. The immediate rise in values is the result of the accelerated hematopoiesis during fetal life, the increased numbers of cells that result from the trauma of birth, and the cutting of the umbilical cord. These events surrounding the birth also are accompanied by the presence of large numbers of immature erythrocytes and leukocytes (particularly granulocytes) in peripheral blood (see Chapter 28). As the infant develops over the irst 2 to 3 months of life, the numbers of these immature blood cells decrease. Average blood volume in the full-term neonate is 85 mL/kg of body weight. The premature infant has a proportionately larger blood volume of 90 to 100 mL/kg of body weight. In both full-term and premature the proximal ends of the infants, blood volume relative to body weight decreases during the irst few months. By 3 years of age, a child’s average blood volume is 75 to filled with red marrow, 77 mL/kg, which is similar to that of older children and adults. In children and adults, necessitating Erythrocytes The hypoxic intrauterine environment stimulates erythropoietin produc- tion in the fetus. This accelerates fetal erythropoiesis, producing polycythemia (excessive proliferation of erythrocyte precursors) of the newborn. After birth the oxygen from the lungs saturates arterial blood, and the amount of oxygen delivered to the tissues increases. In response to the change from a placental to a pulmonary oxygen supply during the irst few days of life, levels of erythropoietin and the rate of blood cell formation decrease. The very active rate of fetal erythropoiesis is reflected by the large numbers of immature erythrocytes (reticulocytes) in the peripheral blood of full-term neonates. The number of reticulocytes decreases abruptly during the irst few days after birth, which is associated with decreased erythropoietin production.1 Finding an elevated reticu- locyte count after the irst week of life is rare. A decrease in extramedullary hematopoiesis also occurs at this time. In the peripheral blood the erythrocyte count drops for 6 to 8 weeks after birth. During this period of rapid growth the rate of erythrocyte destruction is greater than that in later childhood and adulthood. In full-term infants, the normal erythrocyte life span is 60 to 80 days; in premature infants it may be as short as 20 to 30 days; and in children and adolescents, it is the same as that in adults—120 days. (Mechanisms of hemolysis are described in Chapter 28.) In the premature infant, the postnatal decrease in hemoglobin and hematocrit values is more marked than in the full-term infant. In the preschool and school-age child, hemoglobin, hematocrit, and red blood cell (RBC) count values rise gradually. In males and females, these values irst begin to diverge in adolescence. In the female, the gradual 994 CHILDHOOD LEUKOCYTES NEUTROPHILS MCV (fl) (WBC/mm3) (%) LYMPHOCYTES EOSINOPHILS MONOCYTES LOWEST MEAN RANGE MEAN RANGE (%) MEAN* (%) MEAN (%) MEAN 110 18,000 (9000–30,000) 61 (40–80) 31 2 6 12,000 (5000–21,000) 40 63 3 9 12,000 (6000–18,000) 30 48 2 5 UNIT VIII The Hematologic System 70–74 10,000 (6000–15,000) 45 48 2 5 1 76–80 8,000 (4500–13,500) 55 38 2 5 80 7,500 (5000–10,000) 55 (35–70) 35 3 7 80 cells. ed 17, Philadelphia, 2004, Saunders. Alterations of Hematologic Function in Children 995 by phagocytosis, usually in the fetal spleen. (For a complete discussion of HDFN, see Hemolytic Disease of the Fetus and Newborn.) Other acquired hemolytic anemias—some of which begin in utero—include those caused by infections or the presence of toxins. The inherited forms of hemolytic anemia result from intrinsic defects of the child’s erythrocytes, any of which can lead to erythrocyte destruc- tion by the mononuclear phagocyte system. Structural defects include abnormal red blood cell size and abnormalities of plasma membrane structure (spherocytosis). Intracellular defects include enzyme deficien- cies, the most common of which is G6PD deiciency; and defects of hemoglobin synthesis, which manifest as sickle cell disease or thalassemia, depending on which component of hemoglobin is defective. These and other causes of childhood anemia, some more common than others, are listed in Table 31.2. n Acquired Disorders Iron Deficiency Anemia Iron is critical to the developing child, especially for normal brain development, and without it the damage from the periods of iron deiciency anemia (IDA) in children is irreversible. IDA is the most common nutritional disorder worldwide with the highest incidence occurring between 6 months and 2 years of age. IDA is common in the United States where prevalence is higher in toddlers, adolescent girls, and women of childbearing age, and causes clinical manifestations mostly related to inadequate hemoglobin synthesis.7 Its incidence is not related to gender or race; however, socioeconomic factors are important because they affect nutrition. IDA can result from (1) dietary insufficiencies, (2) absorption problems, (3) blood loss, and (4) increased requirement of iron. Inadequate intake is the most common cause of IDA during the first few years of life and blood loss is the most common cause during childhood and adolescence, and for adults in the Western world. Chronic IDA from occult (hidden) blood loss may be caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease. A reasonable hypothesis for infants and young children who develop IDA is they have chronic intestinal blood loss induced by exposure to a heat-labile protein in cow’s milk. Such exposure causes an inlammatory gastro- intestinal reaction that damages the mucosa and results in diffuse microhemorrhage. Growing evidence indicates that cellular components of both innate and adaptive immunity play signiicant roles during the pathogenesis of cow’s milk allergy.8 Dietary lack is not common in developed countries where iron is in the readily absorbed form from heme that comes from meat. IDA has declined in the United States; however, a recent study in the United States found toddlers are vulnerable to IDA, especially those consuming excessive quantities of whole cow’s milk.9 Increased consumption of iron-fortified infant foods, including formula, is hypothesized to have contributed to the overall decline in IDA.10 However, bioavailability of iron from breast milk is higher than that from cow’s milk. At this point, only low-quality evidence for use of micronutrient powders in pregnant women is available.11 Impaired absorption is found in chronic diarrhea, fat malabsorption, and celiac disease. Evidence also is emerging regarding genetic polymorphisms that may contribute to altered iron absorption in cases of refractory IDA with a familial component.12 Children in developing countries are often affected by chronic parasite infestations that result in blood and iron loss greater than dietary intake.13 Treatment of helminth infections results in improvement in appetite, growth, and in the anemia. Controversial is the association of IDA with lead (Pb) poisoning. Newer areas of investigation include iron deiciency in overweight children and the association of H. pylori infection with IDA.14 ANEMIC CONDITION pure red cell aplasia) Normocytic-normochromic anemia in marrow (infection, inflammation, cancer, chronic renal Normocytic-normochromic anemia Megaloblastic anemia Microcytic-hypochromic anemia group incompatibility) Hemolytic disease of the newborn (HDN) symptomatic systemic lupus erythematosus, Autoimmune hemolytic anemia elliptocytosis, stomatocytosis) or cellular size or both Hemolytic anemia cytomegalovirus infection, rubella, toxoplasmosis, disseminated Hemolytic anemia glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase, Hemolytic anemia Sickle cell anemia Thalassemia Hemolytic anemia Hemolytic anemia Hemolytic anemia thrombus, renal artery stenosis, severe coarctation of the Hemolytic anemia Consequences of IDA are signiicant and may include altered neurologic and intellectual function, especially involving attention span, alertness, and learning ability. EVALUATION AND TREATMENT. Laboratory tests confirm the diagnosis of IDA. Laboratory tests include measurements of hemoglobin, hematocrit, serum iron, ferritin, and the total iron-binding capacity. A thorough history of present illness, a dietary history, and a physical examination are essential. Evaluation and treatment of IDA in children are similar to evaluation and treatment in adults (see Chapter 29). Oral administration of simple ferrous salts usually is satisfactory, and additional vitamin C helps promote absorption.15 Iron in a liquid form should be administered through a straw because it can stain teeth. Iron therapy is continued for at least 2 months after erythrocyte indexes have returned to normal in order to replenish iron stores.16 Dietary modiication is required to prevent recurrences of IDA. Intake of iron-rich foods is increased and the intake of cow’s milk may be restricted, with the exact amount restricted to 16 to 32 ounces per day depending on the child’s age. Limiting milk intake makes the child hungrier for other iron-rich foods and prevents gastrointestinal blood loss in children whose anemia is aggravated or caused by inlammatory reactions to proteins in cow’s milk. widened Hemolytic Disease of the Fetus and Newborn Hemolytic disease of the fetus and newborn (HDFN) can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. The antigenic properties of erythrocytes are determined Alterations of Hematologic Function in Children 997 placenta and enter fetal blood, and (3) if IgG binds with suficient numbers of fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal. (Antibody-mediated red blood cell destruction is discussed in Chapter 9.) Maternal antibodies may be formed against type B fetal erythrocytes if the mother is type A or against type A fetal erythrocytes if the mother is type B. Usually, however, the mother is type O and the fetus is A or B. ABO incompatibility can cause HDFN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy. This occurs because the blood of most adults already contains anti-A or anti-B antibodies, which are produced on exposure to certain foods or infection by gram-negative bacteria. (Anti-O antibodies do not exist because type O erythrocytes are not antigenic.) Therefore IgG against type A or B erythrocytes is usually preformed in maternal blood and can enter the fetal circulation throughout the first incompatible pregnancy. Anti-Rh antibodies, on the other hand, are formed only in response to the presence of incompatible (Rh-positive) erythrocytes in the blood of an Rh-negative mother. Sources of exposure include fetal blood that is mixed with the mother’s blood at the time of delivery, transfused blood, and, rarely, previous sensitization of the mother by her own mother’s incompatible blood (Fig. 31.2). Maternal circulation Maternal circulation Maternal Rh-negative Maternal erythrocyte Rh-negative erythrocyte Fetal Rh Rh-positive antibodies erythrocyte enters maternal circulation B Maternal circulation D antigen Hemolysis Maternal Rh antibodies cross the placenta D Fetus and Newborn (HDFN). A, Before or during delivery, Rh-positive blood of an Rh-negative woman through a tear in the placenta. B, The mother produces Rh antibodies. Because this usually happens after delivery, there is no C, During a subsequent pregnancy with an Rh-positive fetus, Rh-positive the maternal circulation, and (D) stimulate the mother to produce antibodies from the mother cross the placenta, using agglutination and hemolysis (Modified from Seeley RR, Stephens TD, Tate P: Anatomy and physiology, cellular damage and eventually death, if exchange transfusions are not administered. Fetuses that do not survive anemia in utero usually are stillborn, exhibiting gross edema throughout the entire body, a condition called hydrops fetalis. Death can occur as early as 17 weeks of gestation and results in spontaneous abortion. CLINICAL MANIFESTATIONS. Neonates with mild HDFN may appear healthy or slightly pale, with slight enlargement of the liver and spleen. Pronounced pallor, splenomegaly, and hepatomegaly indicate severe anemia, which predisposes the neonate to cardiovascular failure and shock. Life-threatening Rh incompatibility is rare today, largely because of maternal testing and the routine use of Rh immune globulin. Because maternal antibodies remain in the neonatal circulation after birth, erythrocyte destruction can continue. This causes hyperbiliru- binemia and icterus neonatorum (neonatal jaundice) that occurs shortly after birth. Without replacement transfusions, in which the child receives Rh-negative erythrocytes, the bilirubin is deposited in the brain, causing a condition termed kernicterus. Kernicterus produces cerebral damage and usually causes death (icterus gravis neonatorum). Infants who do not die may have signiicant developmental delay, cerebral palsy, or high-frequency deafness.17 EVALUATION AND TREATMENT. Routine evaluation for HDFN includes the Coombs test. The indirect Coombs test measures antibody in the mother’s circulation and indicates whether the fetus is at risk for HDFN. The direct Coombs test measures antibody already bound to the surfaces of fetal erythrocytes and is used primarily to confirm the diagnosis of antibody-mediated HDFN. Determining prior history of fetal hemolytic disease, as well as diagnostic tests, may help predict the severity of the disorder. Diagnostic measures include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment.18 The key to treatment of HDFN resulting from Rh incompatibility lies in prevention (immunoprophylaxis). Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D (anti-D Ig) administered within 72 hours of exposure to Rh-positive erythrocytes, ensures that the mother will not produce antibody against the D antigen, and that the next Rh-positive baby will be protected (see Fig. 31.2). Updated recommendations also state that if anti-D Ig is not given within 72 hours every effort should still be made to administer the anti-D Ig within 10 days. The newer updates on the use of anti-D Ig as prophylaxis to prevent sensitization to the D antigen during pregnancy or at delivery for the prevention of HDFN can be found at the National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=34964# Section420 for the use of anti-D immunoglobulin for rhesus D pro- phylaxis and from the British Committee for Standards in Haematology (BCSH) guidelines.19 The injected (anti-D Ig) antibodies remain in the mother’s blood- stream long enough to prevent her immune system from producing its own anti-Rh antibodies but not long enough to affect subsequent offspring. The mother must be given Rh immune globulin injections after the birth of each Rh-positive baby and after a miscarriage. The mother also must be especially careful not to receive a transfusion containing Rh-positive blood, because this would stimulate production of anti-Rh antibodies. If antigenic incompatibility of the mother’s erythrocytes is not discovered in time to administer Rh immune globulin and a child is born with HDFN, treatment consists of exchange transfusions in which the neonate’s blood is replaced with new Rh-positive blood that is not contaminated with anti-Rh antibodies. This treatment is instituted found in blood. Large during the irst 24 hours of extrauterine life to prevent kernicterus. normoblasts. Normal Phototherapy also is used to reduce the toxic effects of unconjugated bilirubin. Alterations of Hematologic Function in Children 999 inactivation. (X-linked inheritance is discussed in Chapter 4.) Several genetic variants of G6PD are identiied but most are harmless.7 Two variants, G6PD and G6PD Mediterranean, cause most of the signiicant hemolytic anemias.7 The deiciency is present in 10% of American blacks, and the G6PD Mediterranean variant is prevalent in Middle East populations. PATHOPHYSIOLOGY. Deficient or abnormal enzyme function can cause abnormalities in the hexose monophosphate shunt or glutathione metabolism that impairs the ability of RBCs to protect themselves against oxidative stress injuries that lead to hemolysis. One of the most important enzymes is G6PD. Oxidants cause both an intravascular and an extravascular hemolysis in G6PD-deicient individuals. G6PD enables erythrocytes to maintain normal metabolic processes despite injury from oxidative stressors, such as exposure to certain classes of drugs (sulfonamides, nitrofurantoins, antimalarial agents, salicylates, or naphthaquinolones), ingestion of fava beans (a dietary staple in some Mediterranean areas), hypoxemia, infection, fever, or acidosis. Therefore G6PD deficiency is usually asymptomatic unless one of these events occurs. Commonly, infections can initiate hemolysis, especially viral hepatitis, pneumonia, and typhoid fever. The fava bean is often ingested in Mediterranean cultures, causing “favism,” and in some parts of Africa. Erythrocyte damage in affected children begins after intense or prolonged exposure to one of these stressors (substances or condi- tions) and ceases when the stressors are removed. In black males, the G6PD defect becomes more pronounced as the erythrocyte ages, and in other populations the defect is profound even in young erythrocytes. A pregnant woman may cause an episode of hemolysis in a fetus with G6PD deiciency by ingesting a substance with oxidant properties, such as a salicylate (aspirin). In the absence of G6PD, oxidative stressors damage hemoglobin and the plasma membranes of erythrocytes and possibly interfere with the activities of other enzymes within the cell. Hemoglobin is oxidized progressively to methemoglobin, sulfmethemoglobin, and denatured globin-glutathione complexes. Exposure to oxidizing substances results in the precipitation of insoluble hemoglobin inclusions, called Heinz bodies, within the cell. Plasma damage and the presence of Heinz bodies cause hemolysis, primarily in the spleen. CLINICAL MANIFESTATIONS. In infants, G6PD deficiency may present as icterus neonatorum. The most common clinical manifestation of G6PD deficiency is acute hemolytic anemia, usually after infections or the ingestion of certain oxidative drugs. The fava bean produces a severe hemolytic reaction in children with G6PD deiciency. Hemolytic episodes are characterized by pallor, icterus, dark urine, back pain, and, in severe cases, shock, cardiovascular collapse, and death. Between hemolytic episodes, the child does not have anemia and erythrocyte survival is normal. EVALUATION AND TREATMENT. Reduced G6PD activity in erythrocytes is required for diagnosis. Immediately after a hemolytic episode, reticulocytes and young erythrocytes are evident. Because young erythrocytes have signiicantly higher enzyme activity than do older cells, laboratory evaluation should be performed shortly after a crisis so that a low level of enzyme activity can be demonstrated. G6PD activity that is within the low normal range in the presence of a high reticulocyte count suggests G6PD deficiency. G6PD deficiency also can be detected by electrophoretic analysis. Prevention of hemolysis is the most important therapeutic measure. Prevention includes avoiding medications and dietary substances associated with hemolysis. Because of the high frequency of G6PD deiciency in areas of the world that are endemic for malaria, the World Health Organization currently recommends testing for G6PD deiciency before administration of antimalarial medications in these regions.22 When hemolysis occurs, supportive treatment may include blood cumoral pallor, tachycardia, nasal flaring, and diaphoresis to lethargy. They also are at increased risk for gallstones because of the presence of extra bile pigment. Infection (speciically parvovirus),24 fever, and stress stimulate the spleen to destroy more RBCs than usual, leading to a worsening anemia in a child with baseline anemia. EVALUATION AND TREATMENT. Ascertaining a family history of spherocytosis is important. Laboratory findings include spherocytes in the peripheral blood smear (spherocytosis), elevated reticulocyte count (with or without anemia), indirect hyperbilirubinemia, and a positive osmotic fragility test. An osmotic fragility test is performed by placing RBCs in a saline solution for 24 hours. Spherocytes do not tolerate saline solutions; as a result, they burst more readily than normal RBCs. Treatment of HS is based on disease severity. Although some children with HS will have severe anemia, blood transfusions are rarely required. Treatment before the age of 5 years consists of daily folic acid supple- mentation to increase production of healthy RBCs. In the past, sple- nectomy was the irst line of treatment. Currently, however, splenectomy is only recommended for those children more than 5 years of age with severe disease or those who develop symptomatic gallstones. Partial splenectomy, in which only a portion of the spleen is removed, is being performed on children with HS in an attempt to decrease the risk of postsplenectomy complications.25 and Sickle Cell Disease Sickle cell disease (SCD) is a group of disorders that affects hemoglobin characterized by the presence of an atypical form of hemoglobin— hemoglobin S (HbS; sickle hemoglobin)—within the erythrocytes. It is a common hereditary hemoglobinopathy where HbS is formed by a genetic point mutation (missense) in β-globin that leads to the replace- ment of one glutamate amino acid with a valine amino acid (Fig. 31.4). Abnormal versions of β-globin can distort erythrocytes into a sickle shape. Hemoglobin consists of four protein subunits called α-globin and two subunits called β-globin. The hemoglobin B (HbB) gene provides instructions for making protein β-globin. Other mutations in the HbB gene lead to other versions of β-globin, such as hemoglobin C (HbC) and hemoglobin E (HbE). HbB gene mutations also can affect the quantity of β-globin, such as low levels of β-globin found in β-thalassemia. Sickle cell disease affects millions of people worldwide and is most common among individuals with ancestors from Africa and less so 5 Macrophages phagocytose 3 Dense trapping of remnants of sickled cells in splenic hemolytic sickled sinusoides. cells. thed s Splenic sinusoid 4 Hemolysis caused by precipitation of Hb and dissociation of the red blood cell plasma membrane from the subjacent cytoskeleton. Brief summary of sickle cell. (From Kierzenbaum AL, Tres LL: Histology to pathology, ed 4, Philadelphia, 2015, Saunders.) Alterations of Hematologic Function in Children 1001 Abnormal HbS present in erythrocytes neonatal Hypoxemia, decreased pH, low temperature, and/or decreased plasma volume occurs Persistent hypoxemia Reversal of causes further reduction Sickled cells hypoxemia in PO2 in the clog vessels (reoxygenation, microcirculation; rehydration) erythrocytes sickle where each Sickled cells slow (SCA; blood flow, promote Sickled erythrocytes hypoxemia, and regain normal shape, increase sickling resume normal function Decreased blood pH decreases hemoglobin’s affinity for O2; PO2 drops, increases sickling FIGURE 31.5 Sickling of Erythrocytes. manifesta- disease Hope for or stiff and irreversibly sickled cells (Fig. 31.6). Recent studies have shown that elevated red cell levels of the enzyme sphingosine kinase 1 (SPH1) underlie sickling and disease progression by increasing sphingosine 1-phosphate (S1P) production in the blood.31 S1P level, a bioactive lipid enriched in red cells, is elevated in red cells and plasma of mice and humans with SCD.31 S1P also is a signaling molecule that regulates diverse biologic functions including inlammation.32 Additionally, investigators demonstrated that the compound 5C can inhibit SPHK1 and, thus, has antisickling properties.33 These data are important for identifying the structure of the sickling process to assess potential new therapeutics. The cells remain sickled even with full oxygenation and some cells are vulnerable to hemolysis. Polymerization of sickled hemoglobin is central to the disorder. Polymerization stiffens the sickled erythrocyte, changing it from a lexible, beneicial cell to an inlexible one where HbS molecules stack into polymers that starve and damage tissues. The pathogenesis of SCD totally derives from the tendency of HbS molecules to stack into polymers when deoxygenated and assemble into needle-like ibers within cells, producing the distorted crescent-like sickle or holly-leaf shape (Fig. 31.7). Sickled cells undergo hemolysis in the spleen or become sequestered there, causing blood pooling and infarction of splenic vessels. The anemia that follows triggers erythropoiesis in the marrow and, in extreme cases, in the liver.34,35 However, the pathogenesis of microvascular occlusions, a main feature of SCD not fully understood, is responsible for the most serious and urgent manifestations. Microvascular occlusions are not related to the quantity of irreversibly sickled cells in the blood but are dependent on understated RBC membrane damages and other local factors, such as inlammation or vasoconstriction, that tends to decrease blood low or arrest red cells through the microcirculation.7 Investigators are studying the microvasculature from a developed model and mathematics of the microvasculature to allow the understanding of the rheology of sickle cell blood.36,37 Sickle RBCs express higher than normal amounts of adhesion molecules and are sticky. During inflammatory reactions, leukocyte release of meditators increases the Point mutation HbA HbS RBC Irreversibly Deoxygenation sickled cell K!, H2O Ca!! Hemolysis Extensive Additional membrane cycles of damage deoxygenation Oxygenation Microvascular occlusion Deoxygenation, prolonged Cell with transit times dehydration and membrane B damage See text for discussion. (B adapted from Kumar V, Abbas AK, basis of disease, ed 9, Philadelphia, 2015, Elsevier Saunders.) Sickled red blood cell B Blood Cells. A, Color-enhanced electron micrograph shows normal B, Scanning electron micrograph of normal and sickle-shaped red blood cells are the sickle cells; the circular cells are the normal blood cells. (From Raven Louis, 1992, Mosby.) inactivate nitric oxide (NO), which is a powerful vasodilator and inhibi- tor of platelet aggregation. Decreased blood pH reduces hemoglobin’s affinity for oxygen leading to an increasing fraction of deoxygenated HbS at any oxygen tension and predisposition to sickling. As less oxygen is taken up by hemoglobin in the lungs, the Po2 drops promoting additional sickling. Alterations of Hematologic Function in Children 1003 Chronic manifestations Eye Hemorrhage Exudation Blindness Retinopathy Pulmonary hypertension Tachypnea Heart High-output failure (congestive heart failure) Spleen Splenic atrophy (autosplenectomy) Kidney Hyposthenuria (dilute urine) Diuresis Penis Priapism Skin Stasis ulcers of hands, ankles, and feet Manifestations of Sickle Cell Disease. affect any part of the body. When sickling occurs, the general manifesta- tions of hemolytic anemia—pallor, fatigue, jaundice, and irritability— sometimes are accompanied by acute manifestations called crises. Extensive sickling can precipitate four types of crises: (1) vaso-occlusive crisis, (2) aplastic crisis, (3) sequestration crisis, or rarely (4) hyperhe- molytic crisis. Sites of speciic dysfunction are shown in Fig. 31.8. Vaso-occlusive crises (pain crises) are events of hypoxic injury and infarction that can cause severe pain in affected areas. However, the specific cause of sensory pain lacks sufficient characterization.38,39 The most common sites include bones, lungs, spleen, liver, brain, and penis. Painful bone crises are very common in children and are dificult to distinguish from acute osteomyelitis.7 These bone alterations can manifest as painful swelling of the hands and feet (hand-foot syndrome or dactylitis). A high-risk type of vaso-occlusive crisis involves the lungs known as acute chest syndrome. It typically presents with fever, cough, chest pain, and accumulations of lung infiltrates. The complications in the lungs create a worsening cycle of hypoxemia, sickling, and vaso-occlusion.7 Acute chest syndrome is the cause of death in approximately 25% of all deaths in people with SCD.40,41 Priapism, or prolonged erection of relatively little hemoglobin (hypochromic). Their small size makes them less likely than normal-size cells to clog the microcirculation, even when in a sickled state. EVALUATION AND TREATMENT. The parents’ hematologic history and clinical manifestations may suggest that a child has SCD, but hematologic tests and the presence of irreversibly sickled cells are necessary for diagnosis. If the sickle solubility test confirms the presence of HbS in blood, hemoglobin electrophoresis provides information about the amount of HbS in erythrocytes. Prenatal diagnosis can be made by chorionic villus sampling as early as 8 to 10 weeks of gestation or amniotic luid analysis at 15 weeks of gestation. Newborn screening for SCD should be performed according to state law. Health maintenance as early interventions in populations identiied by screening is beneficial.28 Young children with SCA have a very high risk of infection, septicemia, and meningitis. The fatality is high and the risk is greatest in young people who lack immunity against pneu- mococcal serotype causing infection. These infections arise because of abnormal or absent splenic function.28 A recent proposal has been presented as a prevention strategy to use prophylactic antibiotics (penicillin), vaccination against pneumococcus and other encapsulated microorganisms, and education to those with SCD, parents, and caregivers to seek immediate medical attention in the event of fever.28 Other recom- mendations for treatment and health maintenance are available at https:// www.nhlbi.nih/sites/www.nhlbi.nih.gov/ilessickle-cell-disease-report.pdf. Treatment advances since the late 1980s have signiicantly decreased morbidity and mortality in children with SCD. Aggressive management of fever, early diagnosis of acute chest syndrome (hypoxia, anemia, progressive multilobar pneumonia, fat emboli), RBC transfusions, and proper pain management can improve quality of life and prognosis for these children. Treatment of SCD consists of supportive care aimed at preventing consequences of anemia and avoiding crises. Crises can be prevented by avoiding fever, infection, acidosis, dehydration, constricting clothes, and exposure to cold. Immediate correction of acidosis and dehydration with appropriate intravenous luids is imperative. Infections require aggressive antibiotic therapy and infections can be reduced by vaccination. Oxygen is not needed unless the child becomes hypoxic. Pain associated with SCD is very complex, requiring accurate assessment and multimodal management.42 A common treatment is hydroxyurea, an inhibitor of DNA synthesis. It increases HbF synthesis, which decreases the proportion of HbS. Transfusion or exchange transfusion also can achieve these changes. Genetic counseling and psychologic support are important for the child and family. an elevated Thalassemias The α- and β-thalassemias are inherited autosomal recessive disorders that cause an impaired synthesis of one of the two chains—α or β—of adult hemoglobin (HbA). The disorder was named thalassemia, which is derived from the Greek word for sea, because it was initially described in people with origins near the Mediterranean Sea. β-Thalassemia, in which synthesis of the β-globin chain is slowed or defective, is prevalent among Greeks, Italians, and some Arabs and Sephardic Jews. α-Thalassemia, in which the α chain is affected, is most common among Chinese, Vietnamese, Cambodians, and Laotians. Both α- and β-thalassemias are common among blacks. Anemia associated with thalassemia is microcytic-hypochromic hemolytic anemia. PATHOPHYSIOLOGY. The β-thalassemias are classiied into two types depending on the severity of symptoms: thalassemia major and thalassemia intermedia. Thalassemia major is more severe. The β-thalassemias are caused by mutations in the HBB gene that decrease the synthesis of β-globin chains. Thalassemia major (Cooley anemia) and thalassemia intermedia are inherited in an autosomal recessive Alterations of Hematologic Function in Children 1005 The α-thalassemias result from deletions involving the HBA1 and HBA2 genes. These genes provide instructions for making a protein called α-globin, a subunit of hemoglobin. The different types of α-thalassemia result from the loss of some or all of the alleles (two copies of the HBA1 gene and two copies of the HBA2 gene in each cell; for each gene, one allele is inherited from the father and the other from the mother). Characteristic features of α-thalassemia are anemia, weakness, fatigue, and other more severe complications (see Clinical Manifestations). Types of α-thalassemia include: 1. Hb Bart syndrome is the most severe form of α-thalassemia and is caused by the loss of all four α-globin alleles. In the fetus, hydrops fetalis is the most severe form of α-thalassemia caused by the deletion of all four α-globin genes. Excess γ-globin chains do have a high afinity for oxygen but deliver small quantities to tissue. Signs of fetal distress may become evident in the third trimester of pregnancy, and intrauterine transfusions may save the baby. 2. HbH disease is caused by a loss of three of the four α-globin alleles. In both Hb Bart syndrome and HbH disease, the decrease in α-globin prevents cells from making normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called Bart (Hb Bart) or hemoglobin H (HbH). These abnormal forms of hemoglobin do not carry oxygen effectively, which causes anemia and other related consequences.44 β-THALASSEMIA Insoluble α-globin aggregate HbA Abnormal erythroblast α-globin Few abnormal aggregate red cells leave Normal HbA Hypochromic red cell Ineffective erythropoiesis Most erythroblasts Extravascular hemolysis die in bone marrow Destruction of aggregate-containing red cells in spleen

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