the anemias

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Chapter 441

The AnemiasNorma B. Lerner

Anemia is dened as a reduction of the hemoglobin concentra-tion or red blood cell (RBC) volume below the range of valuesoccurring in healthy persons. Normal hemoglobin and hema-tocrit (packed red cell volume) vary substantially with age andsex (Table 441-1). There are also racial differences, with signi-cantly lower hemoglobin levels in African-American children

than in white non-Hispanic children of comparable age(Table 441-2).Physiologic adjustments to anemia include increased cardiac

output, augmented oxygen extraction (increased arteriovenousoxygen difference), and a shunting of blood ow toward vitalorgans and tissues. In addition, the concentration of 2,3-diphos-phoglycerate (2,3-DPG) increases within the RBC. The resultantshift to the right of the oxygen dissociation curve reducesthe afnity of hemoglobin for oxygen and results in more com-plete transfer of oxygen to the tissues. (The same shift in theoxygen dissociation curve can also occur at high altitude.)Higher levels of erythropoietin (EPO) and consequent increasedred cell production by the bone marrow further assist the bodyto adapt.

Table 441-1 NORMAL MEAN AND LOWER LIMITS OF NORMAL FORHEMOGLOBIN, HEMATOCRIT, AND MEAN CORPUSCULAR VOLUME

AGE (YR)

HEMOGLOBIN(G/DL) HEMATOCRIT (%)

MEANCORPUSCULARVOLUME (M3)

MeanLowerLimit

MeanLowerLimit

MeanLowerLimit

0.5-1.9 12.5 11.0 37 33 77 70

2-4 12.5 11.0 38 34 79 73

5-7 13.0 11.5 39 35 81 75

8-11 13.5 12.0 40 36 83 76

12-14 female 13.5 12.0 41 36 85 78

12-14 male 14.0 12.5 43 37 84 7715-17 female 14.0 12.0 41 36 87 79

15-17 male 15.0 13.0 46 38 86 78

18-49 female 14.0 12.0 42 37 90 80

18-49 male 16.0 14.0 47 40 90 80

From Brugnara C, Oski FJ, Nathan DG: Nathan and Oskis hematology of infancy and childhood,ed 7, Philadelphia, 2009, WB Saunders, p 456.

Table 441-2 NHANES III HEMOGLOBIN VALUES FOR NON-HISPANICWHITES AND AFRICAN AMERICANS AGED 2-18 YEARS

AGE (YR)WHITE NON-HISPANIC AFRICAN AMERICAN

Mean 2 SD Mean 2 SD

2-5 12.21 10.8 11.95 10.37

6-10 12.87 11.31 12.40 10.7411-15 male 13.76 11.76 13.06 10.88

11-15 female 13.32 11.5 12.61 10.85

16-18 male 15.00 13.24 14.18 12.42

16-18 female 13.39 11.61 12.37 10.37

Sample size is 5,142 (white, 2,264; African American, 2,878).Modied from Robbins EB, Blum S: Hematologic reference values for African American childrenand adolescents,Am J Hematol82:611614, 2007.

HISTORY AND PHYSICAL EXAMINATION

As with any medical condition, a detailed history and thoroughphysical exam are essential when evaluating an anemic child.Important historical facts should include age, sex, race and eth-

nicity, diet, medications, chronic diseases, infections, travel, andexposures. A family history of anemia and/or associated difcul-ties such as splenomegaly, jaundice, or early-age onset of gall-stones is also of consequence. There often are few physicalsymptoms or signs that result solely from a low hemoglobin,particularly when the anemia develops slowly. Clinical ndingsgenerally do not become apparent until the hemoglobin level fallsto


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Chapter 441 The Anemias n 16

Figure 441-1 Use of the mean corpuscular volume (MCV) and reticulocyte count in the diagnosis of anemia. (Adapted from From Brunetti M, Cohen J:The Harriet Lane handbook, ed 17, Philadelphia, 2005, Elsevier Mosby, p 338.)

Microcytic Normocytic Macrocytic

Reticulocyte count

Low/Inadequate

Iron deficiencyThalassemia traitChronic disease/inflammationLead poisoningSideroblastic anemiaCopper deficiency

Chronic disease/inflammationRBC Aplasia(TEC, Infection, Drugs)MalignancyEndocrinopathiesRenal failureAcute bleedingHypersplenismDyserythropoieticAnemia IIHemophagocyticsyndrome

Antibody mediatedhemolysisHypersplenismMicroangiopathy(HUS, TTP, DIC, -Kasabach Merritt)Membranopathies(spherocytosis, elliptocytosisovalocytosis)Enzymopathies(G6PD, PK, Deficiencies)Hemoglobinopathies(HBSS, SC)

Folate deficiencyVitamin B12 deficiencyAcquired aplastic anemiaCongenital aplastic anemia(Diamond-Blackfan,Fanconi Anemia,Peason syndrome)Drug inducedTrisomy 21HypothyroidismOroticaciduria

Dyserythropoietic-Anemia 1, IIIActive hemolysiswith very elevatedreticulocyte count

Thalassemia syndromesHemoglobin C and EdisordersPyropoikilocytosis

High Low/Inadequate High Low/Inadequate High

Reticulocyte count Reticulocyte count

particular underlying disease etiologies are discussed in detail insections describing the associated disorders.

LABORATORY STUDIES

Initial laboratory testing should include hemoglobin, hematocrit,and red cell indices as well as a white blood cell count and dif-ferential, platelet count, reticulocyte count, and examination ofthe peripheral blood smear. The need for additional laboratorystudies is dictated by the history, the physical, and the results ofthis initial testing.

DIFFERENTIAL DIAGNOSIS

Anemia is not a specic entity but rather can result from any ofnumber of underlying pathologic processes. In order to narrowthe diagnostic possibilities, anemias may be classied on the basisof their morphology and/or physiology (Fig. 441-1).

Anemias may be morphologically categorized on the basisof RBC size (mean corpuscular volume [MCV]), and micro-

scopic appearance. They can be classied as microcytic, normo-cytic, or macrocytic based on whether the MCV is low, normal,or high, respectively. RBC size also changes with age, andnormal developmental changes in MCV should be recognizedbefore a designation is made (see Table 441-1). Examinationof a peripheral blood smear often reveals changes in RBCappearance that will help to further narrow the diagnostic cat-egories (Fig. 441-2). Details regarding morphologic changesassociated with particular disorders are described in subsequentsections.

Anemias may also be further divided on the basis of under-lying physiology. The two major categories are decreased produc-tion and increased destruction or loss. The two groups are notalways mutually exclusive. Decreased RBC production may be aconsequence of ineffective erythropoiesis or a complete or relative

failure of erythropoiesis. Increased destruction or loss may besecondary to hemolysis, sequestration, or bleeding. The periph-eral blood reticulocyte percentage or absolute number will helpto make a distinction between the two physiologic categories. Thenormal reticulocyte percentage of total RBCs during most ofchildhood is about 1.0%, with an absolute reticulocyte count of25,000-75,000/mm3. In the presence of anemia, EPO productionand the absolute number of reticulocytes should rise. Low ornormal numbers of reticulocytes generally represent an inade-quate response to anemia that is associated with relative bonemarrow failure or ineffective erythropoiesis. Increased numbersof reticulocytes represent a normal bone marrow response toongoing RBC destruction (hemolysis), sequestration, or loss(bleeding).

Figure 441-1 presents a useful approach to assessing tcommon causes of anemia in the pediatric age group. Childrwith microcytic anemia and low or normal reticulocyte counmost often have defects in erythroid maturation or ineffectierythropoiesis. Iron deciency (Chapter 449) is the most commo

cause. Thalassemia trait (Chapter 456) constitutes the primadifferential diagnosis when iron deciency is suspected. Distintions between these entities are presented in Table 449-1 (Chapt449). Chronic disease or inammation (more often normocytilead poisoning, and sideroblastic anemias should also be cosidered and are discussed in other chapters. Microcytosis anelevated reticulocyte counts are associated with thalassemsyndromes and hemoglobin C and E (Chapter 456). Notabthalassemias and hemoglobinopathies are most commonly sein patients of Mediterranean, Middle Eastern, African, or Asiabackground.

Normocytic anemia and low reticulocyte count characteria large number of anemias. The anemia of chronic diseasinammation (Chapter 445) is usually normocytic. The anemassociated with renal failure, caused by reduced erythropoiet

production, will invariably be associated with clinical and labratory evidence of signicant kidney disease. Decreased or absered cell production secondary to transient erythroblastopenof childhood (TEC), infection, drugs, or endocrinopathy usualresults in a normocytic anemia, as does bone marrow inltratioby malignancy. In the case of invading leukemia or malignancabnormal leukocytes or tumor cells in association with thrombocytopenia or reduced or elevated white cell counts mbe seen. Acute bleeding, hypersplenism, and congenital dyserthropoietic anemia (CDA) type II (Chapter 446) are alnormocytic.

In children with normocytic anemia and an appropriate (higreticulocyte response, the anemia is usually a consequence bleeding, hypersplenism, or ongoing hemolysis. In hemolyconditions, reticulocytosis, indirect hyperbilirubinemia, an

increased serum lactate dehydrogenase are indicators of acceleated erythrocyte destruction. There are many causes of hemolysresulting from conditions that are extrinsic (usually acquireor intrinsic (usually congenital) to the red cell. Abnormal RBmorphology (e.g., spherocytes, sickle forms, microangiopathidentied on the peripheral smear is often helpful in ascertaininthe cause.

The anemia seen in children with macrocytic blood cells sometimes megaloblastic (Chapter 448), resulting from impairDNA synthesis and nuclear development. The peripheral bloosmear in megaloblastic anemias contains large macrovalocyteand the neutrophils often show nuclear hypersegmentation. Tmajor causes of megaloblastic anemia include folate deciencvitamin B12 deciency, and rare inborn errors of metabolism


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Other macrocytic anemias with low or normal reticuclocytecounts include acquired and congenital (Diamond-Blackfan and

Fanconi) aplastic anemias and hypothyroidism. Patients withtrisomy 21 have macrocytic cells, although an accompanyinganemia is generally not present. High MCV and reticulocytosisis seen in CDA I and III and in situations wherein hemolysis

Figure 441-2 Morphologic abnormalities of thered blood cell.A, Normal. B, Macrocytes (folic

acid or vitamin B12 deciency). C, Hypochromic

microcytes (iron deciency). D, Target cells (HbCC

disease). E, Schizocytes (hemolytic-uremic

syndrome). (Courtesy of Dr. E. Schwartz.)

A B

C

E

D

results in such a large outpouring of young red cells that the meanMCV is abnormally high.

BIBLIOGRAPHY

Please visit the Nelson Textbook of Pediatrics website atwww.expertconsult.com for the complete bibliography.
http://www.expertconsult.com/http://www.expertconsult.com/http://www.expertconsult.com/http://www.expertconsult.com/


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BIBLIOGRAPHY

Brugnara C, Oski FJ, Nathan DG: Nathan and Oskis hematology of infancyand childhood, ed 7, Philadelphia, 2009, WB Saunders.

Calis JCJ, Phiri KS, Faragher B, et al: Severe anemia in Malawian children,N Engl J Med358:888898, 2008.

Greer JP, Foerster J, Lukens J, et al: Wintrobes clinical hematology, ed 11,Baltimore, 2004, Williams & Wilkins.

Luby SP, Kazembe PN, Redd SC, et al: Using clinical signs to diagnose anaemiain African children, WHO Bulletin OMS 73:477482, 1995.

May J, Evans JA, Timmann C, et al: Hemoglobin variants and disease manfestations in severe falciparum malaria,JAMA 297:22202226, 2007.

Morris CR, Singer ST, Walters MC: Clinical hemoglobinopathies: iron, lunand new blood, Curr Opin Hematol13(6):407418, 2006.

Robbins EB, Blum S: Hematologic reference values for African Americchildren and adolescents, Am J Hematol82:611614, 2007.

Yurdakk K, Guner SN, Yalin S: Validity of using pallor to detect childrwith mild anemia, Pediatr Int50:232234, 2008.

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