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Pallor (Anemia)

A decreasein blood Hgb concentration or Hct (a measure of red cell mass) thatis 2 standard deviations below mean for age and gender is definedas anemia.

Pallor as sign of anemia depends onconcentration of Hgb in blood. When Hgb concentration is <8–9g/dL, pallor is usually visible.

Blood Hgb concentration of <13.5g/dL at birth is abnormal. Nadir is reached at about 2mos of age; lower level of normal is 9.5–11.0 g/dLin term infants and 6.5–9.0 g/dL in preterm infantswhose birth weights are <1,200 g. After 2 mos of age, Hgbconcentration increases.

Lower limits of normal blood Hgb concentrationin childhood are 5 mos to 2 yrs, 11 g/dL; 2–12yrs, 12 g/dL; and adolescence, 13 g/dL.

Etiologic classification of anemiapresented here is based on physiologic criteria. Later, a classificationbased on red cell size is presented. A combination of approachesis useful in diagnosis.

Principal Causes of Pallor (Anemia)

1. Disordersof decreased red cell or hemoglobin production
   1. Nutritionaldeficiencies
      1. Irondeficiency
      2. Folic acid deficiency
      3. Vitamin B₁₂ deficiency
   2. Hypoplastic or aplastic anemias
      1. Pure redcell aplasia
         1. Congenitalhypoplastic anemia (Diamond-Blackfan anemia)
         2. Transient erythroblastopenia of childhood
         3. Anemia associated with systemic disease
         4. Drug-related
      2. Aplastic anemia
         1. Congenital
         2. Acquired
      3. Malignancy
   3. Abnormal heme and globin synthesis
      1. Thalassemias
         1. Alpha-thalassemias
         2. Beta-thalassemias
      2. Sideroblastic anemias
      3. Lead poisoning
2. Disorders of increased red cell destruction(hemolytic anemias)
   1. Hemoglobinopathies
      1. Sickle cell disease
      2. Hemogloblin C disease
      3. Hemoglobin SC disease
      4. Hemoglobin E disease
      5. Unstable hemoglobins
   2. Red cell membrane defects
      1. Hereditaryspherocytosis
      2. Hereditary elliptocytosis
      3. Hereditary stomatocytosis
      4. Infantile pyknocytosis
      5. Paroxysmal nocturnal hemoglobinuria
   3. Red cell enzyme defects
      1. Glucose-6-phosphatedehydrogenase deficiency
      2. Pyruvate kinase deficiency
      3. Other
   4. Immune hemolytic anemias
      1. Isoimmunehemolytic anemia (Rh and ABO incompatibility)
      2. Autoimmune hemolytic anemia
   5. Red cell injury
      1. Thermal
      2. Mechanical
      3. Toxins
      4. Infection
      5. Copper toxicity
      6. Hypophosphatemia
3. Blood loss
   1. Neonates
      1. Occult bleeding prior to birth
      2. Obstetric accidents
      3. Internal hemorrhage
      4. Excessive blood sampling
   2. Infants, children, and adolescents
      1. Trauma
      2. Severe epistaxis or hemoptysis
      3. Gastrointestinal bleeding
      4. Excessive menstrual bleeding

Clinical Features and Diagnosis

Disorders of Decreased Red Cell or Hemoglobin Production

Nutritional Deficiencies

Iron Deficiency

Most commoncause of anemia in children is iron deficiency. Decreased iron intake andsignificant blood loss are usual mechanisms. Iron deficiency ismost common in children <2 yrs of age and in adolescence.In preterm infants, it can occur as early as 2 mos of age, whereasin term infants it is most common at 6 mos–2 yrs of age.Peak incidence is 10–15 mos of age.

Iron deficiency usually evolves throughsuccession of stages before anemia develops.

Depletion of storage iron occurs infirst stage, and low serum ferritin (<10 g/dL)reflects diminished stores. Even with this loss in iron reserves,iron supply for red cells is adequate.

In second stage, iron supplied to redcells is low. Although mean corpuscular volume (MCV) is lower thannormal and free erythrocyte porphyrin (FEP) is higher than normal,blood Hgb remains in normal range.

In third and final stage, iron deficiencyanemia occurs and blood Hgb is lower than normal for age.

Mild iron deficiency is usually diagnosedon the basis of dietary history and lab screening.

Clinical manifestations of iron deficiencyanemia include decreased exercise tolerance, fatigue, irritability,anorexia, and pallor. Tachycardia and cardiomegaly occur when anemiais severe.

Diagnosis of iron deficiency anemiais based on history of decreased iron intake or significant bloodloss, lower than normal blood Hgb, low MCV, and presence of microcytichypochromic red cells on blood smear.

Therapeutic trial of iron (4–6mg/kg/day of elemental iron) can be given andHgb rechecked in 1 mo. Iron should be given for ≥1–2mos after blood Hgb and MCV have returned to normal in order toreplenish iron stores.

Brugnara et al. (1999) have reportedthat reticulocyte Hgb content is lower in children with iron deficiencycompared with normal children. In the future, this test may be analternative to biochemical iron studies now used in diagnosis.

Folic Acid Deficiency

Folic acidand vitamin B₁₂ deficiencies account for >95% of megaloblasticanemias. Presence of macrocytes in blood and megaloblasts in bonemarrow characterize this type of anemia.

Common causes of folate deficiencyare inadequate intake (malnutrition, sustained boiling as methodof cooking, goat milk feeding, unusual diets); defective absorption(malabsorption disorders); increased requirements (chronic hemolyticanemias, leukemia, lymphoma); and drugs (trimethoprim-sulfisoxazole,phenytoin).

Clinical features include pallor, lassitude,fatigue, anorexia, glossitis, and splenomegaly. Blood smear showsnormochromic macrocytes, hypersegmented polymorphonuclear leukocytes(≥5 lobes), anisocytosis, and poikilocytosis.

Serum folate level of <3 ng/mLindicates folic acid deficiency.

Vitamin B₁₂ Deficiency

Decreasedintake and intestinal malabsorption are common causes of vitamin B₁₂ deficiency.Deficiency of intrinsic factor and congenital defects in vitamin B₁₂ metabolismare rare.

Onset of vitamin B₁₂ deficiencyis insidious, with findings similar to those for folate deficiency.Infrequent findings include peripheral neuropathy with loss of positionand vibration sense, paresthesias, and ataxia.

Blood smear and bone marrow findingsare same as those with folate deficiency. Serum vitamin B₁₂ levelof <100 pg/mL indicates vitamin B₁₂ deficiency.Then the precise cause must be determined.

The Schilling test measures the availabilityof intrinsic factor and the intestinal phase of vitamin B₁₂ absorption.After radioactive vitamin B₁₂ (0.5–2.0 μg)is given orally, nonradioactive vitamin B₁₂ (1mg) is given 2 hrs later as an intramuscular injection, and urineis collected for 24 hrs. In normal individuals, urinary excretionis 10–35% of radioactive dose, whereas those withvitamin B₁₂ malabsorption excrete <3%.A repeat Schilling test, in which commercial intrinsic factor isadministered along with oral radioactive vitamin B₁₂,bypasses a defect in intrinsic factor, so that vitamin B₁₂ canbe absorbed in those with intrinsic factor deficiency. If intestinalmalabsorption is present, vitamin B₁₂ malabsorptionpersists even when intrinsic factor is given.

Assays for intrinsic factor in gastricjuice and antibodies to parietal cells and intrinsic factor areuseful tests when intrinsic factor deficiency is suspected.

Hypoplastic or Aplastic Anemias

Pure Red Cell Aplasia

Congenital Hypoplastic Anemia (Diamond-Blackfan Anemia)

Onset isusually in first few months of life, and anemia can be severe.

Blood smear shows normocytes or macrocytes,and reticulocyte count is low.

Diagnostic bone marrow aspirate showsdecreased numbers of red cell precursors.

Transient Erythroblastopenia of Childhood

Althoughthe cause of this disorder is uncertain, it is often associatedwith recent viral infection. Affected children are usually 6 mos–6yrs of age.

Blood smear shows normochromic normocyticred cells. Reticulocyte count is low, and Coombs test is negative.Bone marrow exam shows decrease or absence of red cell precursorsinitially and hyperplasia of red cells during recovery.

Anemia Associated with Systemic Disease

Acquired red cell aplasia may be associatedwith infection (parvovirus B19 infection, viral hepatitis, infectiousmononucleosis, endocarditis), chronic inflammatory disorders (juvenilerheumatoid arthritis, ulcerative colitis), endocrine disorders (hypothyroidism,hyperthyroidism), protein-calorie malnutrition, and chronic renaldisease.

Drug-Related

Red cell aplasia may be due to drugs (e.g.,phenytoin, carbamazepine, chloramphenicol, sulfonamides, and azathioprine).

Aplastic Anemia

Congenital

Fanconianemia is autosomal-recessive disorder that affects all bone marrowelements.

Specific physical findings usuallyexist, but this is not always the case. Findings include characteristicfacies (broad nasal base, epicanthal folds, micrognathia), skinpigment changes (café au lait spots, hyperpigmentation),microcephaly, small stature, abnormal thumbs (absent, hypoplastic,duplication), kidney malformations (absent, ectopic, duplication),and mental retardation.

Blood smear shows normochromic macrocytesand decreased numbers of leukocytes and platelets.

Specific diagnostic test is chromosomebreakage analysis that shows high proportion of cells with chromosomalbreaks, gaps, rearrangements, and exchanges.

Acquired

Common causesof acquired aplastic anemia are idiopathic (about 50%),drugs (chloramphenicol), chemical exposure (benzene, pesticides),viral infection (parvovirus, B19, Epstein-Barr virus, HIV), andradiation.

Blood count reveals pancytopenia, andbone marrow aspirate or biopsy is confirmatory.

Malignancy

Anemia maybe the presenting feature of malignancy in childhood. Associatedmanifestations suggestive of malignancy include fever, lymphadenopathy,hepatosplenomegaly, purpura, extremity pain, and abdominal mass.

Most common malignancy in childhoodis acute lymphoblastic leukemia with onset usually at 2–6yrs. Common findings include lymphadenopathy, hepatosplenomegaly,and pancytopenia. Blood smear usually shows lymphoblasts, and bonemarrow aspirate confirms diagnosis.

Neuroblastoma and lymphoma are othercommon malignancies involving bone marrow (see Chap. 1, Abdominal Masses,and Chap. 38, Lymphadenopathy).

Abnormal Heme and Globin Synthesis

Thalassemias

Are a groupof inherited anemias caused by mutations affecting synthesis of Hgb.

In alpha-thalassemias, production ofalpha-globin chains is deficient, whereas in beta-thalassemias,production of beta-globin chains is deficient.

Alpha-Thalassemias

4 alpha-globingenes exist in each individual, 2 from chromosome 16 of each parent.

In African-Americans, virtually allalpha-thalassemia syndromes involve 1-gene deletion in 1 or bothparents. 1 single-gene deletion produces silent carrier, whereas2 single-gene deletions produce alpha-thalassemia trait.

Hgb H occurs from inheritance of singledeletion from 1 parent and double deletion from the other. Inheritanceof double deletion from both parents produces hydrops fetalis.

Anemia does not occur with single-genedeletion (silent carrier), although cord blood may show 1–2% HgbBarts. After 6 mos of age, Hgb Barts disappears, and Hgb electrophoresispattern is Hgb AA.

Deletion of 2 alpha-globin genes producesalpha-thalassemia trait, and Hgb Barts may reach levels of 5–10%.There is mild microcytic hypochromic anemia.

Deletion of 3 alpha-globin genes resultsin production of Hgb H (beta-4), which gradually replaces 20–40% HgbBarts. Hemolytic anemia occurs in neonatal period, and Hgb electrophoresisconfirms diagnosis.

No alpha chains are produced with deletionof all 4 alpha-globin genes. Hgb electrophoresis shows mainly HgbBarts, Hgb H, and small amounts of Hgb Portland. Blood smear showsmicrocytosis, hypochromia, target cells, and increased number ofnucleated red cells. Usual clinical consequence is severe anemia,cardiac failure, and death in utero or few hours after birth. Afew individuals have been treated successfully with exchange transfusions,but they remain transfusion dependent.

Beta-Thalassemias

2 beta-globingenes exist on chromosome 11 in each individual. Defect of 1 beta-globingene produces heterozygous beta-thalassemia, whereas defect in 2of them produces homozygous beta-thalassemia.

In heterozygous beta-thalassemia (beta-thalassemiatrait), Hgb A₂ or Hg F or both are usuallyincreased, although occasionally these levels can be normal. Peripheralsmear shows hypochromic microcytic red cells, target cells, andbasophilic stippling.

Homozygous beta-thalassemia (beta-thalassemiamajor) usually presents with severe anemia between 6 and 12 mosof age, when normal postnatal decrease in gamma-chain synthesis(Hgb F) reveals defect in beta-chain production. Hgb concentrationsare 3–7 g/dL. Pallor, irritability, anorexia,and hepatosplenomegaly are usually found. Blood smear usually showsmicrocytic hypochromic red cells, target cells, increased numbersof nucleated red cells, and basophilic stippling. Quantitative Hgbelectrophoresis before transfusion shows Hgb A (0–80%),Hgb A₂ (2–7%), and HgbF (20–100%), depending on specific genotype. Reticulocytecount rarely exceeds 5%.

Sideroblastic Anemias

Group ofgenetic and acquired disorders characterized by anemia, low reticulocyte count,and ineffective erythropoiesis. In the genetic types, usual inheritancepattern is X-linked.

Causes of acquired sideroblastic anemiaare drugs (chloramphenicol, isoniazid), lead poisoning, and idiopathic.

Red cells are usually normochromicand normocytic, but occasionally they may be hypochromic and microcytic.Thrombocytopenia and neutropenia commonly occur. Bone marrow usually showsmarked hyperplasia of red cells and ringed sideroblasts (iron granulesin ring around nucleus of normoblasts).

Lead Poisoning

Should besuspected in any child with pica who lives in house painted withlead-based paint before 1950.

Although lead impairs uptake and utilizationof iron and production of globin in red cells, significant anemia(microcytic) is unusual unless blood lead level is >50–60μg/dL.

Blood lead level is diagnostic.

Disorders of Increased Red Cell Destruction (Hemolytic Anemias)

Hemoglobinopathies

Virtually all hemoglobinopathies with exceptionof beta-thalassemia trait can be detected by Hgb electrophoresisof cord blood. Table 45.1 listscord blood and adult Hgb electrophoresis patterns of most commonhemoglobinopathies.

Table 45.1. Hemoglobin Electrophoretic Patterns of Common Hemoglobinopathiesin Cord and Adult Blood

Diagnosis	Cord Blood	Adult Blood
Normal	FA	AA
Sickle cell disease	FS	SS
Sickle cell trait	FAS	AS
Hgb SC disease	FSC	SC
Sickle beta-thalassemia	FSA	SA (A2 >3.5%)
Alpha-thalassemia trait	FA + Hgb Barts <10%	AA
Hgb H disease	FA + Hgb Barts >15%	AH
Beta-thalassemia trait	FA	FA (A2 >3.5%)
Homozygous beta-thalassemia	FF	FF (A2 >3.5%)
Hgb C trait	FAC	AC
Hgb CC disease	FC	CC
Hgb E disease	FE	EE

Sickle Cell Disease

Hgb SS iscommon disorder that occurs primarily in African-American individuals. Hgblevel is 6–8 g/dL and reticulocyte count from5–15%. Blood smear that shows sickle cells almostalways signifies homozygous sickle cell disease. Sickle cells donot occur with sickle cell trait, and they are infrequent with othersickle cell syndromes.

Recurrent vasoocclusive pain episodesare most common clinical manifestation of sickle cell disease. Onsetmay be as early as 6–12 mos of age, with abdominal, chest,back, or extremity pain. Another manifestation of this disease,especially in young children, is dactylitis, which is painful swelling ofsmall bones of hands and feet.

Another complication of sickle celldisease that may cause acute anemia is aplastic episode in whichHgb level is lower than normal and reticulocyte count is very lowor 0. Leukopenia and thrombocytopenia also may occur if aplasiapersists long enough. As marrow recovers, nucleated red cells and reticulocytesare seen on blood smear.

In sequestration crisis, large amountsof blood pool in spleen, producing splenomegaly and sometimes hypotension.Hgb level is lower than normal. Thrombocytopenia and leukopeniaalso may occur.

Hemoglobin C Disease

Occurs inabout 2% of African-American individuals.

In homozygous disease (Hgb CC), usualfindings are moderate- to-severe hemolytic anemia with Hgb levelof 8–11 g/dL, reticulocyte count of 5–10%,target cells and spherocytes on blood smear, and splenomegaly.

In heterozygous Hgb C disease (HgbAC), blood smear shows target cells, but there is no anemia.

Hemoglobin SC Disease

Producesclinical picture that is less severe than homozygous sickle celldisease.

Hgb level is 9–12 g/dL.Target cells are seen on blood smear, and reticulocyte count isnormal.

Vasoocclusive, aplastic, and sequestrationepisodes are generally milder and less frequent than in Hgb SS disease.

Hemoglobin E Disease

In Hgb Edisease, which is prevalent in individuals from Southeast Asia andIndia, hemolytic anemia is mild, with Hgb level rarely <10g/dL. Blood smear shows hypochromic microcytic red cellswith some target cells.

In heterozygous form, Hgb concentrationis normal and blood smear shows mild microcytosis and occasionaltarget cells.

Individuals with Hgb E beta-thalassemiahave clinical features of thalassemia major.

Unstable Hemoglobins

>100structurally different unstable Hgb variants have been discovered,and many of them are beta-chain mutants.

Clinical presentation is usually inearly childhood with hemolytic anemia, jaundice and splenomegaly.

Blood smear usually shows mild hypochromiaand basophilic stippling. Because unstable Hgbs are susceptibleto denaturation, Heinz bodies may form.

Hgb electrophoresis usually demonstratesabnormal pattern, and positive Hgb instability test can often demonstratepresence of unstable Hgb.

Red Cell Membrane Defects

Hereditary Spherocytosis

Moleculardefects are in proteins (spectrin, ankyrin, protein 4.2, band 3)that form skeleton of red cell membrane. As a consequence, red cellsare trapped in spleen, leading to decreased life span.

Genetic transmission is usually autosomal-dominantbut may be autosomal-recessive.

Usual clinical findings are jaundice,splenomegaly, and anemia. Blood smear shows dense microspherocytes,and reticulocyte count is increased.

Incubated osmotic fragility test isusually positive, which confirms diagnosis. In this test, red cellsof affected individuals hemolyze at higher osmotic concentrationthan normal red cells.

Viral illness occasionally precipitatesaplastic or hemolytic crisis.

Hereditary Elliptocytosis

Mutationsin alpha-spectrin, beta-spectrin, and band 3 genes are responsiblefor many cases of elliptocytosis, which is usually autosomal dominant.

Hemolytic anemia and mild jaundicemay occur in neonatal period as well as in infancy and childhood.

Diagnostic blood smear shows ellipticalred cells and occasionally microspherocytes.

Hereditary Stomatocytosis

This autosomal-dominant disorder is due todefect in gene for stomatin, a membrane protein in red cells. Bloodsmear shows stomatocytes, which are red cells with slitlike areaof central pallor.

Infantile Pyknocytosis

The causeof infantile pyknocytosis, which produces transient hemolytic anemia,is unknown.

Jaundice and hepatosplenomegaly mayoccur during first few weeks of life.

Diagnostic blood smear shows dense,spiculated red cells, which are called pyknocytes.

Hemolytic anemia usually peaks at 3–4wks of age and generally resolves spontaneously as pyknocytes arereplaced by normal red cells.

Paroxysmal Nocturnal Hemoglobinuria

Red cellmembrane is more susceptible than normal to complement-mediatedlysis.

Hemolysis is primarily intravascular,and clinical hallmark is finding of dark urine on arising from sleep.Headache, abdominal pain, and back pain are frequent complaintsduring hemolytic episodes. Leukopenia and thrombocytopenia are alsocommon.

Most reliable diagnostic test is Hamtest, which can demonstrate unusual susceptibility of red cellsto hemolytic action of complement.

Red Cell Enzyme Defects

Enzyme defectsin both hexose monophosphate and glycolytic pathways can resultin hemolytic anemia.

Clinical presentation depends on specificenzyme defect and oxidizing stress to which red cells have beenexposed.

In all of these enzyme disorders, decreasein specific enzyme activity in red cells confirms diagnosis.

2 most common red cell enzyme deficienciesare G6PD and pyruvate kinase deficiencies, as discussed below.

Glucose-6-Phosphate Dehydrogenase Deficiency

Most commonred cell enzyme deficiency is G6PD deficiency, which is X-linked. Thisenzyme catalyzes conversion of glucose-6-phosphate to 6-phosphogluconateand reduction of NADP to NADPH in hexose monophosphate pathway. >100mutations have been described.

Clinical presentation and course dependon specific enzyme variation. Most common type, which occurs inAfrican-American individuals, results in mild, self-limited hemolysis,when affected individuals are exposed to oxidative stresses [e.g.,infection and certain drugs (sulfonamides, chloramphenicol, nitrofurantoin)].Between hemolytic episodes, red cell and reticulocyte counts are normal.

Pyruvate Kinase Deficiency

Most commonenzyme deficiency of glycolytic pathway. This autosomal-recessive disordercatalyzes conversion of phosphoenolpyruvate to pyruvate. Gene locushas been mapped to chromosome 1q21.

May present in neonatal period withanemia and jaundice or in infancy and childhood as mild anemia.

Immune Hemolytic Anemias

Isoimmune Hemolytic Anemia (Rh and ABO Incompatibility)

In Rh incompatibility,the mother lacks Rh antigen (Rh–), whereas the infant hasRh antigen (Rh+). With previous sensitization by previouspregnancy or abortion, maternal anti-Rh antibody crosses placenta,coats fetal Rh+ cells, and destroys them. Severe hemolyticanemia, cardiac failure, and even death can occur in the fetus.Anti-D immune globulin can be given to a previously sensitized Rh– motherto prevent sensitization in subsequent pregnancy.

ABO hemolytic disease is usually lesssevere than Rh hemolytic disease. Severe hyperbilirubinemia is unusual,and cardiac failure is rare. ABO hemolytic disease almost alwaysoccurs in group O mothers and group A or B infants. Characteristicfeature is presence of microspherocytes on blood smear. PositiveCoombs test result with infant's own cells is evidencefor isosensitization.

Other blood group hemolytic diseasesare less common but occur because of antibodies against other antigensof Rh complex beside D (e.g., C and E) or antibodies against otherblood group antigenic systems (e.g., Kell and Duffy). Using maternalserum against panel of cells with known antigens tests for specificantibody.

Autoimmune Hemolytic Anemia

Characterizedby presence of autoantibodies that bind to surface of red cellsand cause their destruction. Usually acute in onset and may be associatedwith severe anemia. Reticulocyte count is generally increased, andCoombs test result is usually positive. Spherocytes are usuallyseen on blood smear.

Causes include viral infection, drugs(penicillins, sulfonamides), chronic inflammatory disorders (juvenilerheumatoid arthritis, systemic lupus erythematosus, dermatomyositis,ulcerative colitis), malignancy (Hodgkin disease, non-Hodgkin lymphoma),immunodeficiency disorders, and idiopathic (most common).

Red Cell Injury

Thermal

Intravascular hemolysis with red cell fragmentationand spherocytosis may occur during the first 1–2 days aftermajor cutaneous burns.

Mechanical

Injury tored cells in large vessels may occur with incomplete surgical repairof intracardiac defect, abnormal function of prosthetic valve, ordefective attachment of valve. Shearing stresses on red cell causehemolysis. Blood smear shows spherocytes and distorted, fragmentedred cells. Hemoglobinemia and hemoglobinuria occur with significanthemolysis.

Injury to red cells in small vesselsmay occur with hemolytic-uremic syndrome, cavernous hemangioma,malignant hypertension, thrombotic thrombocytopenic purpura, andrenal or hepatic transplant rejection. In each of these conditions,blood smear shows fragmented red cells known as schistocytes.

Toxins

Bites from certain vipers and rattlesnakesas well as brown recluse spiders may produce hemolytic anemia. Spherocytesmay be seen on blood smear.

Infection

Common featureof malaria is hemolytic anemia.

Massive hemolysis with hemoglobinuriahas been called blackwater fever (see Chap.21, Fever).

C. welchii and C. perfringens septicemiaalso may cause acute hemolytic anemia.

Copper Toxicity

Ingestionof copper-containing compounds may produce acute intravascular hemolysis.Clinical manifestations include flushing, nausea, vomiting, diarrhea,abdominal pain, chills, excessive salivation, metallic taste inmouth, and headache. History of ingestion and high serum copperlevel confirms diagnosis.

Hemolytic anemia also may occur inWilson disease, a disorder of copper metabolism characterized bytoxic accumulation of copper in liver, red cells, kidney, cornea,and brain (see Chap. 36, Jaundice).

Hypophosphatemia

Severe hemolytic anemia can occur with hypophosphatemia,and microspherocytes may be seen on blood smear.

Blood Loss

Acute severeblood loss produces hypovolemia, which results in hypotension or shock.There usually is some clinical evidence of bleeding. Blood smearshows normocytic normochromic red cells, and the Coombs test isnegative.

Slow chronic blood loss may just producepallor. Findings of iron deficiency anemia despite normal iron intakeis a clue to presence of chronic blood loss. Blood smear shows hypochromicmicrocytic red cells, and reticulocyte count is higher than normal.The Coombs test is negative, and serum bilirubin is normal.

In neonates blood loss may be due tobleeding prior to birth (maternal trauma, fetomaternal transfusion,twin-to-twin transfusion); obstetric accidents (placenta previa,abruptio placenta); internal hemorrhage from trauma (cephalohematoma,subaponeurotic bleeding, subarachnoid or subdural hemorrhage, ruptureof liver or spleen); and excessive blood sampling. With significantfetomaternal transfusion, fetus may die in utero or have severeanemia and cardiac failure at birth. Presence of fetal red cellsin maternal circulation, indicated by Kleihauer-Betke test, confirmsdiagnosis.

Common causes of blood loss in infants,children, and adolescents are trauma, GI bleeding, severe epistaxisor hemoptysis, and severe menstrual bleeding. See other chaptersfor discussion of disorders that cause this bleeding.

Diagnostic Approach

Completehistory and physical exam including family history should be performed. Ageof child, severity of illness, type of onset (acute or chronic),and presence of associated physical findings (e.g., jaundice, hepatosplenomegaly,splenomegaly, purpura, and visible bleeding) are important diagnosticfeatures in patients who have anemia.

This information combined with CBCand differential, MCV, analysis of blood smear, and reticulocytecount usually permits specific diagnosis to be reached.

Other useful tests are Coombs testand Hgb electrophoresis. In some cases, bone marrow exam may berequired.

Age

Most commoncauses of anemia in neonates are blood loss (placenta previa, abruptio placenta,fetomaternal transfusion, twin-to-twin transfusion, birth trauma,GI bleeding, repeated phlebotomy) and hemolysis (ABO incompatibility,Rh incompatibility, disseminated intravascular coagulation, hereditaryspherocytosis, G6PD deficiency).

Hemolysis is most common cause of anemiain infants 1–3 mos of age, whereas iron deficiency anemiais most common cause in infants 6–24 mos of age. At 2–6yrs of age, infection, drug intake, and neoplasia are frequent causesof anemia. Chronic disease is common cause in school-aged children. Mostcommon cause of anemia in adolescence is iron deficiency due toinadequate diet and rapid growth.

Severity of Illness

Most important first step is to assess severityof illness. For anyone with hypovolemia from blood loss or cardiacfailure from severe anemia, immediate treatment is mandatory.

Type of Onset

Whetheronset of illness is acute or chronic is important in diagnosis.Physical exam determines whether child is acutely ill.

When child is stable, thorough investigationof cause of anemia can be conducted. Degree of pallor and thus degreeof anemia can be roughly assessed by examining mucosal surfacesand palmar creases. Individuals with slow or insidious onset maypresent with pallor, gradual change in activity, tachycardia, splenomegaly,hepatomegaly, or lymphadenopathy.

Most likely mechanisms that produceslow chronic course are decrease in red cell production or chronicblood loss.

Associated Physical Findings

Purpuraor easy bruising signifies involvement of other types of blood cellsin addition to red cells.

Fever, lymphadenopathy, and hepatosplenomegalysuggest infection or neoplasia.

Jaundice suggests active hemolysisdue to hemolytic disorder.

Lab Tests

Complete Blood Count

CBC, including platelet count, provides crucialinformation about all blood cell lines (e.g., presence of pancytopeniasuggests leukemia or aplastic anemia).

Mean Corpuscular Volume

Measurement of MCV, which varies with ageand gender, is useful in the classification of anemias [seeDallman and Simes (1979) for normal values of mean corpuscular volume].Low MCV signifies microcytic anemia, whereas high MCV (101–160fL) signifies macrocytic anemia. Table45.2 lists common causes of anemia based on values ofMCV.

Table 45.2. Morphologic Classification of Anemia Based on Red CellMean Corpuscular Volume

Microcytic anemia

Iron deficiency

Thalassemias

Chronic inflammation

Chronic lead poisoning

Sideroblastic anemias

Unstable hemoglobins

Normocytic anemia

Hemolytic anemias

Red cell membrane defects

Red cell enzyme defects

Hemoglobinopathies

Immune hemolytic anemia

Microangiopathic hemolytic anemias

Secondary to acute infection

Acute blood loss

Chronic renal disease (usually)

Macrocytic anemia

Folic acid deficiency

Vitamin B12 deficiency

Aplastic anemia

Hypothyroidism

Liver disease

Bone marrow infiltration

Congenital hypoplastic anemia (Diamond-Blackfan syndrome)

Adapted from Oski FA, et al. A diagnostic approach to theanemic patient. In: Nathan DG, Oski FA, eds. Hematology of infancyand childhood, 5th ed. Philadelphia: W. B. Saunders, 1998, 377;with permission.

Blood Smear

Analysis of blood smear can reveal changesin red cell morphology and presence of abnormal cells, which maybe diagnostic in many instances (Table45.3 ).

Table 45.3. Abnormal Blood Smear Findings and Possible Causes

Abnormal Finding	Possible Causes
Spherocytes	ABO incompatibility
	Hereditary spherocytosis
	Hypersplenism
	Immunohemolytic anemias
	Burns (severe)
	Hypophosphatasia (severe)
	Hemolytic transfusion reactions
	Spider, bee, and snake venoms
	Septicemia (C. welchii)
Elliptocytes	Hereditary elliptocytosis
	Iron deficiency anemia (severe)
	Thalassemias
Stomatocytes	Hereditary stomatocytosis
Sickle cells	Sickle cell anemia
	Symptomatic sickle syndromes
Target cells	Thalassemias
	Hgbs S, C, and E
	Postsplenectomy
Basophilic stippling (aggregated ribosomes that appear asbluish violet granules in the cytoplasm of red cells)	Thalassemias
	Iron deficiency
	Unstable hemoglobins
	Lead poisoning
Spiculated or crenated red cells	Infantile pyknocytosis
	Vitamin E deficiency
	Abetalipoproteinemia
	Uremia
	Acute hepatic necrosis
	Postsplenectomy
Schistocytes (fragmented cells)	Hemolytic-uremic syndrome
	Thrombotic thrombocytopenic purpura
	Mechanical injury
	Disseminated intravascular coagulation
Howell-Jolly bodies (nuclear remnants)	Iron deficiency anemia (severe)
	Asplenic or hyposplenic states
	Pernicious anemia
Heinz bodies (denatured or aggregated Hgb appears as purple,irregularly shaped bodies in red cells on crystal violet staining)	Thalassemia syndromes
	Unstable hemoglobins
	Asplenia
	Chronic liver disease
	G6DP following oxidant stress

Adapted from Oski FA, et al. A diagnostic approach to theanemic patient. In: Nathan DG, Oski FA, eds. Hematology of infancyand childhood, 5th ed. Philadelphia: WB Saunders, 1998: 381–382;with permission.

Reticulocyte Count

Reflectsred cell synthetic activity in bone marrow. Normal count is 0.5–1.5%.Low reticulocyte count occurs with hypoplastic and aplastic anemias,whereas elevated reticulocyte count occurs with hemolytic anemia.Hallmark of hemolysis is elevated reticulocyte count without increasein Hgb concentration.

The following are criteria for diagnosinghemolytic anemia:

Evidenceof bone marrow regeneration [reticulocytosis; blood smearthat shows polychromasia, nucleated red cells, or specific finding(e.g., sickle cells or spherocytes); bone marrow showing normoblasticerythroid hyperplasia]

Increase in Hgb catabolism (increasein serum unconjugated bilirubin, increase in urine or stool urobilinogen,decrease in serum haptoglobin)

Release of red cell contents into plasma(hemoglobinemia, hemoglobinuria)

Practically, only CBC, reticulocytecount, blood smear, and fractionated serum bilirubin are usuallynecessary to make diagnosis of hemolytic anemia. Diagnosis of specificcause may require more sophisticated tests.

Other Tests

Other tests that may help confirm specificdiagnoses include Coombs test, Hgb electrophoresis, UA, CBC andblood smears of parents, vitamin B₁₂ andserum folate levels, osmotic fragility, and bone marrow aspirationand biopsy.

References

1. Brugnara C, et al. Reticulocyte hemoglobincontent to diagnose iron deficiency in children. JAMA 1999;281:2225–2230.
2. Cohen AR. Choosing the best strategy to prevent childhoodiron deficiency. JAMA 1999;281:2247–2248.
3. Cohen AR. Pallor. In: Fleisher GR, Ludwig S, eds. Textbookof pediatric emergency medicine, 4th ed. Philadelphia: LippincottWilliams & Wilkins, 2000:483–491.
4. Dallman PR, Simes MS. Percentile curves for hemoglobinand red cell volume in infancy and childhood. J Pediatr 1979;94:26–31.
5. Nathan DG, Oski FA, eds. Hematology of infancy andchildhood, 5th ed. Philadelphia: WB Saunders, 1998.
6. Online Mendelian Inheritance in Man (OMIM). McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,MD) and National Center for Biotechnology Information, NationalLibrary of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim.
7. Oski FA, et al. A diagnostic approach to the anemicpatient. In: Nathan DG, Oski FA, eds. Hematology of infancy andchildhood, 5th ed. Philadelphia: WB Saunders, 1998:375–384.
8. Pearson HA. Anemia in the newborn: a diagnostic approachand challenge. Semin Perinatol 1991;15(suppl 2):2–8.
9. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.

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Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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