Relación entre algunas variables y el género

In general, normocytic anemias that are nonresponsive to supplemental iron and not clearly associated with a systemic illness warrant referral to a pediatric hematologist. A reticulocyte count and review of the peripheral blood smear are indicated for every child with normocytic anemia referred to a hematologist. Th e smear may help identify morphologic features to aid in the diagnosis (eg, spherocytosis, sickle cells) or reveal evidence of hemolysis (schistocytes, RBC fragments).

Th e percentage reticulocyte count must be considered within the context of the patient’s hemoglobin level and hematocrit. A high percentage reticulocyte count is expected in a child who can mount an appropriate response to anemia. An apparently normal reticulocyte percentage (1.1%–3.5%) in a child with severe anemia is actually relatively lower than it should be to compensate for the anemia. For this reason, the reticulocyte index is a use- ful calculation: the reticulocyte count multiplied by the ratio represented by the patient’s hematocrit divided by the normal hematocrit.10

A relatively low reticulocyte count (<1%) suggests decreased RBC production. Th e pri- mary care physician must then consider aplastic anemia, malignancy, transient erythroblas- topenia of childhood, and other causes of bone marrow suppression. A bone marrow aspirate and biopsy are rarely indicated but must be considered to rule out malignancy, especially when more than a single blood cell line is abnormal.

An elevated reticulocyte count suggests that the bone marrow is compensating for blood loss either from hemolysis or from hemorrhage. Causes of blood loss must be considered. Patients with an elevated reticulocyte count and an elevated bilirubin level likely have ongo- ing hemolysis. A positive Coombs test (direct antiglobulin test) suggests an autoimmune hemolytic anemia. Without evidence of an autoimmune process, hemoglobinopathies (sickle cell disease and variants and thalassemias) must be evaluated by hemoglobin electrophoresis.

Other specialized assays may defi ne specifi c RBC disorders that result in hemolysis. G6PD defi ciency, which is X-linked, is the most common enzyme defect in males. Many variants have been found, and the assay may be falsely negative in patients with a high reticulocyte count immediately after a hemolytic crisis. Families need to be educated regarding the triggers for hemolysis in G6PD defi ciency, including a variety of medications, infections, exposure to mothballs, and, for some variants, fava beans (favism). A positive osmotic fragility test helps confi rm the diagnosis of hereditary spherocytosis and should be considered in patients with RBC morphology consistent with the diagnosis.18

Macrocytic Anemias

Macrocytic anemias in childhood are extremely rare and are typically the result of defi - ciencies in folate or vitamin B₁₂.1 _{Folate defi ciency can be associated with inborn errors} of metabolism, poor dietary intake, increased utilization in patients with hemolytic ane- mias, malabsorption, and drugs that inhibit folate metabolism (methotrexate). Vitamin B₁₂ defi ciency may be caused by inborn errors of metabolism, poor dietary intake, and malabsorption. In cases of signifi cant defi ciencies, these anemias can be quite severe, with an MCV between 100 and 140 fL. In addition to normochromic macrocytic RBCs, hyper- segmented neutrophils may be visible on the peripheral blood smear. Serum folate and B₁₂ levels may help confi rm the diagnosis, but the underlying cause of the vitamin defi ciency must be determined.

Anemia and Pallor 57

A macrocytic anemia in a child is always concerning for an underlying disorder in bone marrow production. Myelodysplasia, early aplasia, and leukemia may all manifest as mac- rocytosis with or without anemia. In the absence of a clear B₁₂ or folate defi ciency, a referral to a hematologist is warranted for assessment of macrocytosis to rule out myelodysplasia or malignancy.

Anemia of the Newborn

Th e diff erential diagnosis of anemia in a newborn is distinctly diff erent from that in older children. Peripartum hemorrhage and maternal factors, such as alloantibodies, are important in deciphering neonatal anemias. Iron defi ciency in the newborn period is quite rare. Anemias with similar origins may also be displayed diff erently in infants and children.

Table 5-1 lists the normal hematologic parameters for infants and children. Hematologic parameters in children evolve over the fi rst couple of months of life. Typically, a normal hemoglobin level in a term newborn is approximately 19 g/dL. Th e hemoglobin concentra- tion falls gradually to a nadir of 10 to 11 g/dL by 8 to 12 weeks of age. Th is nadir, termed

physiologic anemia of the newborn, is more pronounced in preterm infants with nadirs as

low as 7 to 8 g/dL. Despite the low nadir, transfusions are necessary only if the anemia is uncompensated, although early supplementation with iron is usually indicated.1

When considering the diff erential diagnosis of anemia in newborns, classifying the cause of the anemia into 1 of 3 broad groups is helpful: (1) blood loss, (2) hemolysis, or (3) decreased production.19,20 _{Blood loss may occur at any time during a pregnancy.} Common causes include fetomaternal transfusion, twin-to-twin transfusion, placental abruption, placenta previa, and internal hemorrhage (eg, intraventricular hemorrhage, cephalohematoma, caput succedaneum). Th e Betke-Kleihauer test detects the presence of fetal RBCs in the mother. Fetal cells can be detected in the circulation of 50% of pregnan- cies; however, rarely is the hemorrhage signifi cant enough to cause anemia in the newborn. Mothers who are blood type O with infants who are not type O may have a false-negative Betke-Kleihauer test result.

At least 15% of monochorionic twins develop signifi cant twin-to-twin transfusions, with diff erences in hemoglobin concentrations of 5 g/dL or more. At birth, the donor twin typically is smaller and may have pallor, oligohydramnios, and even shock. Polycythemia, polyhydramnios, and congestive heart failure may be present at birth in the recipient twin.21

Th e clinical manifestation of neonatal anemia from blood loss is dependent on the severity and rapidity of the blood loss. Infants with chronic blood loss throughout pregnancy may have pallor and microcytic, hypochromic anemia but appear otherwise well and hemody- namically stable. Infants with acute blood loss may have pallor, tachypnea, tachycardia, hypotension, and decreased tone. A normocytic, normochromic anemia with a reticulocytosis is detectable soon after birth.19,20

Th e most common cause of hemolytic anemia in the newborn is isoimmune hemolytic anemia caused by an incompatibility in maternal and fetal RBC antigens, including Rh, ABO, and minor blood groups. Mothers who are Rh negative may become immunized against the Rh antigen when pregnant with an Rh-positive fetus. During subsequent preg- nancies, if the fetus is Rh positive, then maternal anti-Rh antibodies will readily cross the placenta and destroy the Rh-positive RBCs in the fetus. In utero and perinatal hemolysis may be rapid and severe, resulting in life-threatening hemolysis and hyperbilirubinemia.

However, with the prenatal administration of Rh immune globulin to Rh-negative mothers, life-threatening Rh incompatibility is rare today. In cases of hemolytic anemia from ABO or minor blood group antigen incompatibility, the mechanism of immunization and hemolysis is similar to Rh incompatibility, but the hemolysis is rarely severe.1 _{Hemolytic anemia in the} newborn may also occur as a result of maternal drug use and neonatal infections, including bacterial sepsis, cytomegalovirus, toxoplasmosis, herpes, and rubella. Microangiopathic hemolysis may occur in infants with thrombi, disseminated intravascular coagulation, and Kasabach-Merritt syndrome (multiple cavernous hemangiomas).

Hemolysis from hemoglobinopathies rarely causes symptomatic anemia in newborns. Anemia from ␤ chain defects (eg, sickle cell disease, ␤-thalassemias) may not appear until later in infancy when the hemoglobin concentration is more dependent on ␤-chain produc- tion. ␣-Th alassemia major will manifest as erythroblastosis fetalis in the newborn period. RBC membrane and enzyme defects may be apparent at birth but more commonly appear later in the newborn period.

RBC production defi ciencies are rare in the newborn period and are typically the result of infection or drugs. Diamond-Blackfan anemia is a rare congenital pure RBC precursor aplasia. However, aff ected patients are typically not anemic until 3 to 12 months of age. Congenital leukemias and osteopetrosis may also result in defi cient RBC production but are also typically associated with disorders in the other cell lines and are extremely rare.

X EVALUATION

Anemia is frequently identifi ed in the fi rst or second year of life and in adolescence on routine screening performed by primary care physicians. By using information obtained from a thorough history and physical examination, as well as results of routine laboratory studies, most causes of anemia can be accurately diagnosed in the primary care physician’s offi ce. Diseases leading to anemia and pallor in infants and children are listed in Table 5-2, Figure 5-1, and Figure 5-2.

History

Many children with anemia are asymptomatic and have their condition diagnosed only on routine screening evaluations. Nonetheless, a thorough history may help identify patients most at risk for developing anemia, as well as help identify the cause of an existing ane- mia. Demographic factors such as age, gender, and ethnicity will identify risk groups for specifi c types of anemia. Toddlers and adolescent girls account for most cases of iron defi ciency anemia. Blacks are at greatest risk for sickle cell anemia, whereas the thalas- semias occur primarily in patients of Mediterranean and Southeast Asian descent. A diet history is crucial in identifying children most likely to develop iron defi ciency anemia. Sulfa drugs can produce a hemolytic anemia in patients with G6PD defi ciency. Many common acute bacterial and viral infections may result in a mild anemia from decreased RBC production or increased RBC destruction, or both. Anemias resulting from such infections are typically short-lived but are commonly the cause of abnormalities identifi ed on routine screening. Acute or chronic blood loss (or both) should be considered in all patients with anemia. Common sites of blood loss in otherwise asymptomatic patients include the gastrointestinal tract for all patients and the genitourinary tract for female

Anemia and Pallor 59

patients. Anemia may be the benign manifestation of an underlying systemic disease such as autoimmune disorders and may be associated with signs of systemic illness (fevers, weight loss, among other signs). Finally, a family history may help guide the workup for a patient with anemia. In addition to a family history of hemoglobinopathies, a history of jaundice during systemic illnesses, cholecystectomy at a young age, or splenectomy may suggest a hereditary hemolytic anemia. Historical factors worthy of note in evaluating an anemic patient are listed in Table 5-3.

Physical Examination

Infants and toddlers may experience fatigue, irritability, pallor, increased periods of sleep, poor feeding, and failure to thrive. Older children and adolescents may experience fatigue, pallor, exercise intolerance, dizziness, headaches, shortness of breath, or palpitations. However, most mild to moderate anemias in childhood are asymptomatic because they develop slowly over time, and patients are usually well compensated. In fact, seeing a child for a routine physical examination only to fi nd out later that routine laboratory studies reveal anemia is not uncommon.

Pallor is the classic physical examination fi nding suggestive of anemia but is rare in mild anemias and frequently only seen reliably with hemoglobin concentrations less than

Table 5-3

Pertinent Historical Factors in the Diagnosis of Childhood Anemia

Age Nutritional anemias are rare in infancy in term infants but are more common in infants born preterm, as well as in school-aged children and adolescents. Signifi - cant anemia diagnosed in the fi rst 6 months of life in a term infant is most likely a congenital anemia.

Gender G6PD is an X-linked disorder. Race and

ethnicity

Hemoglobin S and C are more common among patients of African descent. ␣-Thalassemias are most common in patients of African or Asian ancestry. ␤-Thalassemia syndromes are more common in patients from the Mediterranean. Nutrition Sources of iron, folate, B₁₂, and vitamin E should be documented. A history of pica

suggests iron defi ciency.

Medications Phenytoin and methotrexate can induce a megaloblastic anemia. Oxidants can induce hemolytic anemias.

Family history Document a history of anemia, jaundice, gallstones, cholecystitis, splenomegaly, splenectomy, or hemolytic crisis, which may suggest an inherited hemolytic anemia.

Infection Infections may induce hemolysis or red blood cell hypoplasia or aplasia (parvovirus B19), whereas hepatitis may induce aplastic anemia.

Gastrointestinal The gastrointestinal tract is a common source of blood loss. Nutritional defi cien- cies may result from malabsorption syndromes.

G6PD, glucose-6-phosphate dehydrogenase.

Modifi ed from Nathan DG, Orkin SH. A diagnostic approach to the anemic patient. In: Nathan and Oski’s

Hematology of Infancy and Childhood. 5th Ed. Philadelphia, PA: WB Saunders; 1998. Copyright © 1998,

8 g/dL. Pallor may be more easily identifi ed in the nail beds, mucosa, conjunctiva, and palmar creases than in a cursory examination of the skin. Splenomegaly, scleral icterus, and jaundice in the setting of anemia are highly suggestive of a hemolytic process. In chronic hemolytic anemia such as thalassemia, frontal bossing and maxillary prominence are indica- tive of the marrow expansion necessary to keep pace with ongoing hemolysis. Leukemia or lymphoma may manifest as an anemia associated with focal lymphadenopathy and hepato- splenomegaly. Regardless of the cause of the anemia, a mild to moderate decrease in RBC mass may result in a pulmonary valve fl ow murmur, whereas more severe anemias may be associated with signs and symptoms of congestive heart failure. Compensated anemia usually refers to anemia associated with suffi cient cardiovascular compensation to preserve normal oxygen delivery to tissues. Patients in whom the anemia develops or persists over a long period may have hemoglobin concentrations less than 6 g/dL but no signs or symptoms of anemia other than pallor. Cardiac stroke volume is increased, allowing patients to maintain normal oxygen delivery to tissues with normal or near-normal heart rates. Patients who lose blood more rapidly, from hemolysis or hemorrhage, may not have time for compensatory mechanisms to maintain tissue perfusion and oxygenation. Tachycardia is an early sign, followed by orthostasis, headache, dizziness, and hypotension, all of which are reasons to hospitalize a patient with anemia.

Laboratory Findings

In addition to a determination of the hemoglobin level and hematocrit, which may be done exclusively in some practice settings, RBC morphology and reticulocyte count should be assessed. Anemias may be classifi ed by RBC size as determined by the MCV and by RBC production as determined by the reticulocyte count. An elevated reticulocyte count implies bone marrow compensation for chronic blood loss or hemolysis, whereas a low reticulocyte count may suggest impaired RBC production or acute blood loss. Although not necessary in the initial diagnosis of all patients with anemia, iron studies may be performed and erythrocyte sedimentation rate, serum bilirubin, and serum lactate dehydro- genase levels may be assessed easily in most practice settings and may provide clues to the cause of the anemia. Th e mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are generally of minimal value in the classifi cation and diagnosis of an anemia. Changes in the MCH typically parallel changes in the MCV. Th e MCHC is a measure of RBC hydration status. Higher MCHC values (>35/dL) are seen in dehydrated red cells associated with spherocytosis, and low MCHC values may be seen in iron defi ciency.

X TREATMENT

Treatment of a compensated anemia will be dictated by the cause of the anemia. Patients with uncompensated anemia should be admitted to the hospital for observation and possible transfusion. Eff ective treatment of the anemia is best accomplished by treating the underly- ing disorder. A substantial number of patients with a microcytic anemia or a normocytic anemia have early iron defi ciency anemia, and a course of supplemental iron is appropriate. However, for patients with anemia that is nonresponsive to nutritional supplements and not clearly related to a systemic illness, referral to a pediatric hematologist is warranted. Referral to a pediatric oncologist is also warranted for management of most macrocytic anemias

Anemia and Pallor 61

that are not related to nutritional defi ciencies. Specifi c treatment will be predicated on the underlying hematologic disorder.

When to Refer

• Hemoglobin level less than 8 g/dL or hematocrit less than 25% • Anemia of unknown origin

• Anemia is associated with disorder in white blood cells or platelets

• Diagnosis of hemoglobinopathy or RBC membrane defect is suspected or confi rmed

When to Admit

• Profound anemia (hemoglobin level <5)

• Uncompensated anemia or anemia associated with a rapidly dropping hemoglobin level • Anemia in an ill child

TOOLS FOR PRACTICE

Engaging Patient and Family

• Anemia and Your Young Child (handout), American Academy of Pediatrics (patiented.

solutions.aap.org)

• Iron and Iron Defi ciency (fact sheet), Centers for Disease Control and Prevention (www.

cdc.gov/nccdphp/dnpa/nutrition/nutrition_for_everyone/iron_defi ciency/index.htm)

Medical Decision Support

• Pediatric Nutrition Handbook, 7th ed (book), American Academy of Pediatrics (shop.

aap.org), pp 403–417

REFERENCES

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2. d’Onfrio G, Chirillo R, Zini G, et al. Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia. Blood.

1995;85:818–823

3. Dallman PR, Yip R, Johnson C. Prevalence and causes of anemia in the United States. Am J Clin Nutr.

1984;49:437–445

4. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. 3rd ed. Oxford, UK: Blackwell Scientific

Publications; 1981

5. Higgs DR, Vickers MA, Wilkie AO, et al. A review of the molecular genetics of the human alpha-globin gene cluster. Blood. 1989;73:1081–1104

6. Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med. 2011;13:83–88

7. Piomelli S, Seaman C, Zullow D, Curran A, Davidow B. Th reshold for lead damage to heme synthesis in urban children. Proc Natl Acad Sci U S A. 1982;79:3335–3339

8. Lanzkowsky P. Classifi cation and diagnosis of anemia during childhood. In: Manual of Pediatric Hematology and Oncology. 4th ed. Burlington, MA: Elsevier Academic Press; 2005

9. Brill JR, Baumgardner DJ. Normocytic anemia. Am Fam Physician. 2000;62:2255–2264

10. Perkins SL. Pediatric red cell disorders and pure red cell aplasia. Am J Clin Pathol. 2004;122

(Suppl):S70–S86

11. Mupanomunda OK, Alter BP. Transient erythroblastopenia of childhood (TEC) presenting as leuko- erythroblastic anemia. J Pediatr Hematol Oncol. 1997;19:165–167

12. Gerrits GP, van Oostrom CG, de Vaan GA, Bakkeren JA. Transient erythroblastopenia of childhood. A review of 22 cases. Eur J Pediatr. 1984;142:266–270

13. Irwin JJ, Kirchner JT. Anemia in children. Am Fam Physician. 2001;64:1379–1386

14. Prchal JT, Gregg XT. Red cell enzymes. Hematology Am Soc Hematol Educ Program. 2005;19–23

15. Carreiro-Lewandowski E. Newborn screening: an overview. Clin Lab Sci. 2002;15:229–238

16. Abshire TC. Th e anemia of infl ammation. A common cause of childhood anemia. Pediatr Clin North Am. 1996;43(3):623–637

17. Christensen RD, Hunter DD, Goodell H, Rothstein G. Evaluation of the mechanism causing anemia in infants with bronchopulmonary dysplasia. J Pediatr. 1992;120:593–598

18. Deters A, Kulozik AE. Hemolytic anemia. In: Sills RH, ed. Practical Algorithms in Pediatric Hematology and Oncology. Basel, Switzerland: S. Kargar AG; 2003

19. Lubin B, Vichinsky E. Anemia in the newborn period. Pediatr Ann. 1979;8:416–434

20. Oski FA, Naiman JL. Hematologic Problems of the Newborn. 3rd ed. Philadelphia, PA: WB Saunders; 1982

63

Chapter 6

Anxiety