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Pediatrics_Nelson. adequate marrow synthesis of red blood cells (RBCs).Vitamin B12 and folic acid deficiencies lead to macrocytic anemia. Hemolytic diseases are mediated either by disorders intrinsic or extrinsic to the RBC that increase cell destruction. The most common RBC membrane disorders are hereditary spherocytosis and hereditary elliptocytosis. In both of these disorders, abnormalities of proteins within the cytoskeleton lead to abnormal RBC shapeand function. Numerous RBC enzyme deficiencies maylead to hemolysis, but only two are common: glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency. Immune-mediated hemolysismay be extravascular when RBCs coated with antibodiesor complement are phagocytosed by the reticuloendothelialsystem. The hemolysis may be intravascular when antibodybinding leads to complement fixation and lysis of RBCs. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Acute onset of anemia can result in a poorly compensated state, manifested as an elevated heart rate, a flow murmur, poor exercise tolerance, headache, excessive sleeping (especially in infants) or fatigue, irritability, poor feeding, and syncope. In contrast, chronic anemia often is exceptionally well Age Iron deficiency rare in the absence of blood loss before 6 mo or in term infants or before doubling of birth weight in preterm infants Neonatal anemia with reticulocytosis suggests hemolysis or blood loss; with reticulocytopenia, suggests bone marrow failure Sickle cell anemia and β-thalassemia appear as fetal hemoglobin disappears (4–8 mo of age)


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Pediatrics_Nelson. Family history X-linked: G6PD deficiency and genetic Autosomal dominant: spherocytosis considerations Autosomal recessive: sickle cell anemia, Fanconi anemia Family member with history of cholecystectomy (for bilirubin stones) or splenectomy at an early age Ethnicity (thalassemia in persons of Mediterranean origin; G6PD deficiency in blacks, Greeks, and people of Middle Eastern origin) Race (β-thalassemia in persons of Mediterranean, African, or Asian descent; α-thalassemia in those of African and Asian descent; SC and SS in African descent) Nutrition Cow’s milk diet: iron deficiency Strict vegetarian: vitamin B12 deficiency Goat’s milk diet: folate deficiency Pica: plumbism, iron deficiency Cholestasis, malabsorption: vitamin E deficiency Drugs G6PD: oxidants (e.g., nitrofurantoin, antimalarials) Immune-mediated hemolysis (e.g., penicillin) Bone marrow suppression (e.g., chemotherapy) Phenytoin, increasing folate requirements


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Pediatrics_Nelson. Drugs G6PD: oxidants (e.g., nitrofurantoin, antimalarials) Immune-mediated hemolysis (e.g., penicillin) Bone marrow suppression (e.g., chemotherapy) Phenytoin, increasing folate requirements Diarrhea Malabsorption of vitamin B12 or E or iron Inflammatory bowel disease and anemia of inflammation (chronic disease) with or without blood loss Milk protein intolerance–induced blood loss Intestinal resection: vitamin B12 deficiency Infection Giardia lamblia infection: iron malabsorption Intestinal bacterial overgrowth (blind loop): vitamin B12 deficiency Fish tapeworm: vitamin B12 deficiency Epstein-Barr virus, cytomegalovirus infection: bone marrow suppression, hemophagocytic syndromes Mycoplasma infection: hemolysis Parvovirus infection: bone marrow suppression HIV infection Chronic infection Endocarditis Malaria: hemolysis Hepatitis: aplastic anemia G6PD, Glucose-6-phosphate dehydrogenase.


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Pediatrics_Nelson. G6PD, Glucose-6-phosphate dehydrogenase. tolerated in children because of their cardiovascular reserve. Usually, children with chronic anemia will have minimal tachycardia and a flow murmur on examination. The urgency of diagnostic and therapeutic intervention, especially the use of packed RBC transfusion, should be dictated by the extent of cardiovascular or functional impairment more than the absolute level of hemoglobin. The causes of anemia often can be suspected from a careful history adjusted for the patient’s age (Tables 150-1 and 150-2). Anemia at any age demands a search for blood loss.


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Pediatrics_Nelson. A history of jaundice, pallor, previously affected siblings,drug ingestion by the mother, or excessive blood loss at thetime of birth provides important clues to the diagnosis innewborns. A careful dietary history is crucial. The key findings in patients with hemolytic anemias are jaundice, pallor, and splenomegaly. Because of increased bilirubin production, gallstones (bilirubinate), a result of chronic hemolysis,are a common complication. Systemic complaints suggestacute or chronic illnesses as probable causes of anemia. Inlater childhood and adolescence, the presence of constitutional symptoms, unusual diets, drug ingestion, or bloodloss, especially from menstrual bleeding, often points to adiagnosis. Congenital hemolytic disorders (enzyme deficiencies and membrane problems) often present in the first6 months of life and frequently are associated with neonatal jaundice, although these disorders often go undiagnosed. A careful drug history is essential for detecting problemsthat may


Pediatrics_Nelson

Pediatrics_Nelson. in the first6 months of life and frequently are associated with neonatal jaundice, although these disorders often go undiagnosed. A careful drug history is essential for detecting problemsthat may be drug induced. Pure dietary iron deficiency israre except in infancy, when cow’s milk protein intolerancecauses gastrointestinal blood loss and further complicates analready inadequate iron intake.


Pediatrics_Nelson

Pediatrics_Nelson. The physical examination may point to the potential causes (see Table 150-2). The physiologic stability of the patient may be abnormal with acute blood loss and acute hemolysis, manifesting as tachycardia, blood pressure changes, and, most ominously, an altered state of consciousness. The presence of jaundice suggests hemolysis. Petechiae and purpura indicate a coagulopathy. Hepatosplenomegaly and adenopathy suggest infiltrative disorders. Growth failure or poor weight gain suggests an anemia of chronic disease. An essential element of the physical examination is the investigation of the stool for the presence of occult blood.


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Pediatrics_Nelson. A hemoglobin or hematocrit test indicates the severity of the anemia. Once anemia has been substantiated, the workup should include a complete blood count with differential, platelet count, indices, and reticulocyte count. Examination of the peripheral blood smear assesses the morphology of RBCs (Fig. 150-2), white blood cells (WBCs), and platelets. All cell lines should be scrutinized to determine whether anemia is the result of a process limited to the erythroid line or a process that affects other marrow elements. Using data obtained from the indices and reticulocyte count, the workup can be organized on the basis of whether RBC production is adequate or inadequate and whether the cells are microcytic, normocytic, or macrocytic (see Fig. 150-1).


Pediatrics_Nelson

Pediatrics_Nelson. An appropriate bone marrow response to anemia would be an elevated absolute reticulocyte number, suggestingincreased production and implying either hemolysis orblood loss. Anemia with a normal reticulocyte number suggests decreased or ineffective production for the degree ofanemia. Reticulocytopenia signifies an acute onset so thatthe marrow has not had adequate time to respond, thatreticulocytes are being destroyed in the marrow (antibodymediated), or that intrinsic bone marrow disease is present.The best indicators of the severity of hemolysis are the hemoglobin level and the elevation of the reticulocyte count. Biochemical evidence of hemolysis includes an increase inlevels of bilirubin and lactate dehydrogenase and a decreasein haptoglobin. Head Frontal bossing Thalassemia major, severe iron deficiency, chronic subdural hematoma Microcephaly Fanconi anemia General Small stature Fanconi anemia, HIV infection, malnutrition


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Pediatrics_Nelson. Head Frontal bossing Thalassemia major, severe iron deficiency, chronic subdural hematoma Microcephaly Fanconi anemia General Small stature Fanconi anemia, HIV infection, malnutrition HIV, Human immunodeficiency virus; SLE, systemic lupus erythematosus. Figure 150-2 Morphologic abnormalities of the red blood cell. A, Normal. B, Hypochromic microcytes (iron deficiency). C, Schistocytes (hemolytic uremic syndrome. D, Blister cells (glucose-6-phosphate dehydrogenase deficiency). E, Sickle cells (hemoglobin SS disease). F, Spherocytes (autoimmune hemolytic anemia). (Courtesy B. Trost and J. P. Scott.) Hypochromic, Microcytic Anemia Available @ StudentConsult.com


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Pediatrics_Nelson. J. P. Scott.) Hypochromic, Microcytic Anemia Available @ StudentConsult.com Etiology. Infants fed cow’s milk when younger than 1 year of age, toddlers fed large volumes of cow’s milk, and menstruating teenage girls who are not receiving supplemental iron are at high risk for iron deficiency. Dietary iron deficiency anemia is most common in bottle-fed toddlers who are receiving large volumes of cow’s milk and eat minimal amounts of food high in iron content. (See Chapters 28 and 31.) Iron deficiency anemia also may be found in children with chronic inflammatory diseases, even without chronic blood loss.


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Pediatrics_Nelson. Epidemiology. The prevalence of iron deficiency, the most common cause of anemia in the world, is about 9% in toddlers, 9% to 11% in adolescent girls, and less than 1% in teenage boys. Iron deficiency anemia occurs in about one third of children who are iron deficient (Table 150-3). Some underprivileged minority populations in the United States may be at increased risk for iron deficiency because of poor dietary intake (see Chapter 31). Breastfed infants are less likely to have iron deficiency than bottle-fed infants because, although there is less iron in breast milk, this iron is more efficiently absorbed.


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Pediatrics_Nelson. Clinical Manifestations. In addition to cardiovascular manifestations of anemia, central nervous system (CNS) abnormalities (apathy, irritability, poor concentration)have been linked to iron deficiency, presumably resulting from alterations of iron-containing enzymes (monoamine oxidase) and cytochromes. Poor muscle endurance, gastrointestinal dysfunction, and impaired WBC and T-cell function have been associated with iron deficiency. Iron deficiency in infancy may be associated with later cognitive deficits and poor school performance.


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Pediatrics_Nelson. Treatment. In an otherwise healthy child, a therapeutic trial of iron is the best diagnostic study for iron deficiency as long as the child is re-examined and a response is documented. The response to oral iron includes rapid subjective improvement, especially in neurologic function (within 24 to 48 hours) and reticulocytosis (48 to 72 hours); increase in hemoglobin levels (4 to 30 days); and repletion of iron stores (in 1 to 3 months). The usual therapeutic dose of 4 to 6 mg/day 10–12 nc/nc ↓ Fe2+ absent, erythroid hyperplasia <12 8–10 hypo/nc ↓ Fe2+ absent, erythroid hyperplasia <12 <8 hypo/micro* ↓ Fe2+ absent, erythroid hyperplasia <12


Pediatrics_Nelson

Pediatrics_Nelson. From Andreoli TE, Bennett JC, Carpenter CC, et al: Cecil Essentials of Medicine, ed 4, Philadelphia, 1997, WB Saunders. hypo/micro, Hypochromic, microcytic; hypo/nc, hypochromic, normocytic; nc/nc, normochromic, normocytic. *Microcytosis, determined by a mean corpuscular volume (in fL) <2 SD below the mean, must be adjusted for age (e.g., –2 SD at 3–6 mo = 74; at 0.5–2 yr = 70; at 2–6 yr = 75; at 6–12 yr = 77; and at 12–18 yr = 78). *See Table 150-3 for definition of microcytosis. †α-Thalassemia minor can be diagnosed by the presence of Bart hemoglobin on newborn screening. ‡Usually normochromic; 25% of cases are microcytic. §Red blood cell distribution width quantitates the degree of anisocytosis (different sizes) of red blood cells.


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Pediatrics_Nelson. ‡Usually normochromic; 25% of cases are microcytic. §Red blood cell distribution width quantitates the degree of anisocytosis (different sizes) of red blood cells. of elemental iron induces an increase in hemoglobin of 0.25 to 0.4 g/dL/day (a 1%/day increase in hematocrit). If the hemoglobin level fails to increase within 2 weeks after institution of iron treatment, careful re-evaluation for ongoing blood loss, development of infection, poor compliance, or other causes of microcytic anemia is required (Table 150-4; see Fig. 150-1).


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Pediatrics_Nelson. Prevention. Bottle-fed infants should receive an iron-containing formula until 12 months of age, and breastfed infants older than 6 months of age should receive an iron supplement. The introduction of iron-enriched solid foods at 6 months of age, followed by a transition to a limited amount of cow’s milk and increased solid foods at 1 year, can help prevent iron deficiency anemia. Teenage girls who are menstruating should have a diet enriched with iron-containing foods. A vitamin with iron may also be used. Etiology and Epidemiology. α-Thalassemia and β-thalassemia minor are common causes of microcytosis, either with or without a mild hypochromic, microcytic anemia. They are prevalent in certain ethnic groups (Mediterranean, Southeast Asian, African Americans). Individuals of Asian descent are at risk of having three or four α genes deleted, resulting in hemoglobin H disease (γ4) or hydrops fetalis with only Bart (α4) hemoglobin (Table 150-5 and Fig. 150-3).


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Pediatrics_Nelson. Laboratory Testing. The thalassemia minor syndromes are characterized by a mild hypochromic, microcytic anemia with a low absolute reticulocyte count (see Table 150-5). The RBC count is usually elevated. As a result, if the mean corpuscular volume (MCV) divided by the RBC count is less than 12.5 (Mentzer index), the diagnosis is suggestive of thalassemia trait. The blood smear reveals only microcytosis with α-thalassemia trait. Outside the neonatal period, when Bart hemoglobin is detectable, hemoglobin electrophoresis usually is normal in α-thalassemia minor (see Fig. 150-3). Blood smears of patients with β-thalassemia minor show microcytic RBCs. Target cells and basophilic stippled RBCs, caused by precipitation of alpha chain tetramers, also may be present. The diagnosis is based on an elevation of hemoglobin A2 and F levels in β-thalassemia. Molecular testing is indicated for identification of more severe or unusual variants.


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Pediatrics_Nelson. Treatment. No treatment is required for children with thalassemia minor. However, children with hemoglobin H disease (γ4), especially the Constant Spring variant or hydrops fetalis with only Bart (α4) hemoglobin, are likely to require chronic transfusion therapy. Lead poisoning may be associated with a hypochromic, microcytic anemia. Most patients have concomitant iron deficiency. The history of living in an older home (built before 1980) with chipped paint or lead dust should raise suspicion of lead poisoning, especially in a child with pica. Basophilic stippling on the blood smear is common. Lead intoxication Table 150-5 Thalassemia Syndromes DISORDER GENOTYPIC ABNORMALITY CLINICAL PHENOTYPE β-THALASSEMIA Thalassemia major (Cooley’s anemia) Homozygous β0-thalassemia Severe hemolysis, ineffective erythropoiesis, transfusion dependency, hepatosplenomegaly, iron overload


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Pediatrics_Nelson. Thalassemia intermedia Compound heterozygous β0and β+-thalassemia Moderate hemolysis, splenomegaly, moderately severe anemia, but not transfusion-dependent; main life-threatening complication is iron overload Thalassemia minor Heterozygous β0and β+-thalassemia Microcytosis, mild anemia Hydrops fetalis -/-Severe anemia, intrauterine anasarca from congestive heart failure; death in utero or at birth From Andreoli T, Carpenter C, Griggs R, et al: Cecil Essentials of Medicine, ed 7, Philadelphia, 2007, Saunders. *The Constant Spring variant may require chronic transfusion.


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Pediatrics_Nelson. *The Constant Spring variant may require chronic transfusion. Figure 150-3 Genetic origins of the classic α-thalassemia syndromes due to gene deletions in the α-globin gene cluster. Hb Constant Spring (Hb CS) is an α-globin chain variant synthesized in such small amounts (1%–2% of normal) that it has the phenotypic impact of a severe non-deletion α-thalassemia allele; however, the αCS allele is always linked to a functioning α-globin gene, so it has never been associated with hydrops fetalis. (From Hoffman R, Benz EJ, Shattil SS, et al, editors: Hematology: Basic Principles and Practice, ed 5, Philadelphia, 2008, Churchill Livingstone.) ˜+-Thal trait (”Mild” trait, silent carrier) rarely causes hemolytic anemia. Detection by routine screening, removal from exposure, chelation therapy, and correction of iron deficiency are crucial to the potential development of affected children.


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Pediatrics_Nelson. Etiology and Treatment. Anemia is a common component of chronic inflammatory disease. Hepcidin, a protein made in the liver, plays a key role in iron homeostasis. Inflammation causes an increase in the production of hepcidin, interrupting the process of iron release by macrophages and the absorption Normal ˜-Thalassemia with Hb constant spring of iron from the intestines leading to anemia. The anemia of inflammation may be normocytic or, less often, microcytic. This may pose a clinical challenge, when children with inflammatory disorders associated with blood loss (inflammatory bowel disease) exhibit a microcytic anemia. In these circumstances, only a bone marrow aspiration with staining of the sample for iron can differentiate the two entities clearly (see Table 150-4). Low ferritin levels indicate concurrent iron deficiency. A trial of iron therapy is not indicated without a specific diagnosis in children who appear to be systemically ill.


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Pediatrics_Nelson. Bone marrow infiltration by malignant cells commonly leads to a normochromic, normocytic anemia. The mechanism Table 150-6 Differentiation of Red Blood Cell Aplasias and Aplastic Anemias DISORDER AGE AT ONSET CHARACTERISTICS TREATMENT CONGENITAL Diamond-Blackfan syndrome (congenital Newborn–1 mo; 90% of patients are <1 yr Pure red blood cell aplasia, autosomal recessive trait, elevated fetal hemoglobin, fetal i antigen Prednisone, transfusion, hematopoietic stem cell hypoplastic anemia) of age present, macrocytic, short stature, webbed neck, transplant cleft lip, triphalangeal thumb; late-onset leukemia, mutation analysis Parvovirus Any age Any chronic hemolytic anemia, typically sickle cell; Transfusion new-onset reticulocytopenia Epstein-Barr virus (EBV) Any age; usually <5 yr X-linked immunodeficiency syndrome, Transfusion, bone marrow of age pancytopenia transplantation


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Pediatrics_Nelson. Epstein-Barr virus (EBV) Any age; usually <5 yr X-linked immunodeficiency syndrome, Transfusion, bone marrow of age pancytopenia transplantation CMV, Cytomegalovirus; CSF, cerebrospinal fluid; HHV-6, human herpesvirus 6; IVIG, intravenous immune globulin; MCV, mean corpuscular volume; VP-16, etoposide. by which neoplastic cells interfere with RBC and other marrow cell synthesis is multifactorial. The reticulocyte count is often low. Immature myeloid elements may be released into the peripheral blood because of the presence of the offending tumor cells. An examination of the peripheral blood may reveal lymphoblasts; when solid tumors metastasize to the marrow, these cells are seldom seen in the peripheral blood. Teardrop cells may be seen in the peripheral blood. A bone marrow examination is frequently necessary in the face of normochromic, normocytic anemia.


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Pediatrics_Nelson. Congenital pure RBC aplasia (Diamond-Blackfan syndrome), a lifelong disorder, usually presents in the first few months of life or at birth with severe anemia and mild macrocytosis or a normocytic anemia. It is due to a deficiency of bone marrow red blood cell precursors (Table 150-6). More than a third of patients have short stature. Many patients (50% to 66%) respond to corticosteroid treatment, but must receive therapy indefinitely. Patients who do not respond to corticosteroid treatment are transfusion dependent and are at risk of the multiple complications of long-term transfusion therapy, especially iron overload. These patients have a higher rate of developing leukemia or other hematologic malignancies than the general population.


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Pediatrics_Nelson. In contrast to the congenital hypoplastic anemias, transient erythroblastopenia of childhood, a normocytic anemia causedby suppression of RBC synthesis, usually appears after 6 monthsof age in an otherwise normal infant. Viral infections are thoughtto be the trigger, although the mechanism leading to RBC aplasia is poorly understood. The onset is gradual, but anemia maybecome severe. Recovery usually is spontaneous. Differentiationfrom Diamond-Blackfan syndrome, in which erythroid precursors also are absent or diminished in the bone marrow, may bechallenging. Transfusion of packed RBCs may be necessary ifthe anemia becomes symptomatic before recovery.


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Pediatrics_Nelson. Aplastic crises may complicate any chronic hemolytic anemia. These periods of severe reticulocytopenia, leading to an acute exacerbation of the anemia, may precipitate cardiovascular decompensation. Human parvovirus B19 (the cause of fifth disease) infects erythroid precursors and shuts down erythropoiesis. Transient erythroid aplasia is without consequence in individuals with normal RBC survival. Recovery from parvovirus infection in hemolytic disease is spontaneous, but patients may need transfusion if the anemia is severe. SEE FIGURE 150-1. Available @ StudentConsult.com


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Pediatrics_Nelson. SEE FIGURE 150-1. Available @ StudentConsult.com Etiology. Pancytopenia is a quantitative decrease in formed elements of the blood—erythrocytes, leukocytes, and platelets. Patients more often exhibit symptoms of infection or bleeding than anemia because of the relatively short life span of WBCs and platelets compared with the life span of RBCs. Causes of pancytopenia include failure of production (implying intrinsic bone marrow disease), sequestration (hypersplenism), and increased peripheral destruction.


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Pediatrics_Nelson. Differential Diagnosis. Features that suggest bone marrow failure and mandate an examination of bone marrow include a low reticulocyte count, teardrop forms of RBCs(implying marrow replacement, not just failure), presenceof abnormal forms of leukocytes or myeloid elements lessmature than band forms, small platelets, and an elevatedmean corpuscular volume in the face of a low reticulocytecount. Pancytopenia resulting from bone marrow failure isusually a gradual process, starting with one or two cell lines, but later involving all three cell lines. Features suggestingincreased destruction include reticulocytosis, jaundice,immature erythroid or myeloid elements on the blood smear,large platelets, and increased serum bilirubin and lactic dehydrogenase. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Etiology and Epidemiology. In a child with aplastic anemia, pancytopenia evolves as the hematopoietic elements of the bone marrow disappear and the marrow is replaced by fat. In developed countries, aplastic anemia is most often idiopathic. The disorder may be induced by drugs such as chloramphenicol and felbamate or by toxins such as benzene. Aplastic anemia also may follow infections, particularly hepatitis and infectious mononucleosis (see Table 150-6). Immunosuppression of hematopoiesis is postulated to be an important mechanism in patients with postinfectious and idiopathic aplastic anemia. Laboratory Studies. A bone marrow biopsy is crucial to determine cellularity or the extent of depletion of the hematopoietic elements.


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Pediatrics_Nelson. Treatment. Survival rate is about 20% in severe aplastic anemia with supportive care alone, although the duration of survival may be years when vigorous blood product and antibiotic support is provided. For children with severe aplastic anemia—defined by an absolute reticulocyte count less than 50,000/μL, absolute neutrophil count less than 500/mm3, platelet count less than 20,000/mm3, and bone marrow cellularity on biopsy specimen less than 25% of normal—the treatment of choice is hematopoietic stem cell transplantation (HSCT) from a sibling with identical HLA and compatible mixed lymphocytes. When HSCT occurs before the recipient is sensitized to blood products, survival rate is greater than 80%. The treatment of aplastic anemia without an HLA-matched donor for HSCT is evolving, with two major options: potent immunosuppressive therapy or unrelated or partially matched HSCT. Results of trials using immunosuppressive therapy with antithymocyte globulin, cyclosporine, and


Pediatrics_Nelson

Pediatrics_Nelson. with two major options: potent immunosuppressive therapy or unrelated or partially matched HSCT. Results of trials using immunosuppressive therapy with antithymocyte globulin, cyclosporine, and corticosteroids in combination with hematopoietic growth factors have been encouraging. Such therapy is often toxic, and relapses often occur when therapy is stopped.


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Etiology and Epidemiology. Fanconi anemia is a constitutional form of aplastic anemia that usually presents in the latter half of the first decade of life and may evolve over years. A group of genetic defects in proteins involved in DNA repairhave been identified in Fanconi anemia, which is inherited in an autosomal recessive manner. The diagnosis is based on demonstration of increased chromosomal breakage after exposure to agents that damage DNA. The repair mechanism for DNA damage is abnormal in all cells in Fanconi anemia, which may contribute to the increased risk of malignancies. Terminal acute leukemia develops in 10% of cases. Other malignancies include solid tumors of the head and neck, gastrointestinal tumors, and gynecologic tumors. Clinical Manifestations. Patients with Fanconi anemia have numerous characteristic clinical findings (see Table 150-6).


Pediatrics_Nelson

Pediatrics_Nelson. Clinical Manifestations. Patients with Fanconi anemia have numerous characteristic clinical findings (see Table 150-6). Treatment. Hematopoietic stem cell transplantation can cure the pancytopenia caused by bone marrow aplasia. Many patients with Fanconi anemia and about 20% of children with aplastic anemia seem to respond for a time to androgenic therapy, which induces masculinization and may cause liver injury and liver tumors. Androgenic therapy increases RBC synthesis and may diminish transfusion requirements. The effect on granulocytes, and especially the platelet count, is less impressive.


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Pediatrics_Nelson. Marrow Replacement. Marrow replacement may occur as a result of leukemia, solid tumors (especially neuroblastoma), storage diseases, osteopetrosis in infants, and myelofibrosis, which is rare in childhood. The mechanisms by which malignant cells impair marrow synthesis of normal hematopoietic elements are complex and incompletely understood. Bone marrow aspirate and biopsy are needed for precise diagnosis of the etiology of marrow synthetic failure.


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Pediatrics_Nelson. Pancytopenia Resulting from Destruction of Cells. Pancytopenia resulting from destruction of cells may be caused by intramedullary destruction of hematopoietic elements (myeloproliferative disorders, deficiencies of folic acid and vitamin B12) or by the peripheral destruction of mature cells. The usual site of peripheral destruction of blood cells is the spleen, although the liver and other parts of the reticuloendothelial system may participate. Hypersplenism maybe the result of anatomic causes (portal hypertension or splenic hypertrophy from thalassemia); infections (including malaria); or storage diseases (Gaucher disease, lymphomas, or histiocytosis). Splenectomy is indicated only when the pancytopenia is of clinical significance. Available @ StudentConsult.com


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Pediatrics_Nelson. Etiology. Because alpha chains are needed for fetal erythropoiesis and production of hemoglobin F (α2γ2), alpha chain hemoglobinopathies are present in utero. Four alpha genes are present on the two number 16 chromosomes (see Fig. 150-3 and Table 150-5). Single gene deletions produce no disorder (silent carrier state), but can be detected by measuring the rates of α and β synthesis or by using molecular biologic techniques. Deletion of two genes produces α-thalassemia minor with mild or no anemia and microcytosis. In individuals of African origin, the gene deletions occur on different chromosomes (trans), and the disorder is benign. In the Asian population, deletions may occur on the same chromosome (cis),and infants may inherit two number 16 chromosomes lacking three or even four genes. Deletion of all four genes leads to hydrops fetalis, severe intrauterine anemia, and death, unless intrauterine transfusions are administered. Deletion of three genes produces moderate hemolytic


Pediatrics_Nelson

Pediatrics_Nelson. Deletion of all four genes leads to hydrops fetalis, severe intrauterine anemia, and death, unless intrauterine transfusions are administered. Deletion of three genes produces moderate hemolytic anemia with γ4 tetramers (Bart hemoglobin) in the fetus and β4 tetramers (hemoglobin


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Pediatrics_Nelson. H) in older children and adults (see Table 150-5). Beta chain hemoglobinopathies in the United States are more prevalent than alpha chain disorders, possibly because these abnormalities are not symptomatic in utero. The major beta hemoglobinopathies include those that alter hemoglobin function, including hemoglobins S, C, E, and D, and those that alter beta chain production, the β-thalassemias. Because each RBC has two copies of chromosome 11 and they express both β-globin genes, most disorders of beta chains are not clinically severe, unless both beta chains are abnormal. By convention, when describing β-thalassemia genes, β0 indicates a thalassemic gene resulting in absent beta chain synthesis, whereas β+ indicates a thalassemic gene that permits reduced but not absent synthesis of normal β chains. Disorders of the beta chain usually manifest themselves clinically between 4 and 12 months of age, unless they have been detected prenatally or by cord blood screening.


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Pediatrics_Nelson. β-Thalassemia Major (Cooley Anemia) Etiology and Epidemiology. β-Thalassemia major is caused by mutations that impair beta chain synthesis. Because of unbalanced synthesis of alpha and beta chains, alpha chains precipitate within the cells, resulting in RBC destruction either in the bone marrow or in the spleen. β-Thalassemia major is seen most commonly in individuals of Mediterranean or Asian descent. The clinical severity of the illness varies on the basis of the molecular defect.


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Pediatrics_Nelson. Clinical Manifestations. Signs and symptoms of βthalassemia major result from the combination of chronic hemolytic disease, decreased or absent production of normal hemoglobin A, and ineffective erythropoiesis. The anemia is severe and leads to growth failure and high-output heart failure. Ineffective erythropoiesis causes increased expenditure of energy and expansion of the bone marrow cavities of all bones, leading to osteopenia, pathologic fractures, extramedullary erythropoiesis with resultant hepatosplenomegaly, and an increase in the rate of iron absorption.


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Pediatrics_Nelson. Treatment. Treatment of β-thalassemia major is based on a hypertransfusion program that corrects the anemia and suppresses the patient’s own ineffective erythropoiesis, limiting the stimulus for increased iron absorption. This suppression permits the bones to heal, decreases metabolic expenditures, increases growth, and limits dietary iron absorption. Splenectomy may reduce the transfusion volume, but it adds to the risk of serious infection. Chelation therapy with deferoxamine or deferasirox should start when laboratory evidence of iron overload (hemochromatosis) is present and before there are clinical signs of iron overload (nonimmune diabetes mellitus, cirrhosis, heart failure, bronzing of the skin, and multiple endocrine abnormalities). Hematopoietic stem cell transplantation in childhood, before organ dysfunction induced by iron overload, has had a high success rate in β-thalassemia major and is the treatment of choice. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Etiology and Epidemiology. The common sickle cell syndromes are hemoglobin SS disease, hemoglobin S-C disease, hemoglobin S-β thalassemia, and rare variants (Table 150-7). The specific hemoglobin phenotype must be identified because the clinical complications differ in frequency, type, and severity. As a result of a single amino acid substitution smear: hypochromic, microcytic anemia S-HPFH Sickle-0 70–80 1–2 20–30 – Often asymptomatic; Hb F is uniformly distributed hereditary persistence of Hb F From Andreoli T, Carpenter C, Griggs R, et al: Cecil Essentials of Medicine, ed 7, Philadelphia, 2007, Saunders.


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Pediatrics_Nelson. From Andreoli T, Carpenter C, Griggs R, et al: Cecil Essentials of Medicine, ed 7, Philadelphia, 2007, Saunders. (valine for glutamic acid at the β6 position), sickle hemoglobin crystallizes and forms a gel in the deoxygenated state. When reoxygenated, the sickle hemoglobin is normally soluble. The so-called reversible sickle cell is capable of entering the microcirculation. As the oxygen is extracted and saturation declines, sickling may occur, occluding the microvasculature. The surrounding tissue undergoes infarction, inducing pain and dysfunction. This sickling phenomenon is exacerbated by hypoxia, acidosis, fever, hypothermia, and dehydration.


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Pediatrics_Nelson. Clinical Manifestations and Treatment. A child with sickle cell anemia is vulnerable to life-threatening infection by 4 months of age. By that time, splenic dysfunction is caused by sickling of the RBCs within the spleen, resulting in an inability to filter microorganisms from the bloodstream in most patients. Splenic dysfunction is followed, eventually, by splenic infarction, usually by 2 to 4 years of age. The loss of normal splenic function makes the patient susceptible to overwhelming infection by encapsulated organisms, especially Streptococcus pneumoniae and other pathogens (Table 150-8).The hallmark of infection is fever. A febrile patient with a sickle cell syndrome (temperature >38.5°C) must be evaluated immediately (see Chapter 96). Current precautions to prevent infections include prophylactic daily oral penicillin begun at diagnosis and vaccinations against pneumococcus, Haemophilus influenzae type b, hepatitis B virus, and influenza virus.


Pediatrics_Nelson

Pediatrics_Nelson. The anemia of hemoglobin SS disease is usually a chronic, moderately severe, hemolytic anemia that is not routinely transfusion dependent. The severity depends in part on the patient’s phenotype. Manifestations of chronic anemia include jaundice, pallor, variable splenomegaly in infancy, a cardiac flow murmur, and delayed growth and sexual maturation. Decisions about transfusion should be made on the basis of the patient’s clinical condition, the hemoglobin level, and the reticulocyte count.


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Pediatrics_Nelson. Sickle cell disease is complicated by sudden, occasionally severe and life-threatening events caused by the acute intra-vascular sickling of the RBCs, with resultant pain or organ dysfunction (so-called crisis). In two different clinical situations, an acute, potentially life-threatening decline in the hemoglobin level may be superimposed on the chronic compensated anemia. Splenic sequestration crisis is a life-threatening, hyperacute drop in the hemoglobin level (blood volume) secondary to splenic pooling of the patient’s RBCs and sickling within the spleen. The spleen is moderately to markedly enlarged, and the reticulocyte count is elevated. In an aplastic crisis, parvovirus B19 infects RBC precursors in the bone marrow and induces transient RBC aplasia with reticulocytopenia and a rapid worsening of anemia because of the very short life span of sickle RBCs. Simple transfusion therapy is indicated for sequestration and aplastic crises when the anemia is symptomatic.


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Pediatrics_Nelson. Vasoocclusive painful events may occur in any organ of the body and are manifested by pain and/or significant dysfunction (see Table 150-8). The acute chest syndrome is a vasoocclusive crisis within the lungs with evidence of a new infiltrate on chest radiograph. It is often associated with infection and infarction. The patient may first complain of chest pain but within a few hours develops cough, increasing respiratory and heart rates, hypoxia, and progressive respiratory distress. Physical examination reveals areas of decreased breath sounds and dullness on chest percussion. Treatment involves early recognition and prevention of arterial hypoxemia. Oxygen, fluids, judicious use of analgesic medications, antibiotics, bronchodilators, and RBC transfusion (rarely exchange transfusion) are indicated in therapy for acute chest syndrome. Incentive spirometry may help reduce the incidence of acute chest crisis in patients presenting with pain in the chest or abdomen.


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Pediatrics_Nelson. Pain crisis is the most common type of vasoocclusive event.The pain usually localizes to the long bones of the arms or legsbut may occur in smaller bones of the hands or feet in infancy(dactylitis) or in the abdomen. Painful crises usually last 2 to7 days. Vasoocclusive crises within the femur may lead to avascular necrosis of the femoral head and chronic hip disease.Treatment of pain crises includes administration of fluids, analgesia (usually narcotics and nonsteroidal anti-inflammatorydrugs), and oxygen if the patient is hypoxic. Although pain isoften impossible to quantitate, the risk for drug dependency ishighly overrated, and appropriate use of analgesics is necessary. Priapism occurs in boys usually between 6 and 20 years old. The child experiences a sudden, painful onset of a Anemia Chronic, onset 3–4 mo of age; may require folate therapy for chronic hemolysis; hemoglobin usually 6-10 g/dL


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Pediatrics_Nelson. Anemia Chronic, onset 3–4 mo of age; may require folate therapy for chronic hemolysis; hemoglobin usually 6-10 g/dL Aplastic crisis Parvovirus infection, reticulocytopenia; acute and reversible; may need transfusion Sequestration Massive splenomegaly (may involve liver), crisis shock; treat with transfusion Hemolytic crisis May be associated with G6PD deficiency Painful crisis Microvascular painful vasoocclusive infarcts of muscle, bone, bone marrow, lung, intestines Acute chest Infection, asthma, atelectasis, infarction, fat syndrome emboli, severe hypoxemia, infiltrate, dyspnea, absent breath sounds Chronic lung Pulmonary fibrosis, restrictive lung disease, disease cor pulmonale, pulmonary hypertension Priapism Causes eventual impotence; treated with transfusion, oxygen, or corpora cavernosa-tospongiosa shunt Renal Hematuria, papillary necrosis, renal concentrating defect; nephropathy Skeletal Osteonecrosis (avascular) of femoral or humeral head


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Pediatrics_Nelson. Renal Hematuria, papillary necrosis, renal concentrating defect; nephropathy Skeletal Osteonecrosis (avascular) of femoral or humeral head Infections Functional asplenia, defects in properdin system; pneumococcal bacteremia, meningitis, and arthritis; deafness from meningitis; Salmonella and Staphylococcus aureus osteomyelitis; severe Mycoplasma pneumonia Growth failure, May respond to nutritional supplements delayed puberty Psychological Narcotic addiction (rare), dependence problems unusual; chronic illness, chronic pain syndrome G6PD, Glucose-6-phosphate dehydrogenase. *Clinical manifestations with sickle cell trait are unusual but include renal papillary necrosis (hematuria), sudden death on exertion, intraocular hyphema extension, and sickling in unpressurized airplanes.


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Pediatrics_Nelson. tumescent penis that will not relax. Therapeutic steps for priapism include the administration of oxygen, fluids, analgesia, and transfusion when appropriate to achieve a hemoglobin S less than 30% (often by partial exchange transfusion). Fluid management requires recognition that renal medullary infarction results in loss of the ability to concentrate urine. Overt stroke occurs in approximately 8% to 10% of patients with SS disease. These events may present as the sudden onset of an altered state of consciousness, seizures, or focal paralysis. Silent stroke, which is defined as evidence of cerebral infarction on imaging studies but a normal neurologic examination, is more common and occurs in approximately 20% of patients with SS disease. A significant change in school performance or behavior has been associated with silent stroke. Children with Hg SS disease over 3 years of age should be screened for increased risk of stroke using transcranial Doppler (TCD).


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Pediatrics_Nelson. Laboratory Diagnosis. The diagnosis of hemoglobinopathies is made by identifying the precise amount and type of hemoglobin using hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography. Every member of an at-risk population should have a precise hemoglobin phenotype performed at birth (preferably) or during early infancy. Most states perform newborn screening for sickle cell disease.


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Pediatrics_Nelson. Treatment. Direct therapy of sickle cell anemia is evolving. The mainstay of care is supportive measures. The use of chronic RBC transfusions to treat patients who have had a stroke has been very successful. Chronic RBC transfusions have also been used successfully for short time periods to prevent recurrent vasoocclusive painful events, including acute chest syndrome and priapism. Hydroxyurea, which increases hemoglobin F, decreases the number and severity of vasoocclusive events and frequency of acute chest syndrome in children as early as1 year of age. Hematopoietic stem cell transplantation, using a haploidentical sibling match, has cured many children with sickle cell disease. HSCT using alternative donors for children, without a suitable sibling match, is being studied. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Etiology. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an abnormality in the hexose monophosphate shunt pathway of glycolysis that results in the depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the inability to regenerate reduced glutathione. When a patient with G6PD is exposed to significant oxidant stress, hemoglobin is oxidized, forming precipitates of sulfhemoglobin (Heinz bodies), which are visible on specially stained preparations. The gene for G6PD deficiency is on the X chromosome. The severity of hemolysis depends on the enzyme variant. In many G6PD variants, the enzymes become unstable with aging of the RBC and cannot be replaced because the cell is anucleated. Older cells are most susceptible to oxidant-induced hemolysis. In other variants, the enzyme is kinetically abnormal.


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Pediatrics_Nelson. Epidemiology. The most common variants of G6PD deficiency have been found in areas where malaria is endemic. G6PD deficiency protects against parasitism ofthe erythrocyte. The most common variant with normalactivity is termed type B and is defined by its electrophoretic mobility. The approximate gene frequencies in AfricanAmericans are 70% type B, 20% type A, and 10% type A–. Only the A– variant, termed the African variant, is unstable. Ten percent of black males are affected. A group of variants found in Sardinians, Sicilians, Greeks, Sephardic and Oriental Jews, and Arabs is termed the Mediterranean variant and is associated with chronic hemolysis andpotentially life-threatening hemolytic disease. Because thegene for G6PD deficiency is carried on the X chromosome, clinical hemolysis is most common in males. Heterozygousfemales who have randomly inactivated a higher percentage of the normal gene may become symptomatic, as mayhomozygous females with the A– variant (0.5% to 1%


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Pediatrics_Nelson. is most common in males. Heterozygousfemales who have randomly inactivated a higher percentage of the normal gene may become symptomatic, as mayhomozygous females with the A– variant (0.5% to 1% offemales of African descent).


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Pediatrics_Nelson. Clinical Manifestations. G6PD deficiency has two common presentations. Individuals with the A– variant havenormal hemoglobin values when well, but develop an acute episode of hemolysis triggered by serious (bacterial) infection or ingestion of an oxidant drug. The RBC morphologyduring episodes of acute hemolysis is striking, appearing to have “bites” taken out of them (cookie cells). These areareas of absent hemoglobin that are produced by phagocytosis of Heinz bodies by splenic macrophages; as a result,the RBCs appear blistered. Clinically evident jaundice, darkurine resulting from bilirubin pigments, hemoglobinuriawhen hemolysis is intravascular, and decreased haptoglobinlevels are common during hemolytic episodes. Early on, thehemolysis usually exceeds the ability of the bone marrowto compensate, so the reticulocyte count may be low for 3to 4 days.


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Pediatrics_Nelson. Laboratory Studies. The diagnosis of G6PD deficiency is based on decreased NADPH formation. G6PD levels during an acute, severe hemolytic episode may be normal, however, because the most deficient cells have been destroyed and reticulocytes are enriched with G6PD. Repeating the test at a later time when the patient is in a steady-state condition, testing the mothers of boys with suspected G6PD deficiency, or performing electrophoresis to identify the precise variant present aids in diagnosis.


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Pediatrics_Nelson. Treatment and Prevention. The treatment of G6PD deficiency is supportive. Transfusions are indicated whensignificant cardiovascular compromise is present. Maintaining hydration and urine alkalization protects the kidneysagainst damage from precipitated free hemoglobin. Hemolysis is prevented by avoidance of known oxidants, particularly long-acting sulfonamides, nitrofurantoin, primaquine,dimercaprol, and moth balls (naphthalene). Fava beans(favism) have triggered hemolysis, particularly in patientswith the Mediterranean variant. Serious infection also is a potential precipitant of hemolysis in G6PD-deficient youngchildren.


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Pediatrics_Nelson. Pyruvate kinase deficiency is much less common than G6PD deficiency and represents a clinical spectrum of disorders caused by the functional deficiency of pyruvate kinase.Some individuals have a true deficiency state, and others haveabnormal enzyme kinetics. The metabolic consequence ofpyruvate kinase deficiency is adenosine triphosphate (ATP)depletion, impairing RBC survival. Pyruvate kinase deficiency is usually an autosomal disorder, and most childrenwho are affected (and are not products of consanguinity) aredouble heterozygotes for two abnormal enzymes. Hemolysisis not aggravated by oxidant stress due to the profound reticulocytosis in this condition. Aplastic crises are potentiallylife-threatening. The spleen is the site for RBC removal inpyruvate kinase deficiency. Most patients have amelioration ofthe anemia and a reduction of transfusion requirements aftersplenectomy. Available @ StudentConsult.com


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Pediatrics_Nelson. Etiology. The biochemical basis of hereditary spherocytosis and hereditary elliptocytosis are similar. Both conditions appear to have a defect in the protein lattice (spectrin, ankyrin, protein 4.2, band 3) that underlies the RBC lipid bilayer and provides stability of the membrane shape. In hereditary spherocytosis, pieces of membrane bud off as microvesicles because of abnormal vertical interaction of the cytoskeletal proteins and uncoupling of the lipid bilayer from the cytoskeleton. When the RBC loses membrane, cell shape changes from a biconcave disk to a spherocyte. The RBC is less deformable when passing through narrow passages in the spleen. Hereditary elliptocytosis is a disorder of spectrin dimer interactions that occurs primarily in individuals of African descent. The transmission of the two variants is usually autosomal dominant, but spontaneous mutations causing hereditary spherocytosis are common. Hereditary pyropoikilocytosis (unusual instability of the erythrocytes


Pediatrics_Nelson

Pediatrics_Nelson. of the two variants is usually autosomal dominant, but spontaneous mutations causing hereditary spherocytosis are common. Hereditary pyropoikilocytosis (unusual instability of the erythrocytes when they are exposed to heat at 45°C) is the result of a structural abnormality of spectrin.


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Pediatrics_Nelson. Clinical Manifestations. Hereditary spherocytosis varies greatly in clinical severity, ranging from an asymptomatic, well-compensated, mild hemolytic anemia that may be discovered incidentally to a severe hemolytic anemia with growth failure, splenomegaly, and chronic transfusion requirements in infancy necessitating early splenectomy. The most common variant of hereditary elliptocytosis is a clinically insignificant morphologic abnormality without shortened RBC survival. The less common variant is associated with spherocytes, ovalocytes, and elliptocytes with a moderate, usually compensated, hemolysis. Far more significant hemolysis occurs in hereditary pyropoikilocytosis. The peripheral blood smear in hereditary pyropoikilocytosis often includes elliptocytes, spherocytes, fragmented RBCs, and striking microcytosis. Such patients may have bizarre blood smears in the newborn period with small, fragmented RBCs.


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Pediatrics_Nelson. Laboratory Diagnosis. The clinical diagnosis of hereditaryspherocytosis should be suspected in patients with even a fewspherocytes found on the blood smear because the spleenpreferentially removes spherocytes. An incubated osmotic fragility test confirms the presence of spherocytes andincreases the likelihood of the diagnosis. The osmotic fragility test result is abnormal in any hemolytic disease in whichspherocytes are present—for example, in antibody-mediatedhemolysis.


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Pediatrics_Nelson. Treatment. Splenectomy corrects the anemia and normalizes the RBC survival in patients with hereditaryspherocytosis, but the morphologic abnormalities persist.Splenectomy should be considered for any child with symptoms referable to anemia or growth failure, but should bedeferred until age 5 years, if possible, to minimize the risk ofoverwhelming postsplenectomy sepsis and to maximize theantibody response to the polyvalent pneumococcal vaccine.In several reports, partial splenectomy seems to improvethe hemolytic anemia and maintain splenic function in hostdefense.


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Pediatrics_Nelson. Figure 150-4 Coombs or direct antiglobulin test (DAT). In the DAT, so-called Coombs serum that recognizes human immunoglobulin (Ig) or complement (C) is used to detect the presence of antibody or C on the surface of the red blood cells (RBCs) by agglutination. A, An IgM antibody can bind two RBCs simultaneously because of its multiple antigen-binding sites. The great size of the IgM allows it to bridge the surface repulsive forces (zeta potential) between RBCs and cause agglutination. B, An IgG antibody is too small to bridge the zeta potential and cause agglutination. C, On the addition of Coombs serum, the zeta potential is bridged successfully, and RBCs agglutinate. (Modified from Ware RE, Rosse WF: Autoimmune hemolytic anemia. In Orkin SH, Nathan DG, Look AT, Ginsburg D, editors: Hematology of Infancy and Childhood, ed 6, Philadelphia, 2003, Saunders, p 530.) Hemolytic Anemia Caused by Disorders Extrinsic to the Red Blood Cell Etiology and Clinical Manifestations


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Pediatrics_Nelson. Philadelphia, 2003, Saunders, p 530.) Hemolytic Anemia Caused by Disorders Extrinsic to the Red Blood Cell Etiology and Clinical Manifestations Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Isoimmune hemolysis is caused by active maternal immunization against fetal antigens that the mother’s erythrocytes do not express (see Chapter 62). Examples are antibodies to the A, B, and Rh D antigens; other Rh antigens; and the Kell, Duffy, and other blood groups. Anti-A and anti-B hemolysis is caused by the placental transfer of naturally occurring maternal antibodies from mothers who lack A or B antigen (usually blood type O). Positive results of the direct antiglobulin (Coombs) test on the infant’s RBCs (Fig. 150-4), the indirect antiglobulin test on the mother’s serum, and the presence of spherocytes and immature erythroid precursors (erythroblastosis) on the infant’s blood smear confirm this diagnosis. Isoimmune hemolytic disease varies in clinical severity. There may be no clinical manifestations, or the infant may exhibit jaundice, severe anemia, and hydrops fetalis.


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Pediatrics_Nelson. Autoimmune hemolytic anemia is usually an acute, self-limited process that develops after an infection (Mycoplasma,Epstein-Barr, or other viral infections). Autoimmune hemolyticanemia may also be the presenting symptom of a chronic autoimmune disease (systemic lupus erythematosus, lymphoproliferative disorders, or immunodeficiency). Drugs may induce aCoombs-positive hemolytic anemia by forming a hapten on theRBC membrane (penicillin) or by forming immune complexes(quinidine) that attach to the RBC membrane. Antibodies thenactivate complement-induced intravascular hemolysis. Thethird type of drug-induced immune hemolysis occurs duringtreatment with α-methyldopa and a few other drugs. In this type,prolonged drug exposure alters the RBC membrane, inducingneoantigen formation. Antibodies are produced that bind to theneoantigen; this produces a positive antiglobulin test result farmore commonly than it actually induces hemolysis. In each ofthese conditions, the erythrocyte is an innocent


Pediatrics_Nelson

Pediatrics_Nelson. produced that bind to theneoantigen; this produces a positive antiglobulin test result farmore commonly than it actually induces hemolysis. In each ofthese conditions, the erythrocyte is an innocent bystander.


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Pediatrics_Nelson. A second form of acquired hemolytic disease is caused by mechanical damage to the RBC membrane during circulation. In thrombotic microangiopathy, the RBCs are trapped by fibrin strands in the circulation and physically broken by shear stress as they pass through these strands. Hemolytic uremic syndrome, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, malignant hypertension, toxemia, and hyperacute renal graft rejection can produce thrombotic microangiopathy. The platelets are usually large, indicating that they are young, but have a decreased survival even if the numbers are normal. Consumption of clotting factors is more prominent in DIC than in the other forms of thrombotic microangiopathy. The smear shows RBC fragments (schistocytes), microspherocytes, teardrop forms, and polychromasia. Other examples of mechanical injury to RBCs include damage by exposure to nonendothelialized surfaces (as in artificial heart valves) or as a result of high flow


Pediatrics_Nelson

Pediatrics_Nelson. teardrop forms, and polychromasia. Other examples of mechanical injury to RBCs include damage by exposure to nonendothelialized surfaces (as in artificial heart valves) or as a result of high flow and shear rates in giant hemangiomas (Kasabach-Merritt syndrome).


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Pediatrics_Nelson. Alterations in the plasma lipids, especially cholesterol, may lead to damage to the RBC membrane and shorten RBC survival. Lipids in the plasma are in equilibrium with lipids in the RBC membrane. High cholesterol levels increase the membrane cholesterol and the total membrane surface without affecting the volume of the cell. This condition produces spur cells that may be seen in abetalipoproteinemia and liver diseases. Hemolysis occurs in the spleen, where poor RBC deformability results in erythrocyte destruction. Circulating toxins (e.g., snake venoms and heavy metals) that bind sulfhydryl groups may damage the RBC membrane and induce hemolysis. Irregularly spiculated RBCs (burr cells) are seen in renal failure. Vitamin E deficiency can also cause an acquired hemolytic anemia as a result of abnormal sensitivity of membrane lipids to oxidant stress. Vitamin E deficiency may occur in premature infants who are not being supplemented with vitamin E or who have insufficient nutrition, in


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Pediatrics_Nelson. of abnormal sensitivity of membrane lipids to oxidant stress. Vitamin E deficiency may occur in premature infants who are not being supplemented with vitamin E or who have insufficient nutrition, in infants with severe malabsorption syndromes (including cystic fibrosis), and in infants with transfusional iron overload, which can lead to severe oxidant exposure.


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Pediatrics_Nelson. Laboratory Diagnosis. The peripheral blood smear in autoimmune hemolytic anemia usually reveals spherocytes and occasionally nucleated RBCs. The reticulocyte count varies because some patients have relatively low reticulocyte counts as a result of autoantibodies that cross-react with RBC precursors. Treatment and Prognosis. Transfusion for the treatment of autoimmune hemolysis is challenging because crossmatching is difficult, as the autoantibodies react with virtually all RBCs. In addition to transfusion, which may be lifesaving, management of autoimmune hemolytic anemia depends on antibody type. Management may involve administration of corticosteroids and, at times, intravenous immunoglobulin. Corticosteroids reduce the clearance of sensitized RBCs in the spleen. In drug-induced hemolysis, withdrawal of the drug usually leads to resolution of the hemolytic process. More than 80% of children with autoimmune hemolytic anemia recover spontaneously.


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Pediatrics_Nelson. Hemostasis is the dynamic process of coagulation as it occurs in areas of vascular injury, involving the carefullymodulated interaction of platelets, vascular wall, and pro-coagulant and anticoagulant proteins. After an injury tothe vascular endothelium, subendothelial collagen inducesa conformational change in von Willebrand factor (vWF), an adhesive protein to which platelets bind via their glycoprotein Ib receptor. After adhesion, platelets undergo activation and release numerous intracellular contents, includingadenosine diphosphate (ADP). These activated plateletssubsequently induce aggregation of additional platelets.Simultaneously, tissue factor, collagen, and other matrix proteins in tissue activate the coagulation cascade, leading to theformation of the enzyme thrombin (Fig. 151-1). Thrombincauses further aggregation of platelets, a positive feedbackactivation of factors 5 and 8, the conversion of fibrinogen tofibrin, and the activation of factor 11. A platelet plug forms,


Pediatrics_Nelson

Pediatrics_Nelson. Thrombincauses further aggregation of platelets, a positive feedbackactivation of factors 5 and 8, the conversion of fibrinogen tofibrin, and the activation of factor 11. A platelet plug forms, and bleeding ceases, usually within 3 to 7 minutes. The generation of thrombin leads to formation of a permanent clot bythe activation of factor 13, which cross-links fibrin, forminga stable thrombus. Finally, contractile elements within theplatelet mediate clot retraction. Thrombin also contributes to the eventual limitation of clot size by binding to the protein thrombomodulin on intact endothelial cells, convertingprotein C into activated protein C. Thrombin contributes to the eventual lysis of the thrombus by activating plasminogento plasmin. All of the hemostatic processes are closely interwoven and occur on biologic surfaces that mediate coagulation by bringing the critical players—platelets, endothelialcells, and subendothelium—into close proximity with pro-and anticoagulant proteins.


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Pediatrics_Nelson. Many think of coagulation as having intrinsic and extrinsic pathways, but the reality is that these pathways are closely interactive and do not react independently (Fig. 151-2). For ease of use, all coagulation factors are denoted using Arabic rather than Roman numerals to prevent misreading factor VII (7) as factor VIII (8). In vivo, factor 7 autocatalyzes to form small amounts of factor 7a. When tissue is injured, tissue factor is released and causes a burst of factor 7a generation. Tissue factor, in combination with calcium and factor 7a, activates factor 9 and factor 10. The activation of factor 9 by factor 7a results in eventual generation of thrombin, which feeds back on factor 11, generating factor 11a and accelerating thrombin formation. This process explains why deficiency of factor 8 or factor 9 leads to severe bleeding disorders, whereas deficiency of factor 11 is usually mild, and deficiency of factor 12 is asymptomatic.


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Pediatrics_Nelson. A series of inhibitory factors serve to tightly regulate theactivation of coagulation. Antithrombin III inactivates thrombin and factors 10a, 9a, and 11a. The protein C and protein S system inactivates activated factors 5 and 8, whichare cofactors localized in the “tenase” and “prothrombinase” complexes. The tissue factor pathway inhibitor, an anticoagulant protein, limits activation of the coagulation cascade by factor 7a and factor 10a. Fibrinolysis is initiated by the action of tissue plasminogen activator on plasminogen, producing plasmin, the active enzyme thatdegrades fibrin into split products. Fibrinolysis eventually dissolves the clot and allows normal flow to resume.Deficiencies of anticoagulant proteins may predispose tothrombosis.


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Pediatrics_Nelson. In the fetus, fibrinogen, factor 5, factor 8, and platelets approach normal levels during the second trimester. Levels of other clotting factors and anticoagulant proteins increase gradually throughout gestation. The premature infant issimultaneously at increased risk of bleeding or clottingcomplications that are exacerbated by many of the medical interventions needed for care and monitoring, especiallyindwelling arterial or venous catheters. Most children attainnormal levels of procoagulant and anticoagulant proteins by1 year of age, although levels of protein C lag and normalize inadolescence.


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Pediatrics_Nelson. A detailed family history is crucial for diagnosis of bleeding and thrombotic disorders. Hemophilia is X-linked, and almost all affected children are boys. von Willebrand disease usually is inherited in an autosomal dominant fashion. In the investigation of thrombotic disorders, a personal or family history of blood clots in the legs or lungs, early-onset stroke, or heart attack suggests a hereditary predisposition to thrombosis. The causes of bleeding may be hematologic in origin or due to vascular, nonhematologic causes (Fig. 151-3). Thrombotic disorders can be congenital or acquired (Table 151-1) and frequently present after an initial event (central catheter, trauma, malignancy, infection, pregnancy, treatment with estrogens) provides a nidus for clot formation or a procoagulant stimulus.


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Pediatrics_Nelson. Figure 151-1 Diagram of the multiple interactions of the hemostatic mechanism. Solid lines indicate reactions that favor coagulation, and dashed lines indicate reactions that inhibit clotting. Epi, Epinephrine; GAGs, glycosaminoglycans; NO, nitric oxide; PAI, plasminogen activator inhibitor; PGI2, prostaglandin I2 (prostacyclin); TAFI, thrombin-activated fibrinolytic inhibitor; TXA2, thromboxane A2; vWF, von Willebrand factor. (Modified from Scott JP, Montgomery RR: Hemorrhagic and thrombotic diseases. In Kliegman RM, Behrman RE, Jenson HB, Stanton BF, editors: Nelson Textbook of Pediatrics, ed 18, Philadelphia, 2007, Saunders, p 2062.) Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Patients with hemostatic disorders may have complaints ofeither bleeding or clotting. Age at onset of bleeding indicateswhether the problem is congenital or acquired. The sites of bleeding (mucocutaneous or deep) and degree of trauma(spontaneous or significant) required to induce injury suggest the type and severity of the disorder. Certain medications (aspirin and valproic acid) are known to exacerbatepreexisting bleeding disorders by interfering with plateletfunction. The physical examination should characterize the presence of skin or mucous membrane bleeding and deepersites of hemorrhage into the muscles and joints or internalbleeding sites. The term petechia refers to a non-blanching lesion less than 2 mm in size. Purpura is a group of adjoining petechiae, ecchymoses (bruises) are isolated lesions larger than petechiae, and hematomas are raised, palpable ecchymoses.


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Pediatrics_Nelson. The physical examination should also search for manifestations of an underlying disease, lymphadenopathy,hepatosplenomegaly, vasculitic rash, or chronic hepatic orrenal disease. Deep venous thrombi may cause warm, swollen (distended), tender, purplish discolored extremities ororgans or no findings. Arterial clots cause acute, painful,pale, and poorly perfused extremities. Arterial thrombi ofthe internal organs present with signs and symptoms ofinfarction. Screening laboratory studies for bleeding patients include a platelet count, prothrombin time, partial thromboplastin time, fibrinogen, and bleeding time or other screening test of platelet function. Many laboratories have adopted the platelet function analyzer (PFA) to replace the bleeding time as a screening test for platelet function abnormalities and


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Pediatrics_Nelson. Figure 151-2 Simplified pathways of blood coagulation. The area inside the solid black line is the intrinsic pathway measured by the activated partial thromboplastin time (APTT). The area inside the green line is the extrinsic pathway, measured by the prothrombin time (PT). The area encompassed by both lines is the common pathway. AT-III, Antithrombin III; F, factor; HMWK, high-molecular-weight kininogen; P-C/S, protein C/S; PL, phospholipid; TFPI, tissue factor pathway inhibitor. (Modified from Scott JP, Montgomery RR: Hemorrhagic and thrombotic diseases. In Kliegman RM, Behrman RE, Jenson HB, Stanton BF, editors: Nelson Textbook of Pediatrics, ed 18, Philadelphia, 2007, Saunders, p 2061.) Prothrombin time Extrinsic and common pathway <12 sec beyond neonate; Defect in vitamin K–dependent factors; 12–18 sec in term neonate hemorrhagic disease of newborn, malabsorption, liver disease, DIC, oral anticoagulants, ingestion of rat poison


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Pediatrics_Nelson. Thrombin time Fibrinogen to fibrin conversion 10–15 sec beyond neonate; Fibrin split products, DIC, 12–17 sec in term neonate hypofibrinogenemia, heparin, uremia Bleeding time Hemostasis, capillary and platelet 3–7 min beyond neonate Platelet dysfunction, thrombocytopenia, von function Willebrand disease, aspirin Platelet count Platelet number 150,000–450,000/mL Thrombocytopenia differential diagnosis (see Fig. 151-4) von Willebrand disease. The PFA has variable sensitivity and specificity for common bleeding disorders. No single laboratory test can screen for all bleeding disorders. The findings on screening tests for bleeding vary with the specific disorder (Table 151-2). From Scott JP: Bleeding and thrombosis. In Kliegman RM, editor: Practical Strategies in Pediatric Diagnosis and Therapy, Philadelphia, 1996, WB Saunders. Disorders of Platelets Available @ StudentConsult.com


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Pediatrics_Nelson. Platelet counts less than 150,000/mm3 constitute thrombocytopenia. Mucocutaneous bleeding is the hallmark of platelet disorders, including thrombocytopenia. The risk of bleeding correlates imperfectly with the platelet count. Children with platelet counts greater than 80,000/mm3 are able to withstand all but the most extreme hemostatic challenges, such as surgery or major trauma. Children with platelet counts less than 20,000/mm3 are at risk for spontaneous bleeding. These generalizations are modified by factors such as the age of the platelets (young, large platelets usually function better than old ones) and the presence of inhibitors of platelet function, such as antibodies, drugs (especially aspirin), fibrin degradation products, and toxins formed in the presence of hepatic or renal disease. The size of platelets is routinely measured as the mean platelet volume (MPV). The etiology of thrombocytopenia (Fig. 151-4) may be organized into three mechanisms: 1. 2. 3.


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Pediatrics_Nelson. 2. 3. Primary disorders of megakaryopoiesis (platelet production)are rare in childhood, other than as part of an aplastic syndrome. Thrombocytopenia with absent radii syndromeis characterized by severe thrombocytopenia in association with orthopedic abnormalities, especially of the upper DIC, Disseminated intravascular coagulation; PFA, platelet function analyzer-100; RBC, red blood cell. extremity. The thrombocytopenia usually improves over time.Amegakaryocytic thrombocytopenia presents at birth or shortly thereafter with findings of severe thrombocytopenia,but no other congenital anomalies. The marrow is devoid ofmegakaryocytes and usually progresses to aplasia of all hematopoietic cell lines.


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Pediatrics_Nelson. Acquired thrombocytopenia as a result of decreased production is rarely an isolated finding. It is seen more often inthe context of pancytopenia resulting from bone marrow failure caused by infiltrative or aplastic processes. Certain chemotherapeutic agents may affect megakaryocytes selectively ITP 2 to SLE, HIV Drug-induced


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Pediatrics_Nelson. Figure 151-4 Differential diagnosis of childhood thrombocytopenic syndromes. The syndromes initially are separated by their clinical appearances. Clues leading to the diagnosis are presented in italics. The mechanisms and common disorders leading to these findings are shown in the lower part of the figure. Disorders that commonly affect neonates are listed in the shaded boxes. HSM, Hepatosplenomegaly; ITP, idiopathic immune thrombocytopenic purpura; NATP, neonatal alloimmune thrombocytopenic purpura; SLE, systemic lupus erythematosus; TAR, thrombocytopenia with absence of radius (syndrome); TTP, thrombotic thrombocytopenic purpura; UAC, umbilical artery catheter; WBC, white blood cell. (From Scott JP: Bleeding and thrombosis. In Kliegman RM, Greenbaum LA, Lye PS, editors: Practical Strategies in Pediatric Diagnosis and Therapy, Philadelphia, 2004, Saunders, p 920.) more than other marrow elements. Cyanotic congenital heart disease with polycythemia often is associated with


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Pediatrics_Nelson. Strategies in Pediatric Diagnosis and Therapy, Philadelphia, 2004, Saunders, p 920.) more than other marrow elements. Cyanotic congenital heart disease with polycythemia often is associated with thrombocytopenia, but this is rarely severe or associated with significant clinical bleeding. Congenital (TORCH [toxoplasmosis,other agents, rubella, cytomegalovirus, herpes simplex]) andacquired viral infections (human immunodeficiency virus[HIV], Epstein-Barr virus, and measles) and some drugs (anticonvulsants, antibiotics, cytotoxic agents, heparin, and quinidine) may induce thrombocytopenia. Postnatal infections anddrug reactions usually cause transient thrombocytopenia,whereas congenital infections may produce prolonged suppression of bone marrow function.


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Pediatrics_Nelson. Etiology. In a child who appears well, immune-mediated mechanisms are the most common cause of thrombocytopeniaresulting from rapid peripheral destruction of antibody-coatedplatelets by reticuloendothelial cells. Neonatal alloimmune thrombocytopenic purpura (NATP) occurs as a result of sensitization of the mother to antigens present on fetal platelets. Antibodies cross the placenta and attack the fetal platelet (see Chapter 59). Many platelet alloantigens have been identified and sequenced, permitting prenatal diagnosis of the condition in an at-risk fetus. Mothers with idiopathic thrombocytopenic purpura (maternal ITP) or with a history of ITP may have passive transfer of antiplatelet antibodies, with resultant neonatal thrombocytopenia (see Chapter 59). The maternal platelet count is sometimes a useful indicator of the probability that the infant will be affected.


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Pediatrics_Nelson. Clinical Manifestations. The infant with NATP is at risk for intracranial hemorrhage in utero and during the immediate delivery process. In ITP, the greatest risk seems to be present during passage through the birth canal, during which molding of the head may induce intracranial hemorrhage. Fetal scalp sampling or percutaneous umbilical blood sampling may be performed to measure the fetal platelet count. Treatment. Administration of intravenous immunoglobulin (IVIG) before delivery increases fetal platelet counts and may alleviate thrombocytopenia in infants with NATP and ITP. Delivery by cesarean section is recommended to prevent central nervous system (CNS) bleeding (see Chapter 59). Neonates with severe thrombocytopenia (platelet counts <20,000/mm3) may be treated with IVIG or corticosteroids or both until thrombocytopenia remits. If necessary, infants with NATP may receive washed maternal platelets.


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Pediatrics_Nelson. Etiology. Autoimmune thrombocytopenic purpura of childhood (childhood ITP) is a common disorder that usually follows an acute viral infection. Childhood ITP is caused by an antibody (IgG or IgM) that binds to the platelet membrane. The condition results in Fc receptor–mediated splenic destruction of antibody-coated platelets. Rarely, ITP may be the presenting symptom of an autoimmune disease, such as systemic lupus erythematosus (SLE). Clinical Manifestations. Young children typically exhibit ITP 1 to 4 weeks after viral illness, with abrupt onset of petechiae, purpura, and epistaxis. The thrombocytopenia usually is severe. Significant adenopathy or hepatosplenomegaly is unusual, and the red blood cell (RBC) and white blood cell (WBC) counts are normal.


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Pediatrics_Nelson. Diagnosis. The diagnosis of ITP usually is based on clinical presentation and the platelet count and does not often require a bone marrow examination. If atypical findings are noted, however, marrow examination is indicated to rule out an infiltrative disorder (leukemia) or an aplastic process (aplastic anemia). In ITP, an examination of the bone marrow reveals increased megakaryocytes and normal erythroid and myeloid elements.


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Pediatrics_Nelson. Treatment and Prognosis. Therapy is seldom indicated for platelet counts greater than 30,000/mm3. Therapy does not affect the long-term outcome of ITP but is intended to increase the platelet count acutely. For moderate and severe clinical bleeding with severe thrombocytopenia (platelet count <10,000/mm3), therapeutic options include prednisone, 2 to 4 mg/kg/24 hours for 2 weeks or IVIG, 1 g/kg/24 hours for 1 to 2 days. All of these approaches seem to decrease the rate of clearance of sensitized platelets, rather than decreasing production of antibody. The optimal choice for therapy (if any) is controversial. Splenectomy is indicated in acute ITP only for life-threatening bleeding. Approximately 80% of children have a spontaneous resolution of ITP within 6 months after diagnosis. Serious bleeding, especially intracranial bleeding, occurs in fewer than 1% of patients with ITP. There is no evidence that early treatment prevents intracranial bleeding.


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Pediatrics_Nelson. ITP that persists for 6 to 12 months is classified as chronic ITP. Repeated treatments with IVIG, IV anti-D, or high-dose pulse steroids are effective in delaying the need for splenectomy. Secondary causes of chronic ITP, especially SLE and HIV infection, should be ruled out. Splenectomy induces a remission in 70% to 80% of childhood chronic ITP cases. The risks of splenectomy (surgery, sepsis from encapsulated bacteria, pulmonary hypertension) must be weighed against the risk of severe bleeding. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Wiskott-Aldrich syndrome is an X-linked disorder characterized by hypogammaglobinemia, eczema, and thrombocytopenia caused by a molecular defect in a cytoskeletal proteincommon to lymphocytes and platelets (see Chapter 74). Smallplatelets are seen on a peripheral blood smear. Nevertheless,thrombocytopenia often is improved by splenectomy. Hematopoietic stem cell transplantation cures the immunodeficiencyand thrombocytopenia. Familial X-linked thrombocytopeniacan be seen as a variant of Wiskott-Aldrich syndrome or amutation in the GATA1 gene. Autosomal macrothrombocytopenia is due to deletions in chromosomes 22q11 or mutationsin 22q12.


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Pediatrics_Nelson. Thrombotic microangiopathy causes thrombocytopenia, anemia secondary to intravascular RBC destruction, and, in some cases, depletion of clotting factors. Children with thrombotic microangiopathy usually are quite ill. In a child with disseminated intravascular coagulation (DIC), the deposition of fibrin strands within the vasculature and activation of thrombin and plasmin result in a wide-ranging hemostatic disorder with activation and clearance of platelets. Hemolytic uremic syndrome occurs as a result of exposure to a toxin that induces endothelial injury, fibrin deposition, and platelet activation and clearance (see Chapter 164). In thrombotic thrombocytopenic purpura, platelet consumption, precipitated by a congenital or acquired deficiency of a metalloproteinase that cleaves von Willebrand factor, seems to be the primary process, with a modest deposition of fibrin and RBC destruction. Disorders of Platelet Function


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Pediatrics_Nelson. Disorders of Platelet Function Etiology. Primary disorders of platelet function may involvereceptors on platelet membranes for adhesive proteins. Deficiency of glycoprotein Ib complex (vWF receptor) causesBernard-Soulier syndrome. A deficiency of glycoprotein IIb-IIIa (the fibrinogen receptor) causes Glanzmann thrombasthenia. Mild abnormalities of platelet aggregation and release,detectable by platelet aggregometry, are far more common.Secondary disorders caused by toxins and drugs (uremia, valproic acid, aspirin, nonsteroidal anti-inflammatory drugs, andinfections) may cause a broad spectrum of platelet dysfunction.


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Pediatrics_Nelson. Clinical Manifestations. Disorders of platelet function present with mucocutaneous bleeding and a prolonged bleeding time or long PFA closure time and may be primary or secondary. The bleeding time is an insensitive screen for mild and moderate platelet function disorders but is usually prolonged in severe platelet function disorders, such as Bernard-Soulier syndrome or Glanzmann thrombasthenia. Disorders of Clotting Factors Available @ StudentConsult.com


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Pediatrics_Nelson. Disorders of Clotting Factors Available @ StudentConsult.com Etiology. Hereditary deficiencies of most procoagulant proteins lead to bleeding. The genes for factor 8 and factor 9are on the X chromosome, whereas virtually all the otherclotting factors are coded on autosomal chromosomes. Factor 8 and factor 9 deficiencies are the most common severe inherited bleeding disorders. von Willebrand disease is the most common congenital bleeding disorder. Of the procoagulant proteins, low levels of the so-called contact factors(prekallikrein, high-molecular-weight kininogen, and Hageman factor [factor 12]) cause a prolonged activated partialthromboplastin time but are not associated with a predisposition to bleeding.


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Pediatrics_Nelson. Etiology. Hemophilia A (factor 8 deficiency) occurs in 1 in 5000 males. Hemophilia B (factor 9 deficiency) occurs in approximately 1 in 25,000. Clinically the two disorders are indistinguishable other than by their therapy (Table 151-3).The lack of factor 8 or factor 9 delays the generation of thrombin, which is crucial to forming a normal, functional fibrin clot and solidifying the platelet plug that has formed in areas of vascular injury. The severity of the disorder is determined by the degree of clotting factor deficiency. Table 151-3 Comparison of Hemophilia A, Hemophilia B, and von Willebrand Disease FEATURE HEMOPHILIA A HEMOPHILIA B VON WILLEBRAND DISEASE Inheritance X-linked X-linked Autosomal dominant Factor deficiency Factor 8 Factor 9 vWF, factor 8 Bleeding site(s) Muscle, joint, Muscle, joint, Mucous membranes, skin, surgical surgical surgical, menstrual Ristocetin-induced platelet Normal Normal Normal, low, or increased at agglutination


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Pediatrics_Nelson. Bleeding site(s) Muscle, joint, Muscle, joint, Mucous membranes, skin, surgical surgical surgical, menstrual Ristocetin-induced platelet Normal Normal Normal, low, or increased at agglutination PFA, Platelet function analyzer-100; vWF, von Willebrand factor. *Desmopressin (DDAVP) for mild to moderate hemophilia A or type 1 von Willebrand disease.


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Pediatrics_Nelson. PFA, Platelet function analyzer-100; vWF, von Willebrand factor. *Desmopressin (DDAVP) for mild to moderate hemophilia A or type 1 von Willebrand disease. Clinical Manifestations. Patients with less than 1% (severehemophilia) factor 8 or factor 9 may have spontaneous bleeding or bleeding with minor trauma. Patients with 1% to 5% (moderate hemophilia) factor 8 or factor 9 usually require moderatetrauma to induce bleeding episodes. In mild hemophilia (>5%factor 8 or factor 9), significant trauma is necessary to inducebleeding; spontaneous bleeding does not occur. Mild hemophiliamay go undiagnosed for many years, whereas severe hemophiliamanifests in infancy when the child reaches the toddler stage. Insevere hemophilia, spontaneous bleeding occurs, usually in themuscles or joints (hemarthroses).


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Pediatrics_Nelson. Laboratory Studies. The diagnosis of hemophilia is based on a prolonged activated partial thromboplastin time(aPTT). In the aPTT, a surface-active agent activates the intrinsic system of coagulation, of which factors 8 and 9 are crucial components. In factor 8 or factor 9 deficiency, the aPTT is quite prolonged but should correct to normal when the patient’s plasma is mixed 1:1 with normal plasma. When an abnormal aPTT is obtained, specific factor assays are needed to make a precise diagnosis (see Table 151-2) to determine the appropriate factor replacement therapy. Prenatal diagnosis and carrier diagnosis are possible using molecular techniques.


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Pediatrics_Nelson. Treatment. Early, appropriate replacement therapy is the hallmark of excellent hemophilia care. Acute bleeding episodes are best treated in the home when the patient has attained the appropriate age and the parents have learned home treatment. Bleeding associated with surgery, trauma, or dental extraction often can be anticipated, and excessive bleeding can be prevented with appropriate replacement therapy. Prophylactic therapy starting in infancy has greatly diminished the likelihood of chronic arthropathy in children with hemophilia. For life-threatening bleeding, levels of 80% to 100% of normal factor 8 or factor 9 are necessary. For mild to moderate bleeding episodes (hemarthroses), a 40% level for factor 8 or a 30% to 40% level for factor 9 is appropriate. The dose can be calculated using the knowledge that 1 U/kg body weight of factor 8 increases the plasma level 2%, whereas 1.5 U/kg of recombinant factor 9 increases the plasma level 1%:


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Pediatrics_Nelson. Dose for factor 8=desired level (%)× weight (kg)× 0.5 Dose for recombinant factor 9=desired level (%) × weight (kg) ×1.5 Desmopressin acetate is a synthetic vasopressin analog with minimal vasopressor effect. Desmopressin triples or quadruples the initial factor 8 level of a patient with mild or moderate (not severe) hemophilia A, but has no effect on factor 9 levels. When adequate hemostatic levels can be attained, desmopressin is the treatment of choice for individuals with mild and moderate hemophilia A. Aminocaproic acid is an inhibitor of fibrinolysis that may be useful for oral bleeding.


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Pediatrics_Nelson. Patients treated with older factor 8 or 9 concentrates derived from large pools of plasma donors were at high risk for hepatitis B, C, and D and HIV. Recombinant factor 8 and factor 9 concentrates are safe from virally transmitted illnesses. Acquiredimmunodeficiency syndrome (AIDS) is the most common causeof death in older hemophilia patients (who received plasma-derived factors). Many older patients also have chronic hepatitis C.


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Pediatrics_Nelson. Inhibitors are IgG antibodies directed against transfusedfactor 8 or factor 9 in congenitally deficient patients. Inhibitorsarise in 15% of severe factor 8 hemophiliacs but are less common in factor 9 hemophiliacs. They may be high or low titerand show an anamnestic response to treatment. The treatmentof bleeding patients with an inhibitor is difficult. For low titerinhibitors, options include continuous factor 8 infusions. Forhigh titer inhibitors, it is usually necessary to administer a product that bypasses the inhibitor, preferably recombinant factor 7a.Activated prothrombin complex concentrates, used in the pastto treat inhibitor patients, paradoxically increased the risks ofthrombosis, resulting in fatal complications, such as myocardial infarction. For long-term treatment of inhibitor patients, induction of immune tolerance by repeated infusion of the deficientfactor with or without immunosuppression may be beneficial.


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Pediatrics_Nelson. Early institution of factor replacement and continuous prophylaxis beginning in early childhood should prevent the chronic joint disease associated with hemophilia. Etiology. Von Willebrand disease is a common disorder (1% ofthe population) caused by a deficiency of vWF, an adhesive protein that serves two functions: acting as a bridge between sub-endothelial collagen and platelets and binding and protectingcirculating factor 8 from rapid clearance from circulation. Von Willebrand disease usually is inherited as an autosomal dominanttrait and rarely as an autosomal recessive trait. vWF may be eitherquantitatively deficient (partial = type 1 or absolute = type 3) orqualitatively abnormal (type 2 = dysproteinemia). Approximately80% of patients with von Willebrand disease have classic (type 1)disease (i.e., a mild to moderate deficiency of vWF). Several othersubtypes are clinically important, each requiring different therapy.


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Pediatrics_Nelson. Clinical Manifestations. Mucocutaneous bleeding, epistaxis, gingival bleeding, cutaneous bruising, and menorrhagia occur in patients with von Willebrand disease. In severe disease, factor 8 deficiency may be profound, and the patient may also have manifestations similar to hemophilia A (hemarthrosis). Findings in classic von Willebrand disease differ from findings in hemophilia A and B (see Table 151-3). Laboratory Testing. vWF testing involves measurement ofthe amount of protein, usually measured immunologically as thevWF antigen (vWF:Ag). vWF activity (vWF:Act) is measuredfunctionally in the ristocetin cofactor assay (vWFR:Co), whichuses the antibiotic ristocetin to induce vWF to bind to platelets.


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Pediatrics_Nelson. Treatment. The treatment of von Willebrand disease depends on the severity of bleeding. Desmopressin is the treatment of choice for most bleeding episodes in patients with type 1 disease and some patients with type 2 disease. When high levels of vWF are needed but cannot be achieved satisfactorily with desmopressin, treatment with a virally attenuated, vWF-containing concentrate (Humate P) may be appropriate. The dosage can be calculated as for factor 8 in hemophilia. Cryoprecipitate should not be used because it is not virally attenuated. Hepatitis B vaccine should be given before the patient is exposed to plasma-derived products. As in all bleeding disorders, aspirin should be avoided. For discussion of vitamin K deficiency, see Chapters 27 and 31. Available @ StudentConsult.com


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Pediatrics_Nelson. For discussion of vitamin K deficiency, see Chapters 27 and 31. Available @ StudentConsult.com Etiology. Disseminated intravascular coagulation (DIC) is a disorder in which widespread activation of the coagulation mechanism is usually associated with shock. Normal hemostasis is a balance between hemorrhage and thrombosis. In DIC, Meningococcemia (purpura fulminans) Other gram-negative bacteria (Haemophilus, Salmonella, Escherichia coli) Rickettsiae (Rocky Mountain spotted fever) Virus (cytomegalovirus, herpes, hemorrhagic fevers) Malaria Fungus Central nervous system trauma (massive head injury) Multiple fractures with fat emboli Crush injury Profound shock or asphyxia Hypothermia or hyperthermia Massive burns Maternal toxemia Group B streptococcal infections Abruptio placentae Severe respiratory distress syndrome Necrotizing enterocolitis Congenital viral disease (e.g., cytomegalovirus infection or herpes) Erythroblastosis fetalis


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Pediatrics_Nelson. Severe acute graft rejection Acute hemolytic transfusion reaction Severe collagen vascular disease Kawasaki disease Heparin-induced thrombosis Infusion of “activated” prothrombin complex concentrates Hyperpyrexia/encephalopathy, hemorrhagic shock syndrome From Scott JP: Bleeding and thrombosis. In Kliegman RM, editor: Practical Strategies in Pediatric Diagnosis and Therapy, Philadelphia, 1996, WB Saunders. this balance is altered by the severe illness, so the patient has activation of coagulation (thrombosis) mediated by thrombin and fibrinolysis mediated by plasmin (bleeding). Coagulation factors—especially platelets, fibrinogen, and factors 2, 5, and 8—are consumed, as are the anticoagulant proteins, especially antithrombin, protein C, and plasminogen. Endothelial injury, tissue release of thromboplastic procoagulant factors, or, rarely, exogenous factors (snake venoms) directly activate the coagulation mechanism (Table 151-4).


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Pediatrics_Nelson. Differential Diagnosis of Coagulopathies That Can Be Confused with Disseminated Intravascular Coagulation Vitamin K deficiency ↑↑ Normal Normal Normal Malabsorption, liver disease From Scott JP: Bleeding and thrombosis. In Kliegman RM, editor: Practical Strategies in Pediatric Diagnosis and Therapy, Philadelphia, 1996, WB Saunders. DIC, Disseminated intravascular coagulation. Clinical Manifestations. The diagnosis of DIC usually is suspected clinically and is confirmed by laboratory findings of Thrombomodulin a decline in platelets and fibrinogen associated with elevated Thrombin prothrombin time, partial thromboplastin time, and elevated levels of D-dimer, formed when fibrinogen is clotted and then Protein Ca degraded by plasmin (Table 151-5). In some patients, DIC may evolve more slowly and there may be a degree of compensation. S


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Pediatrics_Nelson. In a severely ill patient, the sudden occurrence of bleeding from a venipuncture or incision site, gastrointestinal or pulmonary hemorrhage, petechiae, or ecchymosis or evidence of periph-V T: AT III Fibrin eral gangrene or thrombosis suggests the diagnosis of DIC. Treatment. The treatment of DIC is challenging. General guidelines include the following: treat the disorder inducing the DIC first; support the patient by correcting hypoxia, acidosis, and poor perfusion; and replace depleted blood-clotting factors, platelets, and anticoagulant proteins by transfusion. Heparin may be used to treat significant arterial or venous thrombotic disease unless sites of life-threatening bleeding coexist.


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Pediatrics_Nelson. Etiology. A hereditary predisposition to thrombosis (see Table 151-1) may be caused by a deficiency of an anticoagulant protein (protein C or S, antithrombin, or plasminogen) (Fig. 151-5), by an abnormality of a procoagulant protein making it resistant to proteolysis by its respective inhibitor (factor 5 Leiden), by a mutation resulting in an increased level of a procoagulant protein (prothrombin 20210), or by damage to endothelial cells (homocysteinemia). Neonates with deficiency syndromes may be particularly vulnerable to thrombosis. Neonates with homozygous protein C deficiency present with purpura fulminans or thrombosis of the major arteries and veins or both. Many individuals with an inherited predisposition to thrombosis exhibit symptoms in adolescence or early adulthood. Protein C deficiency presenting in adulthood usually is inherited as an autosomal dominant trait, whereas the homozygous form usually is autosomal recessive. Protein S and antithrombin III deficiencies are


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Pediatrics_Nelson. C deficiency presenting in adulthood usually is inherited as an autosomal dominant trait, whereas the homozygous form usually is autosomal recessive. Protein S and antithrombin III deficiencies are inherited as autosomal dominant traits. Factor 5 Leiden is the most common hereditary cause of a predisposition to thrombosis, appearing in 3% to 5% of whites. Acquired antiphospholipid antibodies (anticardiolipin and lupus anticoagulant) also predispose to thrombosis.


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Pediatrics_Nelson. Clinical Manifestations. Neonates and adolescents are the most likely pediatric patients to present with thromboembolic disease. Indwelling catheters, vasculitis, sepsis, immobilization, nephrotic syndrome, coagulopathy, trauma, infection, surgery, inflammatory bowel disease, oral contraceptive agents, pregnancy, and abortion all predispose to thrombosis. Figure 151-5 Formation of the hemostatic plug at the site of vascular injury. Three major physiologic anticoagulant mechanisms— antithrombin III (AT III), protein C, and the fibrinolytic system—are activated to limit clot formation to the site of damage and to prevent generalized thrombosis. T, Thrombin. (From Schafer A: The hypercoagulable state, Ann Intern Med 102:814–828, 1985.) The manifestations of pulmonary emboli vary from no findings to chest pain, diminished breath sounds, a loud S2, cyanosis, tachypnea, and hypoxemia.


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Pediatrics_Nelson. The manifestations of pulmonary emboli vary from no findings to chest pain, diminished breath sounds, a loud S2, cyanosis, tachypnea, and hypoxemia. Diagnostic and Imaging Studies. Venous thrombosis can be detected noninvasively by ultrasound Doppler flow compression studies. The gold standard for diagnosis is the venogram. An abnormal (high probability) ventilation-perfusion scan or detection of an intravascular thrombus on helical computed tomography (CT) is diagnostic of pulmonary emboli. There are no appropriate screening studies for thrombotic disorders. Diagnosis of a congenital or acquired predisposition to thrombosis requires a battery of specific assays.


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Pediatrics_Nelson. Treatment. Therapy of thrombotic disorders depends on the underlying condition and usually involves standard or low-molecular-weight heparin and then longer term anticoagulation with warfarin. Major vessel thrombosis or life-threatening thrombosis may necessitate treatment with fibrinolytic agents (recombinant tissue plasminogen activator). In newborns, inherited deficiency syndromes may present as emergencies and necessitate replacement with plasma, antithrombin III concentrates, or protein C concentrates.


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Pediatrics_Nelson. Transfusion of red blood cells (RBCs), platelets, plasma,cryoprecipitate, and granulocytes can be life-saving orlife-maintaining (Table 152-1). Whole blood is rarely indicated and is most useful to provide both oxygen-carryingcapacity and functional procoagulant and anticoagulant factors. Otherwise, packed RBCs are used to treat anemia to increase oxygen-carrying capacity. RBC transfusions shouldnot be used to treat asymptomatic nutritional deficienciesthat can be corrected by administering the appropriate deficient nutrient (iron or folic acid).


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Pediatrics_Nelson. Blood component therapy requires proper anticoagulation of the component unit, screening for infectious agents and blood group compatibility testing before administration. Typical transfusion reactions are listed in Table 152-2. Transfusion may also result in circulatory overload, especially in the presence of cardiopulmonary deficiency. Filtering of blood products to remove white blood cells (WBCs) may prevent febrile reactions. Long-term complications of transfusions bleeding 50,000/μL 30,000-50,000/μL Cryoprecipitate Fibrinogen, factor 8, Hypofibrinogenemia, factor 1 unit/5-10 kg ↑ Fibrinogen by 50–100 mg/dL vWF, factor 13 13 deficiency Recombinant factor Units as labeled Hemophilic bleeding or F8: 20–50 units/kg F8: ↑ 2%/unit/kg concentrates prophylaxis F9: 40–120 units/kg F9: ↑ 0.7 unit/kg Hgb, Hemoglobin; RBCs, red blood cells; vWF, von Willebrand factor.


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Pediatrics_Nelson. Hgb, Hemoglobin; RBCs, red blood cells; vWF, von Willebrand factor. Acute hemolytic transfusion Acute shock, back pain, flushing, early fever, 1. Stop transfusion; return blood to bank with reaction (incidence of 1:250,000 to intravascular hemolysis, hemoglobinemia, fresh sample of patient’s blood 1:1,000,000) hemoglobinuria (may be delayed 5–10 days and 2. Hydrate intravenously*; support blood less severe if anamnestic response is present) pressure, maintain high urine flow, alkalinize urine 3. Check for and correct electrolyte abnormalities (hyperkalemia) Allergic transfusion reaction (incidence of 1:100) Urticaria, pruritus, maculopapular rash, edema, respiratory distress, hypotension during or within 4 hours of transfusion; often because recipient has preformed antibodies against donor antigens, occasionally from passive infusion of antibodies from atopic donor Diphenhydramine ± hydrocortisone for acute management For future transfusions consider: 1.