Alterations of Hematologic Function in Children

Chapter 30


Alterations of Hematologic Function in Children


Nancy E. Kline



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 deficiency 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 idiopathic thrombocytopenic purpura, autoimmune neonatal thrombocytopenias, and autoimmune vascular purpuras. Finally, leukocyte disorders, such as leukemia and the lymphomas (non-Hodgkin lymphoma as well as Hodgkin disease), 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 production shifts from the vessels to the liver sinusoids, and the production of leukocytes and platelets begins in the liver and spleen. Erythropoiesis in the liver and, to a lesser extent, in the spleen and lymph nodes, reaches a peak at approximately 4 months. Hepatic blood formation 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 hematopoietic (red) marrow fills the entire bone marrow space. By the time of delivery, the marrow is the only significant site of hematopoiesis.


In neonates and young infants, hematopoietic marrow progressively fills 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 45.) 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 because erythropoietin causes hematopoietic marrow to increase in volume. Initially, hematopoietic marrow expands from the ends of the long bones toward the middle of the shafts, replacing fatty marrow. Next, blood cell production begins 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 filled with red marrow (Figure 30-1). This is why hemolytic disease causes especially pronounced enlargement of the spleen and liver in children.



The erythrocytes undergo striking changes during gestation, particularly during the first two trimesters, at which time they nearly double in numbers and in hemoglobin content. A proportionate increase in hematocrit 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 Figure 27-15, and types of hemoglobin are defined in Table 27-5.) 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.


Fetal hemoglobin has greater affinity for oxygen than does adult hemoglobin because it interacts less readily with an enzyme (2,3-diphosphoglycerate [DPG]) that inhibits hemoglobin-oxygen binding. The decreased inhibitory effects of 2,3-DPG enable fetal blood to transport oxygen despite the relative lack of oxygen in the uterine environment. The increased affinity for oxygen enables Hb F 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 Hb A 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, Hb F constitutes 90% of the total. This percentage then begins to decline. At birth, neonatal hemoglobin consists of 70% Hb F, 29% Hb A, and 1% Hb A2. Between 6 and 12 months of age, normal adult hemoglobin percentages are established (see Chapter 27).



Postnatal Changes in the Blood


Blood cell counts tend to rise above adult levels at birth and then decline gradually throughout childhood. Table 30-1 lists normal ranges during infancy and childhood. The immediate rise in values is the result of accelerated hematopoiesis during fetal life, increased numbers of cells that result from the trauma of birth, and 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 27). As the infant develops over the first 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 slightly larger blood volume of 90 ml/kg of body weight, with the mean increasing to 150 mg/kg during the first few days after birth. In full-term and premature infants, blood volume decreases during the first few months. Thereafter the average blood volume is 75 to 77 ml/kg, which is similar to that of older children and adults.



Erythrocytes


The hypoxic intrauterine environment stimulates erythropoietin production 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 first 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. After birth the number of reticulocytes decreases about 50% every 12 hours, so it is rare to find an elevated reticulocyte count after the first week of life. 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, 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 27.)


In the premature infant the postnatal fall in hemoglobin and hematocrit values is more marked than in the full-term infant. In the preschool and school-age child, there is a gradual rise in hemoglobin, hematocrit, and red blood cell (RBC) count. Values in males and females first begin to diverge in adolescence. In the female the gradual hemoglobin increase continues into early puberty, at which time it stabilizes. In the male the hemoglobin increase keeps pace with growth and maturation and eventually surpasses that of the female. This higher value of hemoglobin in the mature male is related to androgen secretion.


Metabolic processes within the erythrocytes of neonates differ significantly 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 significance of these differences is unknown. One possible explanation 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 administration of immunizations may result in lymphocyte changes.1


The lymphocyte count is high at birth and continues to rise in some healthy infants during the first year of life. Then a steady decline occurs throughout childhood and adolescence until lower adult values are reached. It is unknown whether these developmental variations are physiologic or are a pathologic response to frequent viral infections and immunizations in children.


At birth the neutrophil count is very high and rises further during the early days of life.2 After 2 weeks neutrophil counts fall to within or below normal adult ranges. By approximately 4 years of age the neutrophil count is the same as that of an adult. White children have slightly higher counts than black children.3


Eosinophil count is high in the first year of life and is higher in children than in teenagers or adults.4 Monocyte counts are high in the first year of life 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. Like anemia in adults, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes. The most common cause of insufficient erythropoiesis is iron deficiency, 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 extraerythrocytic factors. The hemolytic anemias are inherited, congenital, or both.


The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the newborn (HDN), also termed erythroblastosis fetalis. HDN is 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 by phagocytosis, usually in the fetal spleen. (For a complete discussion of HDN, see p. 1059.) 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 destruction by the mononuclear phagocyte system. Structural defects include abnormal red blood cell size and abnormalities of plasma membrane structure (spherocytosis). Intracellular defects include enzyme deficiencies, the most common of which is G6PD deficiency, 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 30-2.



TABLE 30-2


ANEMIAS OF CHILDHOOD




























































Cause Anemic Condition
Deficient Erythropoiesis or Hemoglobin Synthesis
Decreased stem cell population in marrow (congenital or acquired pure red cell aplasia) Normocytic-normochromic anemia
Decreased erythropoiesis despite normal stem cell population in marrow (infection, inflammation, cancer, chronic renal disease, congenital dyserythropoiesis) Normocytic-normochromic anemia
Deficiency of a factor or nutrient needed for erythropoiesis  
Cobalamin (vitamin B12), folate Megaloblastic anemia
Iron Microcytic-hypochromic anemia
Increased or Premature Hemolysis
Alloimmune disease (maternal-fetal Rh, ABO, or minor blood group incompatibility) Hemolytic disease of the newborn (HDN)
Autoimmune disease (idiopathic autoimmune hemolytic anemia, symptomatic systemic lupus erythematosus, lymphoma, drug-induced autoimmune processes) Autoimmune hemolytic anemia
Inherited defects of plasma membrane structure (spherocytosis, elliptocytosis, stomatocytosis) or cellular size or both (pyknocytosis) Hemolytic anemia
Infection (bacterial sepsis, congenital syphilis, malaria, cytomegalovirus infection, rubella, toxoplasmosis, disseminated herpes) Hemolytic anemia
Intrinsic and inherited enzymatic defects (deficiencies of glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase, 5′-nucleotidase, glucose phosphate isomerase) Hemolytic anemia
Inherited defects of hemoglobin synthesis Sickle cell anemia
  Thalassemia
Disseminated intravascular coagulation (see Chapter 29) Hemolytic anemia
Galactosemia Hemolytic anemia
Prolonged or recurrent respiratory or metabolic acidosis Hemolytic anemia
Blood vessel disorders (cavernous hemangioma, large vessel thrombus, renal artery stenosis, severe coarctation of the aorta) (see Chapter 33) Hemolytic anemia


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Acquired Disorders


Iron Deficiency Anemia


Iron deficiency anemia is the most common blood disorder of infancy and childhood, with the highest incidence occurring between 6 months and 2 years of age. Incidence is not related to gender or race, but socioeconomic factors are important because they affect nutrition, for example, the risk of iron deficiency anemia in children of single, homeless women.6 However, greater use of iron-fortified products has decreased the prevalence of anemia in low-income infants.7 Iron deficiency anemia is a common disorder in children because of their extremely high need for iron for normal growth to occur.


Between 4 years of age and the onset of puberty, dietary iron deficiency is uncommon. During adolescence, however, it is relatively common, especially in menstruating females. Rapid growth, together with the average adolescent’s dietary habits, causes iron depletion. (Mechanisms of iron depletion are described in Chapter 27.)



Pathophysiology

Although inadequate intake of iron is the most common cause of iron deficiency anemia during the first few years of life and during adolescence, blood loss is the most common cause in childhood. Chronic iron deficiency anemia from occult (hidden) blood loss may be caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease. Infants and young children who develop severe iron deficiency anemia have chronic intestinal blood loss induced by exposure to a heat-labile protein in cow’s milk. Such exposure causes an inflammatory gastrointestinal reaction that damages the mucosa and results in diffuse microhemorrhage.


The amount of iron available for hemoglobin synthesis in the infant depends on maternal iron stores present at birth, rate of growth, the amount of dietary iron absorbed, and physiologic or pathologic loss of iron. During the period of inactive erythropoiesis immediately after birth, iron from erythrocytes that die at the end of their normal life span is stored, as hemosiderin, in bone marrow and liver tissue. This creates an iron reserve that can be used in lieu of dietary intake. The greatest stores are present 4 to 8 weeks after birth. Until erythropoiesis resumes, these iron stores are mobilized. In the premature infant, resumption of erythropoiesis depletes iron stores within 6 to 12 weeks; in the full-term infant, depletion takes longer—about 16 to 20 weeks. Once iron stores have been used, the infant depends on dietary iron.


The amount of dietary iron available for erythropoiesis depends on which foods are consumed. Iron-fortified cereals, green and yellow vegetables, fruits, and milk are common in the average 6-month-old infant’s diet and provide iron in the amount of 0.9 to 1.5 mg/kg/day, amounts that satisfy the normal average daily requirement. Iron-fortified formulas are available commercially, and although the amount of iron in breast milk is low, it is easily absorbed.



Clinical Manifestations

The symptoms of mild anemia—lethargy and listlessness—usually are not present or inconsequential 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 iron deficiency anemia (hemoglobin 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 falls below 5 g/dl, however, pallor, tachycardia, and systolic murmurs often occur.


Splenomegaly is evident in 10% to 15% of children with iron deficiency anemia, and if the condition is long-standing, the sutures of the skull may be widened. Chronic anemia also may result in decreased physical growth and developmental delays. Some children exhibit pica, a behavior in which nonfood substances are eaten. Weight is not necessarily an indicator of iron deficiency anemia because children may be obese, underweight, or of normal weight.


Iron deficiency anemia may affect neurologic and intellectual function. Decreased iron in the blood may affect attention span, alertness, and learning ability, even when anemia is not severe.



Evaluation and Treatment

The most definitive test for differentiating iron deficiency from other microcytic anemias is the absence of iron stores in the bone marrow. However, measurement of serum ferritin iron concentration, transferrin saturation, iron-binding capacity, and serum transferrin receptors often is an adequate diagnostic tool and often prevents proceeding to actual bone marrow evaluation. Evaluation and treatment of iron deficiency anemia in children are similar to evaluation and treatment in adults (see Chapter 27). Oral administration of simple ferrous salts usually is satisfactory, and additional vitamin C helps promote absorption.8 Administration of supplementary trace metals or other vitamins is not necessary. Iron in a liquid form should be administered through a straw because it can stain teeth. If malabsorption is the cause of the anemia (or if oral administration has not been successful), iron dextran is given intravenously. Iron therapy is continued for at least 2 months after erythrocyte indexes have returned to normal in order to replenish iron stores.9


Dietary modification is required to prevent recurrences of iron deficiency anemia. Intake of iron-rich foods is increased, and the intake of cow’s milk may be restricted, with the exact amount depending on the child’s age (from 16 to 32 ounces). 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 inflammatory reactions to proteins in cow’s milk.



Hemolytic Disease of the Newborn


HDN can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. The antigenic properties of erythrocytes are determined 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 pregnancies, but only 1 in 10 cases of ABO incompatibility results in HDN. Rh incompatibility occurs in less than 10% of pregnancies and rarely causes HDN in the first incompatible fetus. Even after five or more pregnancies, only 5% of women have babies with hemolytic disease. Usually erythrocytes from the first incompatible fetus cause the mother’s immune system to produce antibodies that affect the fetuses of subsequent incompatible pregnancies. Only one in three cases of HDN is caused by Rh incompatibility; most cases are caused by ABO incompatibility.



Pathophysiology

If the mother and fetus have antigenically incompatible erythrocytes, HDN will result if the mother’s blood contains preformed antibodies against fetal erythrocytes or produces them on exposure to fetal erythrocytes, if sufficient amounts of antibody (usually immunoglobulin G [IgG]) cross the placenta and enter fetal blood, and if IgG binds with sufficient numbers of fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal. (Antibody-mediated red blood cell destruction is discussed in Chapter 9.)


IgM antibodies are formed against the ABO antigen that a person does not express, the A antigen if the mother is blood type O or B, or the B antigen if the mother is type O or A. These antibodies are produced early in life against gastrointestinal bacteria that make antigens similar to A and B. IgM antibodies do not cross the placenta or cause HDN. Occasionally a mother with blood type O may have also produced IgG against the A or B antigen. If the fetus is blood group A or B, the ABO incompatibility can cause HDN in the first pregnancy. HDN is usually not severe because A and B antigens are expressed on most cells, including the placenta, and much of the IgG against A or B is absorbed before encountering fetal blood cells.


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 or transfused blood.


The first Rh-incompatible pregnancy usually presents no difficulties 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 accelerates, particularly in the liver and spleen, and immature nucleated cells (erythroblasts) are released into the bloodstream, hence the name erythroblastosis fetalis (Figure 30-2). The degree of anemia depends on the length of time the antibody has been in the fetal circulation, antibody concentration, 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 occurs in the neonate after birth because excretion of lipid-soluble unconjugated bilirubin through the placenta no longer is possible.



The pathophysiologic effects of HDN 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 28). 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 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 HDN 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 hyperbilirubinemia 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 significant developmental delay, cerebral palsy, or high-frequency deafness.



Evaluation and Treatment

Routine evaluation for HDN includes the Coombs test. The indirect Coombs test measures antibody in the mother’s circulation and indicates whether the fetus is at risk for HDN. 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 HDN. 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.10


The key to treatment of HDN resulting from Rh incompatibility lies in prevention (immunoprophylaxis). Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D administered within 72 hours of exposure to Rh-positive erythrocytes, ensures that the mother will not produce antibody against the D antigen, and the next Rh-positive baby will be protected (Figure 30-3). The injected antibodies remain in the mother’s bloodstream 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 must be especially careful not to receive a transfusion containing Rh-positive blood, because this would stimulate production of anti-Rh antibodies. In many hospitals Rh immune globulin is given prophylactically at 28 weeks to all pregnant Rh-negative women with Rh-positive partners. Various international recommendations suggest that antenatal anti-D prophylaxis should be administered to unsensitized Rh(D)-negative women as a complement to postpartum prophylaxis.11



If antigenic incompatibility of the mother’s erythrocytes is not discovered in time to administer Rh immune globulin and a child is born with HDN, 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 during the first 24 hours of extrauterine life to prevent kernicterus. Phototherapy also is used to reduce the toxic effects of unconjugated bilirubin.


Jaundice and indirect hyperbilirubinemia are reduced when the infant is exposed to high-intensity light in the visible spectrum from 420 to 470 nm. 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 phototherapy 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.





Inherited Disorders


A number of inherited and intrinsic erythrocyte defects are known to cause increased hemolysis (see Table 30-2). These defects may be associated with enzymatic abnormalities that disrupt metabolic processes and prevent normal biochemical balance within the cell, with alterations of hemoglobin structure or synthesis, or with 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, X-linked recessive disorder, most fully expressed in homozygous males, although partial expression and a carrier state are possible in heterozygous females. (X-linked inheritance is discussed in Chapter 4.) The deficiency is present in 10% of blacks and tends to occur in Sephardic Jews, Greeks, Iranians, Chinese, Filipinos, and Indonesians, with a frequency ranging from 5% to 40%.



Pathophysiology

G6PD is an enzyme that normally enables erythrocytes to maintain metabolic processes despite injury, such as the presence of certain drugs (sulfonamides, 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. Erythrocyte damage in affected children begins after intense or prolonged exposure to one of these substances or conditions, and it will cease when they 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. By ingesting a substance with oxidant properties, such as a salicylate (aspirin), a pregnant woman may cause an episode of hemolysis in a fetus with G6PD deficiency.


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. Eventually, exposure to oxidating 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.




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 significantly 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. Males from high-risk groups (Greeks, southern Italians, Sephardic Jews, Filipinos, Chinese, Africans, Thais) should be tested for the defect before being given drugs known to be oxidative. When hemolysis occurs supportive treatment may include blood transfusions and oral iron therapy. Spontaneous recovery generally follows treatment.



Hereditary Spherocytosis


Hereditary spherocytosis (HS), also known as congenital hemolytic anemia or congenital acholuric jaundice, is the most common of the hemolytic disorders in which there is no hemoglobin abnormality.



Pathophysiology

Transmitted as an autosomal dominant trait, HS represents approximately new mutations in about 25% of cases. The defect is believed to be caused by an undefined abnormality in the erythrocyte membrane. Affected cells are overly permeable to sodium and acquire a particular characteristic structure (Figure 30-4). An increased concentration of intracellular sodium is believed to lead to increased use of adenosine triphosphate (ATP) to drive the so-called cation pump. Early aging or destruction of erythrocytes is believed to result from metabolic overwork and loss of erythrocyte membrane.



The spleen is intimately involved in the hemolytic process. The spherocyte is relatively rigid and passes with difficulty through the small openings between the splenic cords and sinuses. 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 physiologic compensation. If this is the case the reticulocyte count will be elevated. Splenomegaly is usually mild. HS can present at any age, from the neonatal period until older adulthood. More severe types of HS present during the newborn period when the infant develops signs of hemolytic anemia and hyperbilirubinemia.12 These children therefore may have life-threatening anemia with clinical symptoms ranging from difficulty feeding, circumoral pallor, tachycardia, nasal flaring, diaphoresis, and lethargy. They also are at increased risk for gallstones because of the presence of extra bile pigment. Infection (specifically parvovirus),13 fever, and stress stimulate the spleen to destroy more red blood cells than usual, leading to a worsening anemia in an already baseline anemic child.



Evaluation and Treatment

It is important to ascertain family history of spherocytosis. Laboratory findings include spherocytes in the peripheral blood smear, elevated reticulocyte count (with or without anemia), indirect hyperbilirubinemia, and a positive osmotic fragility test. An osmotic fragility test is performed by placing red blood cells in a saline solution for 24 hours. Spherocytes do not tolerate saline solutions, thus causing them to burst more readily than normal red blood cells. 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 supplementation to increase production of healthy red blood cells. In the past, splenectomy was the first 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.14



Sickle Cell Disease


Sickle cell disease (SCD) is a group of disorders characterized by the presence of an abnormal form of hemoglobin—hemoglobin S (HbS)—within the erythrocytes. Hb S is formed by a genetic mutation in which one amino acid (valine) replaces another (glutamic acid) (Figure 30-5, A). Hb S, also known as sickle hemoglobin, reacts to deoxygenation and dehydration by solidifying and stretching the erythrocyte into an elongated sickle shape. This change causes a variety of pathologic consequences, including hemolytic anemia.



SCD is an inherited autosomal recessive disorder that is expressed as sickle cell anemia, sickle cell–thalassemia disease, or sickle cell–Hb C disease, depending on mode of inheritance (Table 30-3). (See Chapter 4 for a discussion of genetic inheritance of disease.) Sickle cell anemia, a homozygous form, is the most severe. Sickle cell–thalassemia disease and sickle cell–Hb C disease are heterozygous forms in which the child simultaneously inherits another type of abnormal hemoglobin from one parent. Sickle cell trait, in which the child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other, is a heterozygous carrier state that rarely has clinical manifestations. All forms of SCD are lifelong conditions. Bone marrow or stem cell transplants can cure sickle cell anemia. However, they are currently not an option for most children because it is often difficult to find well-matched stem cell donors.



TABLE 30-3


INHERITANCE OF SICKLE CELL DISEASE
























Hemoglobin (Hb) Inherited from First Parent Hemoglobin Inherited from Second Parent Form of Sickle Cell Disease in Child
Hb S (an abnormal Hb) Hb S Sickle cell anemia: homozygous inheritance in which the child’s Hb is mostly Hb S, with the remainder fetal hemoglobin (Hb F)
Hb S Defective or insufficient α- or β-chains of Hb A (alpha- or beta-thalassemia) Sickle cell: thalassemia disease (heterozygous inheritance of Hb S and alpha- or beta-thalassemia)
Hb S Hb C or D (both abnormal Hb) Sickle cell: Hb C (or D) disease (heterozygous inheritance of Hb S and either Hb C or Hb D)
Hb S Normal Hb (mostly Hb A) Sickle cell trait, the carrier state (heterozygous inheritance of Hb S and normal Hb)

See Chapter 27 for a description of normal fetal and adult hemoglobins.


SCD tends to occur in people with origins in equatorial countries, particularly central Africa, the Near East, the Mediterranean, and parts of India. In the United States, about 1 out of 500 black children and 1:36,000 Hispanic-American born have sickle cell anemia. Most infants with SCD born in the United States are now identified by routine neonatal screening. Sickle cell trait occurs among about 1:12 blacks and 1:100 Hispanic-Americans. It is estimated that 2.5 million Americans are heterozygous carriers for the sickle cell trait.15 The sickle cell trait may provide protection against lethal forms of malaria, a genetic advantage to carriers who reside in endemic regions for malaria (Mediterranean and African zones) but no advantage to carriers living in the United States.



Pathophysiology

Deoxygenation is probably the most important variable in determining the occurrence of sickling. The degree of deoxygenation required to produce sickling varies with the percentage of Hb S in the cells. Sickle trait cells will sickle at oxygen tensions of about 15 mmHg, whereas those from an individual with SCD will begin to sickle at about 40 mmHg. Hb S that is not bound with oxygen forms aggregates of semisolid gel that become stacked within the erythrocyte, stretching it into an elongated crescent (see Figure 30-5, C; Figure 30-6). Sickled erythrocytes are stiff and cannot change shape as easily as normal cells when they pass through the microcirculation. (The reversible deformability of erythrocytes is described in Chapter 27.) As a result, sickled erythrocytes tend to plug the blood vessels, causing vascular occlusion, pain, and organ infarction. 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.16


Sep 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Alterations of Hematologic Function in Children
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