Chapter 24
This chapter will include conditions in children that affect red blood cells, the coagulation process and platelets, as well as disorders involving white blood cells. Discussions of both acquired conditions and inherited conditions also are presented.
Disorders of Erythrocytes
Anemia is the most common blood disorder in children. As do adult anemias, anemias occurring in children result from inadequate erythropoiesis or early destruction of erythrocytes. Iron deficiency is the most common cause of inadequate erythropoiesis. Iron deficiency can result from insufficient dietary intake or chronic loss of iron caused by bleeding. The hemolytic anemias of childhood are either inherited or acquired. They may be divided into disorders that result from destruction caused by (1) intrinsic abnormalities of the erythrocytes and (2) damaging factors external to the erythrocytes.
The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the fetus and newborn (HDFN), also termed erythroblastosis fetalis. HDFN results when maternal blood and fetal blood are incompatible, causing the mother's immune system to produce antibodies against fetal erythrocytes. Intracellular defects in red blood cells include enzyme deficiencies, the most common of which is glucose-6-phosphate dehydrogenase (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 are listed in Table 24.1.
TABLE 24.1
Anemias of Childhood
Cause Examples of Anemic Condition
Blood Loss
Trauma
Gastrointestinal lesion
Parasitic infestation
Hemorrhagic disease
Iron deficiency anemia
Decreased Red Cell Production 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) Autoimmune hemolytic anemia
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 G6PD, pyruvate kinase, 5′-nucleotidase, glucose phosphate isomerase Hemolytic anemia
Inherited Defects of Hemoglobin Synthesis
Structurally abnormal globins Sickle cell anemia
Deficient globin synthesis Thalassemia
Other Anemias
Disseminated intravascular coagulation (see Chapter 23) Hemolytic anemia
Galactosemia Hemolytic anemia
Prolonged or recurrent respiratory or metabolic acidosis Hemolytic anemia
Blood vessel disorders (cavernous hemangiomas, large vessel thrombus, renal artery stenosis, severe coarctation of aorta) Hemolytic anemia
ABO; type A, type B, type O blood; G6PD; glucose-6-phosphate dehydrogenase
Acquired Disorders
Iron Deficiency Anemia
Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide, with the highest incidence occurring between 6 months and 2 years of age. Its prevalence in the United States is greatest among toddlers, adolescent girls, and women of childbearing age. Iron is critical to the developing child, especially for normal brain development. Without it the damage from the periods of IDA is irreversible. The clinical manifestations of IDA are mostly related to inadequate hemoglobin synthesis.
IDA can result from (1) dietary lack of iron, (2) problems with iron absorption, (3) blood loss, and (4) increased requirement for iron. During the first few years of life, IDA most often results from inadequate iron intake. During childhood and adolescence, blood loss is the most common cause of IDA.
Dietary lack of iron is not common in developed countries, where iron is readily absorbed from heme found in meat. In developing countries, food may be less available. Although iron is found in plants, it is a more poorly absorbed form. 1 Infants are at increased risk for IDA because milk has only very small amounts of iron. The bioavailability of iron from breast milk is higher than that from cow's milk. Impaired absorption is found in chronic diarrhea, fat malabsorption, and sprue (see Did You Know? A Significant Number of Children Develop and Suffer from Severe Iron Deficiency Anemia).
Did You Know?
A Significant Number of Children Develop and Suffer From Severe Iron Deficiency Anemia
A recent study in the United States found that children aged 36 months to 15 years are particularly vulnerable to iron deficiency anemia (IDA), especially those consuming excessive quantities of whole cow's milk. The prevalence of IDA in infancy has not changed in the past four decades and remains about 7%. Several children who were not anemic at 12 months of age went on to develop IDA as their iron stores became depleted. These children had typical signs of anemia, although their parents were not aware of the abnormalities. Chronic severe IDA in the first years of life increases the risk of irreversible cognition problems, as well as affective and motor development. The American Academy of Pediatrics (AAP) recommends screening for IDA with hemoglobin concentration and clinical assessment at about 1 year of age, and the Centers for Disease Control and Prevention (CDC) recommends that all children aged 2 through 5 years be assessed annually for risk factors for IDA and screened appropriately. IDA is a preventable disease.
Data from Paoletti G et al: Pediatrics 53(4):1352-1358, 2014.
Blood loss may not always be obvious; for example, blood loss caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease can be occult (hidden) and result in chronic IDA. Chronic parasitic infections are an important risk factor for IDA among children in developing countries. Treating these parasitic infections results in improved appetite and growth, as well as reduction of anemia.
Infants and young children who consume excessive amounts of cow's milk also may develop IDA as a result of chronic intestinal blood loss. A heat-labile protein in cow's milk may induce inflammation that damages the intestinal mucosa causing diffuse, chronic microhemorrhage. Cellular components of both innate and adaptive immunity may play significant roles in the development of cow's milk allergy.
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The association between IDA and lead poisoning is controversial. Newer areas of investigation include iron deficiency in overweight children and the association of Helicobacter pylori infection with IDA.
Pathophysiology
No matter the cause, a deficiency of iron produces a hypochromic-microcytic anemia. In the early stages, however, the body may respond by increasing red blood cell activity in the bone marrow, which may temporarily prevent the development of anemia. As the body's iron stores are depleted, anemia develops. Low serum levels of ferritin and transferrin saturation lead to lowered hemoglobin and hematocrit levels.
Clinical Manifestations
The symptoms of mild anemia—listlessness and fatigue—may go unnoticed in infants and young children, who are unable to describe these symptoms. Clinical indicators of anemia also are nonspecific, such as general irritability, decreased activity tolerance, weakness, and lack of interest in play, and may be attributed to other causes. As a result, parents may not note persistent changes in the child's behavior until moderate anemia has developed. Other clinical 550manifestations, such as pallor, anorexia, tachycardia, and systolic murmurs, are often not present until hemoglobin levels fall below 5 g/dl.
Other symptoms and signs of chronic IDA include splenomegaly, widened skull sutures, decreased physical growth, developmental delays, pica (a behavior in which nonfood substances, such as clay, are eaten), and altered neurologic and intellectual functions, especially those involving attention span, alertness, and learning ability.
Evaluation and Treatment
The diagnosis of IDA is confirmed by laboratory tests. These tests include hemoglobin, hematocrit, serum iron, and ferritin levels and determination of the total iron binding capacity. Obtaining a thorough history of the child's present illness and dietary history and performing a complete physical examination also are essential to the evaluation and subsequent clinical management of IDA. Treatment of IDA is similar in children and adults (see Chapter 23). Oral administration of a simple ferrous salt is usually sufficient. Taking iron supplements with a vitamin C source helps promote absorption. 2 If liquid iron supplements are used, they should be given with a straw or a dropper placed back on the tongue to prevent staining the teeth. Dietary modification, including increasing intake of iron-rich food sources, is required to prevent recurrences of iron deficiency anemia. The intake of cow's milk should be restricted to the recommended daily allowance for age.
Hemolytic Disease of the Fetus and Newborn
The most common cause of hemolytic anemia in newborns is alloimmune disease. Hemolytic disease of the fetus and newborn (HDFN) (erythroblastosis fetalis) can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. Most cases are caused by ABO incompatibility, which occurs if the mother and fetus have different ABO blood types. About 1 in 3 cases of HDFN is caused by Rh incompatibility, which occurs when the fetus is Rh-positive and the mother is Rh-negative. Some minor blood antigens also may be involved (see Chapter 8).
ABO incompatibility occurs in about 20% to 25% of all pregnancies. Only 1 in 10 of these cases results in HDFN. Rh incompatibility occurs in less than 10% of pregnancies. It rarely causes HDFN in the first incompatible fetus. During this first pregnancy, erythrocytes from the fetus cause the mother's immune system to produce antibodies. These antibodies can affect fetuses in subsequent incompatible pregnancies. Even after five or more pregnancies, however, only 5% of women have babies with hemolytic disease.
Pathophysiology
Three conditions need to be met for HDFN to occur:
1. the mother's blood contains preformed antibodies against fetal erythrocytes or produces them when exposed to fetal erythrocytes,
2. sufficient amounts of antibody (usually immunoglobulin G [IgG] class) cross the placenta and enter fetal blood, and
3. IgG binds with sufficient numbers of fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal (antibody-mediated cellular destruction is described in Chapter 8).
In most cases of HDFN, the mother has blood type O and the fetus has blood type A or B. Maternal antibodies also may be formed against type B erythrocytes if the mother is type A or against type A erythrocytes if the mother is type 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. These antibodies are produced on exposure to certain foods or infection by gram-negative bacteria. As a result, IgG against type A or B erythrocytes is usually already present in maternal blood and can enter the fetal circulation during the first incompatible pregnancy. Anti-O antibodies do not exist because type O erythrocytes are not antigenic.
Anti-Rh antibodies, on the other hand, form only in response to the presence of Rh-positive erythrocytes from the fetus in the blood of an Rh-negative mother. This exposure typically occurs when fetal blood is mixed with the mother's blood at the time of delivery. Exposure may also occur through transfused blood, and, rarely, previous sensitization of the mother by her own mother's incompatible blood (Fig. 24.1).
FIGURE 24.1 Hemolytic Disease of the Fetus and Newborn (HDFN). A, Before or during delivery, Rh-positive erythrocytes from the fetus enter the blood of an Rh-negative woman through a tear in the placenta. B, The mother is sensitized to the Rh antigen and produces Rh antibodies. Because this usually happens after delivery, there is no effect on the fetus in the first pregnancy. C, During a subsequent pregnancy with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal circulation, and (D) stimulate the mother to produce antibodies against the Rh antigen. (Modified from Seeley RR et al: Anatomy and physiology, ed 3, St Louis, 1995, Mosby.)
The first Rh-incompatible pregnancy generally presents no difficulties for the fetus. This is because few fetal erythrocytes cross the placental barrier during the pregnancy. When the placenta detaches at birth, a large number of fetal erythrocytes often enter the mother's bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, the mother produces anti-Rh antibodies. These anti-Rh antibodies persist in the mother's bloodstream for a long time. If the next offspring is Rh-positive, the mother's anti-Rh antibodies can enter the bloodstream of the fetus and destroy the erythrocytes.
Antibody-coated fetal erythrocytes are usually destroyed in the spleen. As hemolysis proceeds, the fetus becomes anemic. Erythropoiesis accelerates, particularly in the liver and spleen. Immature nucleated cells (erythroblasts) are released into the bloodstream (hence the name erythroblastosis fetalis). The degree of anemia depends on several factors: (1) the length of time the antibody has been in the fetal circulation, (2) the concentration of the antibody, and (3) the ability of the fetus to compensate for increased hemolysis. During the pregnancy, unconjugated (indirect) bilirubin, which forms during the 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 bilirubin is no longer excreted through the placenta.
HDFN is typically more severe in Rh incompatibility than in ABO incompatibility. Rh incompatibility is more likely to result in severe or even life-threatening anemia, death in utero, or damage to the central nervous system. Severe anemia alone can cause death as a result of cardiovascular complications. Extensive hemolysis can result in increased levels of unconjugated bilirubin in the neonate's circulation. If bilirubin levels exceed the liver's ability to conjugate and excrete bilirubin, it can be deposited in the brain, a condition known as kernicterus, causing cellular damage and, eventually, death if the neonate does not receive exchange transfusions.
Fetuses that do not survive anemia in utero are usually stillborn, with gross edema in the entire body, a condition called hydrops fetalis. Death can occur as early as 17 weeks’ gestation and results in spontaneous abortion.
Clinical Manifestations
Neonates with mild HDFN may appear healthy or slightly pale, with slight enlargement of the liver or spleen. Pronounced pallor, splenomegaly, and hepatomegaly indicate severe anemia, which predisposes the neonate to cardiovascular failure and shock. Life-threatening symptoms as a consequence of Rh incompatibility, however, are rare, largely because of the routine use of Rh immunoglobulin.
Because the maternal antibodies remain in the neonate's circulatory system after birth, erythrocyte destruction can continue. Without exchange transfusions, in which the neonate receives Rh-negative red blood cells, severe hyperbilirubinemia and icterus neonatorum (neonatal jaundice) can develop shortly after birth. If kernicterus develops, it can cause cerebral damage, including intellectual disabilities, cerebral palsy, or high-frequency deafness. It may even cause death (icterus gravis neonatorum).
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Evaluation and Treatment
Fetuses and neonates with ABO incompatibility typically do not require additional monitoring or treatment. Fetuses and infants at risk for HDFN as a consequence of Rh incompatibility may require additional monitoring and treatment. Routine evaluation of fetuses at risk 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. It is used primarily to confirm the diagnosis of antibody-mediated HDFN. If a prior history of fetal hemolytic disease is present, additional diagnostic tests are done to determine risk with the current pregnancy. These include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment.
Prevention is the key to managing HDFN that results from Rh incompatibility. Immunoprophylaxis through the use of Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D (anti-D Ig), prevents an Rh-negative woman from producing antibodies.
If an Rh-negative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce antibody against the D antigen. As a result, the next Rh-positive baby she conceives will be protected. Updated United States and United Kingdom guidelines also state that if anti-D Ig is not given within 72 hours, every effort should be made to administer it within 10 days. 3 , 4
Inherited Disorders
Sickle Cell Disease
Sickle cell disease is a group of autosomal recessive disorders characterized by the production of hemoglobin S (Hb S; sickle hemoglobin) within the erythrocytes. Hb S is formed as a result of a genetic mutation in which one amino acid (valine) replaces another (glutamic acid) (Fig. 24.2). Under conditions of decreased oxygen tension and dehydration, Hb S stretches and elongates, causing the erythrocyte to assume a characteristic sickle shape. These sickled cells also die prematurely, resulting in hemolytic anemia (Fig. 24.3).
FIGURE 24.2 Sickle Cell Hemoglobin. A, Sickle cell hemoglobin is produced by a recessive allele of the gene encoding the β-chain of the protein hemoglobin. It represents a single amino acid change—from glutamic acid to valine at the sixth position of the chain. In this model of a hemoglobin molecule, the position of the mutation can be seen near the end of the upper arm. B, Color-enhanced electron micrograph shows normal erythrocytes and sickled blood cell. C, Brief summary of the process of cell sickling. (A from Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby; B copyright Dennis Kunkel Microscopy, Inc; C from Kierszenbaum A, Tres L: Histology and cell biology: an introduction to pathology, ed 3, St Louis, 2012, Mosby.)
FIGURE 24.3 Normal and Sickle-Shaped Blood Cells. Scanning electron micrograph of normal and sickle-shaped red blood cells. The irregularly shaped cells are the sickle cells; the circular cells are the normal blood cells. (From Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby.)
The most prevalent types of sickle cell disease are sickle cell anemia, sickle cell–thalassemia disease, and sickle cell–Hb C disease (Table 24.2). (See Chapter 2 for a discussion of genetic inheritance of disease.) Sickle cell anemia, a homozygous form, is the most severe. It results when the individual inherits two copies of Hb S. Sickle cell–thalassemia and sickle cell–Hb C disease are compound heterozygous forms in which the child inherits Hb S from one parent and another type of abnormal hemoglobin from the other parent. Sickle cell trait occurs when the 552child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other. This heterozygous carrier state rarely has clinical manifestations. All forms of sickle cell disease are lifelong conditions.
TABLE 24.2
Inheritance of Sickle Cell Disease
Hemoglobin Inherited From First Parent Hemoglobin Inherited From Second Parent Form of Sickle Cell Disease in Child
Hb S (an abnormal hemoglobin) Hb S Sickle cell anemia: homozygous inheritance in which child's hemoglobin is mostly Hb S, with remainder Hb F (fetal hemoglobin)
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 hemoglobins) Sickle cell–hemoglobin C (or D) disease (heterozygous inheritance of hemoglobin S and either C or D)
Hb S Normal hemoglobins (mostly Hb A) Sickle cell trait, carrier state (heterozygous inheritance of Hb S and normal hemoglobin)
Sickle cell disease is most common among persons with ancestry from sub-Saharan Africa. Although less common, it also is present among individuals with ancestry from Mediterranean countries, the Arabian Peninsula, parts of India, and Spanish-speaking areas of South America. In the United States, sickle cell anemia is most common in black people, with a reported incidence of around 1 : 365 live births. 5 In the general population, the risk of two black parents having a child with sickle cell anemia is 0.7%. Sickle cell–Hb C disease occurs in 1 in 800 births, and sickle cell–thalassemia is even less common (1 in 1700 births).
Sickle cell trait occurs in 7% to 13% of African Americans. Its prevalence in African countries, such as Nigeria and the Democratic 553Republic of Congo, may be as high as 30%. 6 The sickle cell trait may provide protection against lethal forms of malaria. This results in a genetic advantage for carriers who reside in regions of the world that are endemic for malaria, such as sub-Saharan Africa and some Mediterranean countries.
Pathophysiology
Hb S is soluble and usually causes no problem when it is properly oxygenated. When oxygen tension decreases, the abnormal β-globin chain of Hb S polymerizes, forming abnormal fluid polymers. As these polymers realign, they cause the red cell to form into the sickle shape. Decreased oxygenation (hypoxemia) and pH, as well as dehydration, trigger the sickling process. Acute illness, stress, temperature changes, and living at altitude can cause decreased oxygen tension, leading to sickling.
Sickled erythrocytes tend to plug the blood vessels. This increases the viscosity of the blood, which slows circulation, and causes vascular occlusion, pain, and organ infarction. The increased blood viscosity also increases the time that erythrocytes are exposed to less oxygenation, which promotes further sickling. Sickled cells undergo hemolysis in the spleen or become sequestered there, causing blood pooling and infarction of splenic vessels. The anemia that follows these sickling episodes triggers erythropoiesis in the marrow and, in extreme cases, in the liver (Fig. 24.4).
FIGURE 24.4 Sickling of Erythrocytes. O2, Oxygen; Po2, partial pressure of oxygen
Sickling usually is not permanent. Most sickled erythrocytes regain a normal shape after reoxygenation and rehydration. Irreversible sickling is caused by irreversible plasma membrane damage caused by sickling. In persons with sickle cell anemia, in which the erythrocytes contain a high percentage of Hb S (75% to 95%), up to 30% of the erythrocytes can become irreversibly sickled.
Clinical Manifestations
The clinical manifestations of sickle cell disease can vary. Some individuals have mild symptoms; others suffer from repeated vasoocclusive crises. The general manifestations of hemolytic anemia from the sickling process include pallor, fatigue, jaundice, and irritability. Extensive sickling can precipitate four types of acute crises:
1. Vasoocclusive crisis (thrombotic crisis). This crisis type begins with sickling in the microcirculation. As blood flow is obstructed by sickled cells, vasospasm occurs and a logjam effect blocks all blood flow through the vessel. Unless the process is reversed, thrombosis and infarction of local tissue occur. Vasoocclusive crisis is extremely painful and may last for days or even weeks, with an average duration of 4 to 6 days. The frequency of this type of crisis is variable and unpredictable. Vasoocclusion in vessels to the brain can result in stroke. Chronic vasoocclusion in vessels to the kidneys results in end-stage renal disease.
5542. Sequestration crisis. This type of crisis is typically seen only in children less than 5 years of age. Large amounts of blood become acutely pooled in the liver and spleen. Because the spleen can hold as much as one-fifth of the body's blood supply at one time, the risk of mortality is high if the condition is not recognized and managed appropriately. Approximately half of children who experience sequestration crises will have recurrent episodes.
3. Aplastic crisis. Profound anemia is caused by lowered erythropoiesis despite an increased need for new erythrocytes. In sickle cell anemia, erythrocyte survival is only 10 to 20 days. Normally the bone marrow is able to compensate to replace the cells lost through premature hemolysis. When this compensatory response is compromised, often after a viral infection, aplastic crisis develops. This type of crisis typically lasts 7 to 10 days.
4. Hyperhemolytic crisis. Although unusual, this type of crisis may occur in association with certain drugs or infections. It has also been reported as an acute or chronic reaction following a blood transfusion.
The clinical manifestations of sickle cell disease usually do not appear until the infant is at least 6 months old. At this time, postnatal concentrations of Hb F decrease, causing concentrations of Hb S to rise (Fig. 24.5). Infection is the most common cause of death related to sickle cell disease. Sepsis and meningitis develop in as many as 10% of children with sickle cell anemia during the first 5 years of life. Advances in identification of sickle cell disease and supportive care have improved survival of children with sickle cell disease.
FIGURE 24.5 Differences between effects of normal (A) and sickled (B) red blood cells on blood circulation and selected consequences in a child. C, Tissue effects of sickle cell anemia. CVA, Cerebrovascular accident. (A and B adapted from Hockenberry MJ et al, editors: Wong's nursing care of infants and children, ed 10, St Louis, 2015, Mosby.)
Sickle cell–Hb C disease is usually milder than sickle cell anemia. The main clinical problems are related to vasoocclusive crises, which are thought to result from higher hematocrit values and viscosity. In older children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of the femoral heads can occur along with obstructive crises.
Sickle cell–thalassemia has the mildest clinical manifestations of all the sickle cell diseases. The normal hemoglobins, particularly Hb F, inhibit sickling. The erythrocytes tend to be small (microcytic) and to contain relatively little hemoglobin (hypochromic), making them less likely to occlude the microcirculation, even when in a sickled state.
Evaluation and Treatment
The parents’ hematologic history and clinical manifestations may suggest that a child has sickle cell disease, but hematologic tests are necessary for diagnosis. If the sickle solubility test confirms the presence of Hb S in peripheral blood, hemoglobin electrophoresis provides information about the amount of Hb S in erythrocytes. Prenatal diagnosis can be made after chorionic villus sampling as early as 8 to 10 weeks’ gestation or by amniotic fluid analysis at 15 weeks’ gestation (Fig. 24.6). Hemoglobinopathies, including sickle cell disease, are now included as part of routine newborn screening in all 50 states and the District of Columbia.
FIGURE 24.6 Prepregnancy Sickle Cell Test. This technique has potential for detection of other inherited diseases. 1, Fertilization produces several embryos. 2, The embryos are tested for the presence of the gene. 3, The embryos without the gene are implanted. 4, Amniocentesis confirms whether the fetus (or fetuses) has the sickle cell gene. 5, Woman has a normal child.
Sickle cell trait typically does not affect life expectancy or interfere with daily activities. On rare occasions, however, severe hypoxia caused by shock, vigorous exercising at high altitudes, flying at high altitudes in unpressurized aircraft, or undergoing anesthesia is associated with 555vasoocclusive episodes in persons with sickle cell trait. These cells form an ivy shape instead of a sickle shape.
Advances in supportive care have led to decreased morbidity and mortality among children with sickle cell disease. Supportive care emphasizes preventing consequences of anemia and avoiding crises, including adequate hydration, infection prevention, and pain management. Genetic counseling and psychologic support are important for the child and family.
A common treatment for sickle cell disease is hydroxyurea. Hydroxyurea inhibits deoxyribonucleic acid (DNA) synthesis, which causes an increase in Hb F concentration. It also provides an antiinflammatory effect by decreasing leukocyte production. These outcomes are thought to decrease crises.
Transfusion therapy can decrease morbidity and mortality associated with sickle cell disease, particularly in those at increased risk for stroke. 7 Despite these benefits, it can result in iron overload, which can cause liver damage and fibrosis, delayed physical and sexual development, and heart disease. Chelation therapy to remove excess iron is often required.
Hematopoietic stem cell transplantation offers the only cure for sickle cell disease; however, it is not without important risks. Current research is seeking to reduce the toxicities associated with transplantation while optimizing long-term outcomes.
Thalassemias
The alpha- and beta-thalassemias are autosomal recessive disorders that result in impaired synthesis of one of the two chains—α or β—of adult hemoglobin (Hb A). Beta-thalassemia is most prevalent among Greek, Italian, some Arab, and Sephardic Jewish people. Alpha-thalassemia is most common among Chinese, Vietnamese, Cambodian, and Laotian people. Both alpha- and beta-thalassemias are common among Black people.
Beta-thalassemias are more common than alpha-thalassemias. Both types are further classified as major or minor. The classification is based on the number of genes that control α- or β-chain synthesis. It also is based on the combination of mutations and whether they are homozygous (thalassemia major) or heterozygous (thalassemia minor). The anemic manifestation of both alpha- and beta-thalassemia is microcytic-hypochromic hemolytic anemia.
Pathophysiology
The beta-thalassemias are caused by mutations that decrease the synthesis of β-globin chains, leading to anemia, tissue hypoxia, and red cell hemolysis. β-Globin chain production is depressed moderately in the heterozygous form, beta-thalassemia minor, and severely in the homozygous form, beta-thalassemia major (also called Cooley anemia). As a result, erythrocytes have a reduced amount of hemoglobin and free α-chains accumulate (Fig. 24.7). Free α-chains are unstable and easily precipitate in the cell. Most erythroblasts that contain precipitates are destroyed by mononuclear phagocytes in the marrow. Destruction results in ineffective erythropoiesis and anemia. Some of the precipitate-carrying cells mature and enter the bloodstream. These cells are destroyed prematurely in the spleen, resulting in mild hemolytic anemia.
FIGURE 24.7 Pathogenesis of Beta-Thalassemia Major. The aggregates of unpaired α-globin chains are a hallmark of the disease. Blood transfusions can diminish the anemia, but they add to the systemic iron overload. (From Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders.)
There are four forms of alpha-thalassemia: (1) alpha trait (the heterozygous carrier state), in which a single α-chain–forming gene is defective; (2) alpha-thalassemia minor, in which two genes are defective; (3) hemoglobin H disease, in which three genes are defective; and (4) alpha-thalassemia major, in which all four α-forming genes are defective. Alpha-thalassemia major is fatal, often in utero, because α-chains are not produced and oxygen cannot be released to the tissues.
Clinical Manifestations
Beta-thalassemia minor causes mild to moderate microcytic-hypochromic anemia. The degree of reticulocytosis depends on the severity of the anemia and results in skeletal changes. Hemolysis of immature (and therefore fragile) erythrocytes may cause a slight elevation in serum iron and indirect bilirubin levels. Persons with beta-thalassemia minor may experience mild splenomegaly, bronze coloring of the skin, and hyperplasia of the bone marrow, but they are less likely to experience life-threatening complications.
Persons with beta-thalassemia major may become quite ill and show impaired physical growth and development. The severe anemia resulting from this condition can cause a significant cardiovascular burden with high-output congestive heart failure. In the past, death resulted from cardiac failure, often by age 20. Today, blood transfusions can increase the life span by one to two decades. Death is usually caused by consequences of hemochromatosis resulting from chronic transfusions. Liver enlargement occurs as a result of progressive hemosiderosis, and enlargement of the spleen is caused by extramedullary hemopoiesis and increased destruction of red blood cells. Skeletal changes begin in 556infancy and include spinal impairment that retards linear growth and subsequent upper and lower limb-length discrepancy. Deformity of the facial bones in response to hyperplastic marrow results in a characteristic chipmunk-like facial appearance.
Persons who inherit the mildest form of alpha-thalassemia (the alpha trait) usually are symptom free or have mild microcytosis. Alpha-thalassemia minor has clinical manifestations that are virtually identical to those of beta-thalassemia minor: mild microcytic-hypochromic reticulocytosis, bone marrow hyperplasia, increased serum iron concentrations, and moderate splenomegaly.
Signs and symptoms of alpha-thalassemia minor are similar to those of beta-thalassemia minor but milder. Moderate microcytic-hypochromic anemia, enlargement of the liver and spleen, and bone marrow hyperplasia are evident.
Alpha-thalassemia major causes hydrops fetalis, whereby the developing fetus suffers from severe tissue anoxia and may develop fulminant intrauterine congestive heart failure. Signs of fetal distress became evident by the third trimester of pregnancy. In the past, severe tissue anoxia led to death in utero; now many such infants are saved by intrauterine transfusions.
Evaluation and Treatment
Evaluation of thalassemia is based on the familial disease history, clinical manifestations, and blood tests. Diagnostic tests include peripheral blood smears that show microcytosis and hemoglobin electrophoresis that demonstrates diminished amounts of α- or β-chains. Prenatal diagnosis is sometimes done, and families are referred for genetic counseling. Identification of thalassemia is now included as part of routine newborn screening for hemoglobinopathies in all 50 states and the District of Columbia. Molecular genetic testing of at-risk siblings should be offered to allow for early diagnosis and appropriate treatment.
Treatment is largely supportive and involves a regular transfusion program and chelation therapy to reduce transfusion iron overload. Milder forms of thalassemia rarely require transfusion. The only available definitive cure for thalassemia major is allogeneic hematopoietic stem cell transplantation (HSCT) from a matched family or unrelated donor or cord blood transplantation from a related donor. 8 Optimal clinical management may decrease the need for splenectomy.
Quick Check 24.1
1. Why is Rh incompatibility rare today?
2. Why do clinical manifestations of sickle cell disease not appear until the infant is at least 6 months old?
3. Why do children with thalassemia major develop cardiovascular complications?
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Disorders of Coagulation and Platelets
Inherited Hemorrhagic Disease
Hemophilias
The hemophilias are a group of inherited bleeding disorders resulting from mutations in coagulation factors. The focus of this section will be hemophilia A and hemophilia B, both of which are X-linked recessive conditions. A third type of hemophilia, hemophilia C, is an autosomal recessive condition that results from a deficiency of factor XI. Table 24.3 lists the coagulation factors and deficiencies associated with clinical bleeding.
TABLE 24.3
The Coagulation Factors and Associated Disorders
Clotting Factors Synonym Disorder
I Fibrinogen Congenital deficiency (afibrinogenemia) and dysfunction (dysfibrinogenemia)
II Prothrombin Congenital deficiency or dysfunction
V Labile factor or proaccelerin Congenital deficiency (parahemophilia)
VII Stable factor or proconvertin Congenital deficiency
VIII AHF Congenital deficiency is hemophilia A (classic hemophilia)
IX Christmas factor Congenital deficiency is hemophilia B
X Stuart-Prower factor Congenital deficiency
XI Plasma thromboplastin antecedent Congenital deficiency, sometimes referred to as hemophilia C
XII Hageman factor Congenital deficiency is not associated with clinical symptoms
XIII Fibrin-stabilizing factor Congenital deficiency
AHF; antihemophilic factor.
Hemophilia A results from a mutation in the F8 gene, which codes for factor VIII, an essential cofactor for factor IX in the coagulation cascade. It is the most common hereditary disease associated with life-threatening bleeding. Hemophilia B results from a mutation in the F9 gene, which codes for factor IX. Because both factors VIII and IX function together to activate factor X, hemophilia A and B are clinically indistinguishable.
The incidence of hemophilia A is approximately 1 in 5000 male births. Hemophilia B is five times less common, with an incidence of approximately 1 in 30,000 male births. The worldwide prevalence of hemophilia it is estimated to be at more than 400,000 people. 9 All racial groups are equally affected.
Pathophysiology
As X-linked recessive conditions, hemophilia A and B are most frequently inherited from a mother who is heterozygous for a mutation in either the F8 or F9 gene. Approximately 30% of cases, however, result from a new mutation. This new mutation can occur in either a carrier female or in an affected male. More than 1300 mutations have been associated with factor VIII and IX deficiency. Affected individuals within the same family will have the same mutation; however, the mutation causing hemophilia may be different across families. 10
The F8 and F9 genes are located on the long arm of the X chromosome. A mutation in either of these genes typically results in either deficient or abnormal function of the corresponding clotting factor. Because males have only one copy of the X chromosome, the mutation results in the clinical manifestations of hemophilia. In females, the second copy of the X chromosome usually produces a sufficient quantity of normal functioning clotting factor. Females who are heterozygous carriers typically do not experience excessive bleeding. Because X-inactivation, or lyonization (see Chapter 2), is a random process, phenotypes of women who are heterozygous carriers can vary. Fifty percent of female carriers have lower than normal clotting factor levels. Although very uncommon, it is plausible for a female to be homozygous for mutations in the F8 or F9 gene and therefore have hemophilia. 10
Clinical Manifestations
The clinical manifestations and severity of hemophilia depend largely on the level of factor VIII and IX activity. Joint bleeding is the most characteristic type of bleeding in hemophilia. The joints most often affected are the knees, ankles, and elbows. Bleeding into muscles, usually from trauma, also can occur. Oral bleeding is common in the setting of dental surgery. Spontaneous painless hematuria is relatively common in hemophilia; it does not result in significant blood loss but requires evaluation. Hematuria accompanied by pain requires prompt evaluation and treatment.
Intracranial bleeds, bleeding of internal organs, and bleeding into the tissues of the neck, chest, or abdomen are all life-threatening. Delayed or suboptimal treatment of these bleeds may lead to permanent brain injury, loss of organ function, or death.
Evaluation and Treatment
A positive family history may expedite a diagnosis of hemophilia. When a mother who is a known or suspected carrier is pregnant, prenatal genetic testing through chorionic villus sampling (CVS) or amniocentesis may reveal a diagnosis of hemophilia. In the absence of a positive family history, a personal bleed history, laboratory testing, family history, and physical assessment contribute to a thorough evaluation and accurate diagnosis. In general, those with hemophilia A or B will have a prolonged partial thromboplastin time (PTT) and the prothrombin time (PT) will be normal. Measuring factor VIII and factor IX levels also is necessary for diagnosis.
The majority of children with hemophilia A can be treated with recombinant factor VIII. The majority of children with hemophilia B can be treated with recombinant factor IX. Recombinant factor is reconstituted in a small volume of diluent, administered by slow intravenous push, and raises the factor level almost immediately. Emerging therapies for hemophilia include the use of PEGylated factor. Adding a polyethylene glycol (PEG) molecule results in an extended half-life of the involved factor. 11
Antibody-Mediated Hemorrhagic Disease
Antibody-mediated hemorrhagic diseases are caused by the immune response. Antibody-mediated destruction of platelets or antibody-mediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues. The thrombocytopenic purpuras may be intrinsic or idiopathic. They also may be transient phenomena transmitted from mother to fetus. The inflammatory, or “allergic,” purpuras, although rare, occur in response to allergens in the blood. All of these disorders first appear during infancy or childhood.
Primary Immune Thrombocytopenia
Primary immune thrombocytopenia (ITP) (previously referred to as idiopathic thrombocytopenic purpura) is the most common disorder of platelet consumption. Autoantibodies bind to the plasma membranes of platelets, causing platelet sequestration and destruction by mononuclear phagocytes in the spleen and other lymphoid tissues at a rate 558that exceeds the ability of the bone marrow to produce them. The destruction of platelets is triggered by drugs, infections, lymphomas, or an unknown cause.
Pathophysiology
The autoantibodies that produce the destruction are often of the IgG class and are usually against the platelet membrane glycoproteins (IIb-IIIa or Ib-IX). Approximately 70% of cases of ITP are preceded by a viral illness (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV], parvovirus, or respiratory tract infection) prior to the eruption of petechiae or purpura by 1 to 3 weeks.
Clinical Manifestations
Bruising and a generalized petechial rash often occur about 1 to 3 weeks after a viral illness. Petechiae can develop into ecchymoses. Asymmetric bruising is typical and is found most often on the legs and trunk. Hemorrhagic bullae of the gums, lips, and other mucous membranes may be prominent. Epistaxis (nose bleeding) may be severe and difficult to control. Except for signs of bleeding, the child appears well. The principal changes are found in the spleen, bone marrow, and blood. The acute phase lasts 1 to 2 weeks, but thrombocytopenia often persists. Intracranial hemorrhage is the most serious complication of ITP, however, the incidence is less than 1%. In some cases, the onset is more gradual, and clinical manifestations consist of moderate bruising and a few petechiae.
Evaluation and Treatment
Laboratory examination reveals an isolated low platelet count. The few platelets observed on a smear are large, reflecting increased bone marrow production. The Ivy bleeding time is prolonged. Bone marrow aspiration is not recommended for children with typical features of ITP. The primary treatment for children with ITP is observation regardless of the platelet count. When bleeding is present, primary treatment is with an infusion of intravenous immune globulin (IVIG) or a short course of corticosteroids.
Even without treatment, the prognosis for children with ITP is excellent: 75% recover completely within 3 months. After the initial acute phase, spontaneous clinical manifestations subside. By 6 months after onset, 80% to 90% of affected children have regained normal platelet counts. ITP that persists longer than 12 months in children is considered chronic, and immunosuppressive therapies are used.
Quick Check 24.2
1. List the major disorders of coagulation and platelets found in children.
2. What is the mechanism of inheritance associated with hemophilia and how does it contribute to the clinical manifestations associated with factor VIII or IX deficiency in males and females?
3. What are the most common sites of bleeding in individuals with hemophilia?
4. What is the primary abnormality in primary immune thrombocytopenia (ITP)?
Neoplastic Disorders
Leukemia
Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells. Once in the blood, leukemic cells can spread to other organs, such as the lymph nodes, spleen, and brain. Leukemia is the most common malignancy in children and teens. The four most common types of leukemia are (1) acute lymphoblastic leukemia (ALL), (2) acute myeloid leukemia (AML), (3) chronic lymphocytic leukemia (CLL), and (4) chronic myeloid leukemia (CML) 12 (see Chapter 23).
About 75% of leukemias among children and teens are ALL; the remaining cases are classified as AML and related neoplasms. Chronic leukemias are rare in children and account for fewer than 5% of cases.
ALL is most common in early childhood, peaking between 2 and 4 years of age. AML is slightly more common during the first 2 years of life and during the teenage years and occurs about equally among boys and girls of all races. ALL is more common in boys than girls and among Hispanic and white children than among black and Asian American children.
The cause of most childhood cancer, including leukemia, is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations that predispose the child to cancer development can occur during fetal development. Genetic conditions associated with leukemia include Down syndrome, neurofibromatosis, Shwachman-Diamond syndrome, Bloom syndrome, and ataxia-telangiectasia. Epigenetic modifications, including DNA methylation, have been proposed as mediating events between environmental exposures and subsequent disease development. 13
Many studies have shown that exposure to ionizing radiation (prenatal exposure to x-rays and postnatal exposure to high doses) can lead to the development of childhood leukemia and possibly other cancers. 14 There is recent concern for performing computed tomography (CT) scans in children. The increased use of these scans combined with wide variability in radiation doses has resulted in many children receiving a high dose of radiation. 15 Studies of other possible environmental risk factors, including parental exposure to cancer-causing chemicals, prenatal exposure to pesticides, childhood exposure to common infectious agents, and living near a nuclear power plant, have so far produced inconsistent results. Higher risks of cancer have not been seen in children of individuals treated for sporadic cancer (cancer not caused by an inherited mutation). 16 , 17
Pathophysiology
ALL is composed of immature B (pre-B) or T (pre-T) cells called lymphoblasts. As leukemia develops, the bone marrow becomes dense with lymphoblasts that replace the normal marrow and disrupt normal function. Many of the chromosomal abnormalities documented in ALL cause dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development. 18 The mutations can include both gain of function and loss of function that are required for normal development.
AML is caused by acquired oncogenic mutations that impair differentiation, resulting in the accumulation of immature myeloid blasts in the marrow and other organs. Epigenetic alterations are frequent in AML and have a central role. The bone marrow crowding by blast cells produces marrow failure and complications, including anemia, thrombocytopenia, and neutropenia. AML is very heterogeneous because myeloid cell differentiation is very complex. Leukemia, ALL or AML, is typically distinguished from lymphoma by the presence of greater than 20% leukemic blasts in the bone marrow.
Clinical Manifestations
The onset of leukemia may be abrupt or insidious. Children with leukemia may present with symptoms only 1 week before diagnosis. Regardless of how leukemia develops, the most common symptoms reflect consequences of bone marrow failure. These include decreased levels of red blood cells and platelets, as well as changes in white blood cells. Pallor, fatigue, petechiae, purpura, bleeding, and fever generally are present. Approximately 45% of children present with a hemoglobin level below 7 g/dl. Epistaxis often occurs in children with severe thrombocytopenia.
Fever can be present as a result of (1) infection associated with the decrease in functional neutrophils and (2) hypermetabolism associated with the ongoing rapid growth and destruction of leukemic cells. White blood cell counts greater than 200,000/mm3 can cause leukostasis, an intravascular clumping of cells resulting in infarction and hemorrhage, usually in the brain and lung.
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Renal failure as a result of hyperuricemia (high uric acid levels) can be associated with ALL, particularly at diagnosis or during the initial phase of treatment. Extramedullary invasion with leukemic cells can occur in nearly all body tissue. The central nervous system (CNS) is a common site of infiltration of extramedullary leukemia. Less than 10% of children with ALL, however, will have CNS involvement at diagnosis. The most common symptoms of CNS involvement relate to increased intracranial pressure, causing early morning headaches, nausea, vomiting, irritability, and lethargy. Gonadal involvement, with testicular infiltration, also may occur.
Leukemic infiltration into bones and joints is common. Reports of bone or joint pain actually lead to the diagnosis of leukemia in some children. In most children, bone pain is characterized as migratory, vague, and without areas of swelling or inflammation. In some cases, however, joint pain is the primary symptom and some swelling is associated with the pain. Occasionally, these children are initially misdiagnosed as having rheumatoid arthritis. Other organs reported to be sites of leukemic invasion include the kidneys, heart, lungs, thymus, eyes, skin, and gastrointestinal tract.
Evaluation and Treatment
Leukemia is diagnosed through blood tests and examination of peripheral blood smears. A bone marrow aspiration is usually performed to further characterize the leukemia. The blast cell is the hallmark of acute leukemia (Fig. 24.8). Healthy children have less than 5% blast cells in the bone marrow and none in the peripheral blood. In ALL, the bone marrow often is replaced by 80% to 100% blast cells. Counts of normally developing red blood cells, granulocytes, and platelets are typically reduced. Occasionally, the marrow appears hypocellular, making the diagnosis difficult to differentiate from aplastic anemia. When this occurs, bone marrow biopsy or biopsy of extramedullary sites is necessary to confirm the diagnosis.
FIGURE 24.8 Monoblasts From Acute Monoblastic Leukemia. Monoblasts in a marrow smear from an individual with acute monoblastic leukemia. The monoblasts are larger than myeloblasts and usually have abundant cytoplasm, often with delicate scattered azurophilic granules (an element that stains well with blue aniline dyes). (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)
Approximately 85% of children with ALL will become 5-year survivors of their illness. Chemotherapy, using a combination of medications, is the treatment of choice for acute leukemia. Radiation of the CNS is used only in selected cases. Identification of various risk groups among children with ALL has led to the development of different intensities of drug protocols. As a result, treatment can be targeted specifically for a particular risk group. For children who experience relapses of ALL, treatment with chimeric antigen receptor T cells (CAR-T cells) is showing promise. 19 , 19a
AML is more difficult to treat than ALL. Combination chemotherapy is the most common approach to treatment. Those children with unfavorable cytogenetic markers and those who experience a relapse of their disease will often undergo hematopoietic stem cell transplantation. 20
CML accounts for less than 5% of childhood leukemias. Biologically targeted therapies, specifically tyrosine kinase inhibitors (TKIs), are becoming the mainstay of treatment, specifically for individuals whose disease has the BCR/ABL translocation 21 (see Chapter 23). TKIs are administered orally, and several are now approved for use in children. Treatment requires continued adherence to the medication regimen, and the health impact of long-term TKI therapy is not yet known. 21
Lymphomas
Lymphoma (Hodgkin lymphoma [HL] and non-Hodgkin lymphoma [NHL]) develops from the proliferation of malignant lymphocytes in the lymphoid system (see Chapters 12 and 23). Lymphomas arise from discrete tissue masses. Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation.
Some lymphomas occasionally have leukemic presentations, and evolution to “leukemia” is not unusual during the progression of incurable “lymphomas.” The terms therefore merely reflect the usual tissue distribution. The World Health Organization (WHO) provides a classification scheme for lymphoma that was updated in 2016 22 (also see Chapter 23).
NHL and HL constitute about 11% of all cases of childhood cancer. Approximately 1800 children younger than 20 years of age are diagnosed with lymphoma in the United States each year. 23 NHL (including Burkitt lymphoma) occurs more often than Hodgkin lymphoma. Either group of diseases is rare before the age of 5 years, and the relative incidence increases throughout childhood. Boys are more likely to be diagnosed with lymphoma than are girls. Children with inherited or acquired immunodeficiency syndromes, such as Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Bloom syndrome, are at particular risk for developing NHL.
Non-Hodgkin Lymphoma
Non-Hodgkin lymphomas (NHLs) are cancers of immune cells. NHLs are a large and diverse group of tumors. Some tumors develop more slowly, whereas others develop more quickly and aggressively. Childhood NHL typically becomes evident as a diffuse disease and can be further subdivided into four major types: (1) B-cell non-Hodgkin lymphoma (Burkitt and Burkitt-like lymphoma and Burkitt leukemia); (2) diffuse large B-cell lymphoma; (3) lymphoblastic lymphoma; and (4) anaplastic large cell lymphoma. 24 The common types of NHL in children are different from those in adults. The most common types of NHL in children are Burkitt lymphoma (40%), lymphoblastic lymphoma (25% to 30%), and large cell lymphoma (10%).
Pathophysiology
Burkitt lymphoma will be discussed as an example of the pathogenesis of NHL in children. All forms of Burkitt lymphoma are associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels. 25 MYC is a transcriptional regulator that increases the expression of genes required for aerobic glycolysis, called the Warburg effect (see Chapter 11). Most Burkitt lymphomas are latently infected with the EBV. 26 EBV also is present in about 25% of tumors associated with human immunodeficiency virus (HIV) infection and in 15% to 20% of sporadic cases. 27
Clinical Manifestations
NHL can arise from any lymphoid tissue. Signs and symptoms therefore are specific for the involved site. Associated 560signs of NHL include swelling of the lymph nodes in the neck, underarm, stomach, or groin; trouble swallowing; a painless lump or swelling in a testicle; weight loss for unknown reason; night sweats; and possibly trouble breathing. Involvement of facial bones, particularly the jaw, is common in African Burkitt lymphoma.
Evaluation and Treatment
Diagnosis is made by physical exam and health history, followed by a needle biopsy of disease sites, usually the involved lymph nodes, tonsils, spleen, liver, bowel, or skin. Burkitt lymphoma is very aggressive and responds well to treatment. With intensive chemotherapy, most children and young adults can be cured.
Hodgkin Lymphoma
Hodgkin lymphoma (HL) is a group of lymphoid cancers. In contrast to NHL, HL arises in a single chain of lymph nodes and spreads first in a contiguous way to lymphoid tissue. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal center of B cells (Fig. 24.9; also see Chapter 23). WHO has identified five types of HL: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte rich, (4) lymphocyte depletion, and (5) lymphocyte predominance. The first four types are considered the classic types of HL with similar expression of Reed-Sternberg cells. In the lymphocyte-predominance type, the Reed-Sternberg cell is distinctive but different from the others. HL is more common among adolescents, relative to younger childhood, and young adults.
FIGURE 24.9 Diagnostic Reed-Sternberg Cell. A large multinucleated or multilobated cell with inclusion body–like nucleoli (arrow) surrounded by a halo of clear nucleoplasm. (From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)
Pathophysiology
The Reed-Sternberg cells fail to express most of the normal B-cell markers, as well as those of T-cells. The causes of the genetic rearrangements or reprogramming are not fully known but are thought to be the result of widespread epigenetic changes.
The abnormal pattern of gene expression in Reed-Sternberg cells suggests that the activity of many transcription factors is also altered. 28 Abnormalities in the activation of the transcription factor nuclear factor-kappa B (NF-κB) may be influenced by EBV infection. NF-κB is involved in many biologic processes, including inflammation, immunity, cell growth, differentiation, and apoptosis. EBV-infected B cells, resembling Reed-Sternberg cells, are found in lymph nodes in individuals with infectious mononucleosis, suggesting that the EBV proteins may have a role in changes of the B cells into Reed-Sternberg cells. 29 Loss-of-function mutations in major histocompatibility class I antigens may allow Reed-Sternberg cells to avoid the normal host immune response. 30
Clinical Manifestations
Painless lymphadenopathy in the lower cervical chain, with or without fever, is the most common symptom in children. Other lymph nodes and organs also may be involved (Fig. 24.10). Mediastinal involvement can cause pressure on the trachea or bronchi, leading to airway obstruction. Extranodal primary sites in Hodgkin lymphoma are rare. Initial symptoms consist of anorexia, malaise, and fatigue. Intermittent fever is present in 30% of children, and weight loss also may be present. Hodgkin lymphoma has a well-defined staging system that considers the extent and location of disease and the presence of fever, weight loss, or night sweats at diagnosis.
FIGURE 24.10 Main Areas of Lymphadenopathy and Organ Involvement in Hodgkin Lymphoma. (From Hockenberry MJ et al, editors: Wong's nursing care of infants and children, ed 10, St Louis, 2015, Mosby.)
Evaluation and Treatment
Treatment for Hodgkin lymphoma includes chemotherapy and radiation therapy. Historically, survivors had a much greater risk of developing a secondary cancer, such as lung cancer, melanoma, and breast cancer. Treatment protocols have been modified to minimize the use of radiotherapy and use less toxic chemotherapy. Targeted therapies, including monoclonal antibodies such as brentuximab vedotin and immune checkpoint inhibitors, may have a greater role in treating Hodgkin lymphoma.
Quick Check 24.3
1. List the childhood leukemias in order of incidence.
2. Why do children with leukemia experience bone or joint pain?
3. What are the common types of non-Hodgkin lymphoma (NHL) in children?
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Summary Review
Disorders of Erythrocytes
1. Anemia is the most common blood disorder in children. Like the anemias of adulthood, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes.
2. Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide. Its incidence is greatest among children between 6 months and 2 years of age. Iron is critical for the developing child and without it damage from the periods of IDA is irreversible.
3. Regardless of its cause, IDA produces a hypochromic-microcytic anemia. Symptoms of mild anemia are often nonspecific, so parents may not notice changes until moderate anemia has developed.
4. Hemolytic disease of the fetus and newborn (HDFN) results from incompatibility between the maternal and the fetal Rh factors or blood type (ABO)Maternal antibodies (anti-Rh antibodies) form in response to the presence of fetal incompatible (Rh-positive) erythrocytes in the blood of an Rh-negative mother. The maternal antibodies then enter the fetal circulation and cause hemolysis of fetal erythrocytes. ABO incompatibility can cause HDFN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy.
5. The key to treatment of HDFN resulting from Rh incompatibilities lies in prevention or immunoprophylaxis.
6. Sickle cell disease is a group of disorders characterized by the production of abnormal hemoglobin S (Hb S) within the erythrocytes. It is most common among people with ancestry from sub-Saharan Africa.
7. Sickle cell disease is an inherited, autosomal recessive disorder expressed as sickle cell anemia, sickle cell–thalassemia disease, or sickle cell–Hb C disease, depending on mode of inheritance. Sickle cell anemia, in which the individual is homozygous for Hb S, is the most severe. Sickle cell–thalassemia and sickle cell–Hb C disease are compound heterozygous forms in which the child inherits Hb S from one parent or another type of abnormal hemoglobin from the other parent. All forms of sickle cell disease are lifelong conditions.
8. 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.
9. Sickle cell disease causes a change in the shape of red blood cells into the sickle shape. Sickling is triggered by decreased oxygen or dehydration. Most sickled erythrocytes regain a normal shape after reoxygenation and rehydration.
10. The alpha- and beta-thalassemias are inherited autosomal recessive disorders. These conditions result in an impaired rate of synthesis of one of the two chains—α or β—of adult hemoglobin (Hb A).
Disorders of Coagulation and Platelets
1. Hemorrhagic diseases can be either inherited (hemophilias) or antibody-mediated (primary immune thrombocytopenia [ITP]).
2. The hemophilias are a group of inherited bleeding disorders resulting from mutations in coagulation factors.
3. Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are caused by mutations in the genes coding for factors VIII and IX, factors essential in the coagulation cascade. Because factors VIII and IX function together, hemophilia A and B are clinically indistinguishable. Hemophilia A is the most common hereditary disease associated with life-threatening bleeding.
4. Hemophilias A and B are inherited as X-linked recessive conditions. Approximately one-third of cases, however, are the result of a spontaneous mutation in the involved gene.
5. The antibody-mediated hemorrhagic diseases are a group of disorders caused by the immune response. Antibody-mediated destruction of platelets or antibody-mediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues.
6. ITP is the most common disorder of platelet consumption in which antiplatelet antibodies bind to the plasma membranes of platelets. ITP results in platelet sequestration and destruction by mononuclear phagocytes at a rate that exceeds the ability of the bone marrow to produce them.
Neoplastic Disorders
1. Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells.
2. About 75% of childhood leukemias are acute lymphoblastic leukemia (ALL). The remaining cases are classified as acute myeloid leukemia (AML) and related neoplasms. Chronic leukemias are rare in children.
3. The cause of most childhood cancer, including leukemia, is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations that predispose the child to cancer development can occur during fetal development.
4. Exposure to ionizing radiation can lead to the development of childhood leukemia and possible other cancers.
5. ALL causes dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development.
6. Epigenetic alterations are frequent in AML and have a central role in its development.
7. The onset of leukemia may be abrupt or insidious. The most common symptoms reflect consequences of bone marrow failure and can include decreased levels of red blood cells and platelets, as well as changes in white blood cells.
8. Lymphomas are proliferations of malignant lymphocytes that arise from discrete tissue masses. Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation.
9. Some lymphomas occasionally have leukemic presentations, and evolution to leukemia is not unusual during the progression of incurable lymphoma.
10. The lymphomas of childhood are Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
11. NHLs are cancers of immune cells. Children with inherited or acquired immunodeficiency syndromes have an increased risk of developing NHL.
12. The most common types of NHL in children are Burkitt lymphoma, lymphoblastic lymphoma, and large cell lymphoma. Most Burkitt lymphomas are latently infected with the Epstein-Barr virus (EBV).
13. HL is a group of lymphoid cancers. HL arises in a single chain of lymph nodes and spreads first in a contiguous way to lymphoid tissue.
14. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal center of B cells.
1. Why is Rh incompatibility rare today?
2. Why do clinical manifestations of sickle cell disease not appear until the infant is at least 6 months old?
3. Why do children with thalassemia major develop cardiovascular complications?
expand on these questions
Why is Rh incompatibility rare today?
Rh incompatibility was more common before the advent of modern prenatal care practices. Today, mothers who are Rh-negative can receive Rh immunoglobulin (RhoGAM) during and after pregnancy to prevent the development of anti-Rh antibodies. This proactive treatment significantly reduces the risk for subsequent pregnancies involving an Rh-positive fetus. Additionally, routine blood typing and screening practices in pregnancy ensure that potential incompatibilities are identified early, allowing for proper monitoring and management.
Why do clinical manifestations of sickle cell disease not appear until the infant is at least 6 months old?
Clinical manifestations of sickle cell disease typically do not appear until about 6 months of age due to the presence of fetal hemoglobin (Hb F) in infants. Hb F is produced during fetal development and has a structure that prevents sickling. As the infant matures, the concentration of Hb F decreases, and the proportion of sickle hemoglobin (Hb S) increases. The shift from Hb F to Hb S typically results in the clinical symptoms becoming evident, as the sickling leads to painful vasoocclusive crises and other complications.
Why do children with thalassemia major develop cardiovascular complications?
Children with thalassemia major suffer from severe anemia due to reduced hemoglobin synthesis, which can result in a strain on the cardiovascular system as the heart works harder to compensate for the low oxygen carrying capacity of the blood. This overexertion can lead to high-output cardiac failure over time. Additionally, repeated blood transfusions, a common treatment for thalassemia major, can lead to iron overload in the body, further damaging the heart and other organs. The combination of chronic anemia and iron overload contributes significantly to the increased risk of cardiovascular complications in these children.
1. List the major disorders of coagulation and platelets found in children.
2. What is the mechanism of inheritance associated with hemophilia and how does it contribute to the clinical manifestations associated with factor VIII or IX deficiency in males and females?
3. What are the most common sites of bleeding in individuals with hemophilia?
4. What is the primary abnormality in primary immune thrombocytopenia (ITP)?
expand on these questions
Here’s an expanded discussion on the provided questions:
List the major disorders of coagulation and platelets found in children.Major disorders of coagulation and platelets in children include:
Hemophilia A: This is a hereditary bleeding disorder caused by a deficiency in factor VIII, leading to prolonged bleeding episodes. It primarily affects males and is inherited in an X-linked recessive pattern.
Hemophilia B: Similar to hemophilia A, this disorder is caused by a deficiency of factor IX. It also follows an X-linked recessive inheritance pattern and is less common than hemophilia A.
Von Willebrand Disease: A genetic disorder resulting from a deficiency of von Willebrand factor, which is crucial for platelet adhesion. It can lead to easy bruising and excessive bleeding.
Vitamin K Deficiency: This can occur due to malabsorption or inadequately balanced diets, which affects the synthesis of clotting factors II, VII, IX, and X, causing bleeding issues.
Primary Immune Thrombocytopenia (ITP): A condition where the immune system mistakenly destroys platelets, leading to low platelet counts and increased bleeding risk.
What is the mechanism of inheritance associated with hemophilia and how does it contribute to the clinical manifestations associated with factor VIII or IX deficiency in males and females?Hemophilia is inherited in an X-linked recessive manner. This means:
Males have one X chromosome, so if they inherit an X chromosome with the mutated gene for factor VIII or IX, they will express the disorder since they do not have a second X to compensate.
Females have two X chromosomes, so they can be carriers if one of their X chromosomes has the mutation. Carrier females usually have enough functional factor produced from their other X chromosome to prevent bleeding symptoms. However, about 10% of carrier females may experience some bleeding issues due to reduced levels of clotting factors.
The inheritance pattern means that males are predominantly affected by hemophilia, while females generally serve as carriers who may or may not have significant symptoms. This mechanism leads to the variability in clinical manifestations, which are more severe in affected males.
What are the most common sites of bleeding in individuals with hemophilia?Individuals with hemophilia commonly experience bleeding at various sites, including:
Joints: Hemarthrosis or bleeding into joints (especially the knees, ankles, and elbows) is the most characteristic complication, leading to pain, swelling, and long-term joint damage.
Muscles: Bleeding into muscles is also frequent, which can cause significant pain and swelling.
Mucous Membranes: This includes oral bleeding, especially during dental procedures, as well as bruising and bleeding from the gums and lips.
Intracranial Bleeds: These can result from trauma or spontaneous bleeding and are life-threatening. They require immediate medical attention.
Hematuria: Spontaneous bleeding into the urinary tract leading to blood in urine can occur but is generally less severe.
What is the primary abnormality in primary immune thrombocytopenia (ITP)?The primary abnormality in primary immune thrombocytopenia (ITP) is the production of autoantibodies that specifically target and bind to the platelet membrane glycoproteins. The key points include:
These antibodies lead to increased destruction of platelets as they are recognized and removed by the immune system, particularly by macrophages in the spleen and liver.
The rate of platelet destruction exceeds the ability of the bone marrow to produce new platelets, resulting in thrombocytopenia (low platelet count).
ITP can be triggered by various factors, including viral infections in children, which can lead to an acute form of the disease and is often self-limiting. In chronic cases, the underlying cause is less clear and may involve more complex immune dysregulation.
1. List the childhood leukemias in order of incidence.
2. Why do children with leukemia experience bone or joint pain?
3. What are the common types of non-Hodgkin lymphoma (NHL) in children?
expand on these questions
List the childhood leukemias in order of incidence.
Acute Lymphoblastic Leukemia (ALL): This is the most common type of leukemia in children, accounting for approximately 75% of cases. It primarily affects younger children, with a peak incidence between ages 2 and 5 years.
Acute Myeloid Leukemia (AML): This type ranks second in incidence and is slightly more common in infants and young adults than in school-age children. It includes several subtypes, which can vary in prognosis and treatment response.
Chronic Lymphocytic Leukemia (CLL): While rare in children, CLL can occur, usually seen in adolescents and typically has a slower progression than acute leukemias.
Chronic Myeloid Leukemia (CML): Also rare in children, CML is more commonly diagnosed in adults but can occur in pediatric populations, particularly with the BCR-ABL fusion gene indicating a specific type of CML.
Why do children with leukemia experience bone or joint pain?
Bone and joint pain in children with leukemia can be attributed to several factors:
Bone Marrow Infiltration: Leukemic cells proliferate and infiltrate the bone marrow, crowding out normal hematopoietic cells. This replacement can lead to increased pressure within the bones and cause discomfort or pain, particularly in long bones.
Pain Receptors Activation: The inflammation and metabolic changes associated with leukemia can activate pain receptors in joint and bone tissues, leading to pain perception.
Episodes of Bone Swelling: As leukemic cells accumulate, they can cause localized swelling that may produce joint pain. Symptoms can present as a vague, migratory pain or as more acute pain associated with inflamed joints. In some cases, this bone or joint pain may be misdiagnosed as growing pains or juvenile arthritis.
What are the common types of non-Hodgkin lymphoma (NHL) in children?
Non-Hodgkin lymphoma (NHL) in children includes several subtypes, with the most common being:
Burkitt Lymphoma: This is one of the most aggressive forms of NHL and is characterized by the translocation of the MYC gene, often associated with Epstein-Barr Virus (EBV) infection. It frequently manifests in the abdomen, jaw, or lymph nodes.
Lymphoblastic Lymphoma: This type resembles acute lymphoblastic leukemia and primarily affects T-cells or pre-B cells. It often presents as a mediastinal mass in adolescents.
Diffuse Large B-Cell Lymphoma: This is a fast-growing lymphoma that can occur in children and often presents in nodal or extranodal sites, such as the abdomen or central nervous system.
Anaplastic Large Cell Lymphoma: This subtype can present as a systemic disease or localized to lymph nodes, showing a characteristic pattern of large, abnormal cells.
Each of these types can differ in clinical presentation, prognosis, and treatment protocols, making early diagnosis and classification critical for effective management.