aoriximacion del niño con anemia

17/6/2015 Approach to the child with anemia

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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorClaudio Sandoval, MD

Section EditorsDonald H Mahoney, Jr,MDMartin I Lorin, MD

Deputy EditorCarrie Armsby, MD, MPH

Disclosures: Claudio Sandoval, MD Nothing to disclose. Donald H Mahoney, Jr, MD Nothing todisclose. Martin I Lorin, MD Nothing to disclose. Carrie Armsby, MD, MPH Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, theseare addressed by vetting through a multilevel review process, and through requirements forreferences to be provided to support the content. Appropriately referenced content is required of allauthors and must conform to UpToDate standards of evidence.Conflict of interest policy

Approach to the child with anemia

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: May 2015. | This topic last updated: Jun 04, 2015.

INTRODUCTION — The approach to anemia in the pediatric patient is reviewed here. Included are pertinentissues related to the history and physical examination, the initial laboratory workup, methods for classifyinganemia, and algorithms designed to help guide diagnosis.

A systematic approach to the examination of the peripheral blood smear and bone marrow is discussedseparately. (See "Evaluation of the peripheral blood smear" and "Evaluation of bone marrow aspirate smears".)

DEFINITION OF ANEMIA — Anemia may be defined as a reduction in red blood cell (RBC) mass or bloodhemoglobin concentration. In practice, anemia most commonly is defined by reductions in one or both of thefollowing:

Normal ranges for HGB and HCT vary substantially with age, race, and sex (table 1). The threshold for defininganemia is a HCT or HGB at or below the 2.5 percentile for age, race, and sex.

PATIENT CHARACTERISTICS — Causes of anemia in children vary based upon age at presentation, sex,race, and ethnicity.

Age of patient — The age of the patient is important to consider because normal values of hematocrit (HCT)and hemoglobin (HGB) vary greatly with age, and because different causes of anemia present at different ages(table 1):

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Hematocrit (HCT) − The hematocrit is the fractional volume of a whole blood sample occupied by RBCs,expressed as a percentage. As an example, the normal HCT in a child age 6 to 12 years is approximately40 percent.

Hemoglobin (HGB) − This is a measure of the concentration of the RBC pigment hemoglobin in wholeblood, expressed as grams per 100 mL (dL) of whole blood. The normal value for HGB in a child age 6 to12 years is approximately 13.5 g/dL (135 g/L).

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Birth to three months − The most common cause of anemia in young infants is "physiologic anemia",which occurs at approximately six to nine weeks of age. Erythropoiesis decreases dramatically after birthas a result of increased tissue oxygenation and a reduced production of erythropoietin [1,2]. In healthyterm infants, hemoglobin levels are high (>14 g/dL) at birth and then rapidly decline, reaching a nadir ofapproximately 11 g/dL at six to nine weeks of age, which is called "physiologic anemia of infancy" (alsocalled the "physiologic nadir") (figure 1) [3,4].

Pathologic anemia in newborns and young infants is distinguished from physiologic anemia by any of thefollowing [1]:

Anemia (HGB <13.5 g/dL) within the first month of life•

Anemia with lower HGB level than is typically seen with physiologic anemia (ie, <9 g/dL)•

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Sex — Some inherited causes of anemia are Xlinked (eg, G6PD deficiency and Xlinked sideroblasticanemia), and occur most commonly in males. In postmenarchal girls, excessive menstrual bleeding is animportant cause of anemia. (See "Genetics and pathophysiology of glucose6phosphate dehydrogenasedeficiency" and "Causes of congenital and acquired sideroblastic anemias", section on 'Xlinked sideroblasticanemia' and "Abnormal uterine bleeding in adolescents: Differential diagnosis and approach", section on'Excessive menstrual bleeding'.)

Race and ethnicity — Race and ethnic background are helpful in guiding the workup for hemoglobinopathiesand enzymopathies (eg, G6PD deficiency). Hemoglobin S and C are most commonly seen in black andHispanic populations; thalassemia syndromes are more common in individuals of Mediterranean and SoutheastAsian descent; G6PD deficiency is more common among Sephardic Jews, Filipinos, Greeks, Sardinians,Kurds, and black populations [1]. (See "Clinical manifestations and diagnosis of the thalassemias" and"Diagnosis of sickle cell disorders".)

EVALUATION

History — The evaluation of a child with anemia begins with a thorough history. The degree of symptoms, pastmedical history, family history, dietary history, and developmental history may provide important clues to thecause of anemia (table 2):

Signs of hemolysis (eg, jaundice, scleral icterus, or dark urine) or symptoms of anemia (eg,irritability or poor feeding)

•

Common causes of pathologic anemia in newborns include blood loss, immune hemolytic disease (ie, Rhor ABO incompatibility), congenital infection, twintwin transfusion, and congenital hemolytic anemia (eg,hereditary spherocytosis, glucose6phosphate dehydrogenase [G6PD] deficiency) (algorithm 1).

Hyperbilirubinemia in the newborn period suggests a hemolytic etiology; microcytosis at birth suggestschronic intrauterine blood loss or thalassemia.

Compared with term infants, preterm infants are born with lower HCT and HGB, have shorter red bloodcell (RBC) life span, and have impaired erythropoietin production due to immature liver function [1].Hence the decline in RBC production occurs earlier after birth and is more severe than the anemia seenin term infants. This is referred to as "anemia of prematurity" and is discussed in detail separately. (See"Anemia of prematurity".)

Infants three to six months − Anemia detected at three to six months of age suggests ahemoglobinopathy. Nutritional iron deficiency is an unlikely cause of anemia before the age of six monthsin term infants. (See "Diagnosis of sickle cell disorders" and "Clinical manifestations and diagnosis of thethalassemias".)

Toddlers, children, and adolescents − In toddlers, older children, and adolescents, acquired causes ofanemia are more likely, particularly iron deficiency anemia. Screening for iron deficiency anemia isrecommended in all children at 9 to 12 months of age. (See "Iron deficiency in infants and young children:Screening, prevention, clinical manifestations, and diagnosis", section on 'Screening recommendations'.)

Symptoms — Characterizing the symptoms helps elucidate the severity and chronicity of anemia andmay identify patients with blood loss or hemolytic etiologies:

Onset and severity of symptoms − Common symptoms of anemia include lethargy, tachycardia,and pallor. Infants may present with irritability and poor oral intake. Because of the body'scompensatory abilities, patients with chronic anemia may have few or no symptoms compared withthose with acute anemia at comparable hemoglobin (HGB) levels.

•

Symptoms of hemolysis − Changes in urine color, scleral icterus, or jaundice may indicate thepresence of a hemolytic disorder. Hemolytic episodes that occur only in male family members mayindicate the presence of a sexlinked disorder, such as glucose6phosphate dehydrogenase (G6PD)deficiency. (See "Overview of hemolytic anemias in children" and "Diagnosis and treatment ofglucose6phosphate dehydrogenase deficiency".)

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Bleeding symptoms − Specific questions related to bleeding from the gastrointestinal tract, includingchanges in stool color, the identification of blood in stools, and history of bowel symptoms, shouldbe reviewed. Severe or chronic epistaxis also may result in anemia from blood loss and irondeficiency. In adolescent girls, menstrual history should be obtained, including duration and amountof bleeding. Severe epistaxis and/or menorrhagia should raise suspicion for an underlying bleedingdisorder [5]. In patients who have symptoms of gastrointestinal bleeding, it is important to determinewhether there is a family history of inflammatory bowel disease, intestinal polyps, colorectal cancer,hereditary hemorrhagic telangiectasia, von Willebrand disease, platelet disorders, or hemophilia.(See "Abnormal uterine bleeding in adolescents: Differential diagnosis and approach" and "Approachto upper gastrointestinal bleeding in children" and "Evaluation of epistaxis in children" and "Approachto the child with bleeding symptoms".)

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Past medical history — The past medical history should focus on characterizing past episodes ofanemia and identifying underlying medical conditions:

Birth history − The birth and neonatal history should include gestational age, duration of birthhospitalization, and history of jaundice and/or anemia in the newborn period. Results of newbornscreening (which typically includes screening for sickle cell disease) should be reviewed. (See"Clinical manifestations of glucose6phosphate dehydrogenase deficiency", section on 'Neonatalhyperbilirubinemia' and "Postnatal diagnosis and management of hemolytic disease of the fetus andnewborn" and "Anemia of prematurity" and "Diagnosis of sickle cell disorders", section on 'Newbornscreening'.)

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History of anemia − Previous complete blood counts (CBCs) should be reviewed, and if prioranemic episodes occurred, they should be characterized (including duration, etiology, therapy, andresolution). Prior episodes of anemia suggest an inherited disorder, whereas anemia in a patient withpreviously documented normal CBC suggests an acquired etiology. Patients with certainhemoglobinopathies (such as hemoglobin E or the various thalassemias) may have a history oftreatment on multiple occasions for an erroneous diagnosis of iron deficiency anemia. (See "Clinicalmanifestations and diagnosis of the thalassemias".)

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Underlying medical conditions − Past medical history and review of symptoms should be obtainedto elucidate chronic underlying infectious or inflammatory conditions that may result in anemia.Travel to/from areas of endemic infection (eg, malaria, hepatitis, tuberculosis) should be noted (theCenters for Disease Control and Prevention website provides updated information on malaria andtuberculosis). Recent illnesses should be reviewed to investigate for possible infectious etiologies ofanemia.

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Drug and toxin exposure — Current and past medications (including homeopathic or herbalsupplements) should be reviewed with particular attention to oxidant drugs that can cause hemolysis,particularly in patients with underlying G6PD deficiency (table 3). Possible environmental toxin exposureshould be explored, including lead exposure and nitrates in well water. (See "Clinical manifestations ofglucose6phosphate dehydrogenase deficiency", section on 'Drugs and chemicals' and "Childhood leadpoisoning: Exposure and prevention" and "Extrinsic nonautoimmune hemolytic anemia due to drugs andtoxins", section on 'Nitrites'.)

Family history — Family history of anemia should be reviewed in depth. Family members with jaundice,gallstones, or splenomegaly should be identified. Asking if family members have undergonecholecystectomy or splenectomy may aid in the identification of additional individuals with inheritedhemolytic anemias. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolyticanemias'.)

Dietary history— The dietary history is focused on assessing iron intake and, to a lesser degree, folateand B12 content. The type of diet, type of formula (if iron fortified), and age of infant at the time ofdiscontinuation of formula or breast milk should be documented. In addition, the amount and type of milkthe patient is drinking should be determined. The presence of pica (particularly pagophagia, the eating ofice) may suggest lead poisoning and/or iron deficiency. (See "Childhood lead poisoning: Clinical

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Physical examination — The physical examination also may provide important clues to the cause of anemia.Particular focus should be directed to examination of the skin, eyes, mouth, facies, chest, hands, andabdomen (table 4).

Pallor is assessed by examining sites where capillary beds are visible (eg, conjunctiva, palm, and nail beds).However, the sensitivity of clinical assessment of pallor in these locations in detecting severe anemia (ie, HGB<7 g/dL) is only approximately 50 to 60 percent [79].

Patients with hemolytic processes resulting in anemia may present with signs of scleral icterus, jaundice, andhepatosplenomegaly resulting from increased red cell destruction. However, as with the clinical detection ofanemia through evaluation of pallor, clinical detection of jaundice often is poor. As an example, in anemergency department setting, the clinical detection of jaundice was found to have sensitivity and specificityof only approximately 70 percent [10].

Laboratory evaluation — Initial laboratory studies include a CBC with red blood cell (RBC) indices and reviewof the peripheral blood smear. A reticulocyte count should be obtained, although this is not necessary for thediagnosis of iron deficiency anemia in children <2 years old who present with a mild microcytic anemia and asuggestive dietary history. (See "Iron deficiency in infants and young children: Screening, prevention, clinicalmanifestations, and diagnosis", section on 'Diagnosis'.)

The CBC, RBC indices, blood smear, and reticulocyte count are used to focus the diagnostic considerationsand guide further testing to confirm the etiology of anemia (algorithm 2 and algorithm 3). (See 'Diagnosticapproach' below.)

Complete blood count — The complete blood count (CBC) provides information about the RBCs andother cell lines (ie, white blood cells and platelets). All three cell lines should be evaluated for abnormalities.

Hemoglobin and hematocrit — Normal ranges for HGB and hematocrit (HCT) vary substantially withage, so it is important to use age and sex adjusted norms (figure 1 and table 1).

Falsely elevated results may be obtained when HGB and HCT values are measured using capillary samples(eg, finger or heel "sticks"), particularly when using microhematocrit measurements, although the likelihood ofmasking significant anemia is low [1113]. Spurious results may also occur with automated counters in thepresence of lipemia, hemolysis, leukocytosis (with white blood cell counts >50 x 10 /L), or highimmunoglobulin levels [14].

RBC indices — The red blood cell indices are an integral part of the evaluation of the anemic child.These include:

manifestations and diagnosis" and "Iron deficiency in infants and young children: Screening, prevention,clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents".)

Developmental history — Parents should be asked questions to determine if the child has reached ageappropriate developmental milestones. Developmental delay can be associated with iron deficiency,vitamin B12/folic acid deficiency, and Fanconi anemia [6]. (See "Developmentalbehavioral surveillanceand screening in primary care", section on 'Monitoring milestones'.)

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Mean corpuscular volume (MCV) − MCV is measured directly by automated blood cell counters andrepresents the mean value (in femtoliters [fL]) of the volume of individual RBCs in the blood sample.Normal values for MCV vary based upon age (infants have increased MCV compared with older children)(table 1). In preterm infants, MCV values increase with decreasing gestational age [15].

MCV is the most useful RBC parameter when evaluating a patient with anemia and is used to classifythe anemia as follows:

Microcytic anemia is defined as anemia with a low MCV value (ie, ≤2.5 percentile for age, race,and sex).

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Normocytic anemia is defined as anemia with a normal MCV value (ie, between the 2.5 and 97.5percentile for age, race, and sex).

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White blood count and platelet count — The other cell lines may provide clues to the underlyingcause of anemia (algorithm 3). Leukocytosis (high total white blood cell count) suggests an infectious etiologyor an acute leukemia. Thrombocytosis (high platelet count) is a common finding in iron deficiency [18].Thrombocytosis commonly occurs as part of the acute phase reaction in response to infection and otherinflammatory conditions, particularly Kawasaki disease. (See "Approach to the patient with neutrophilia" and"Kawasaki disease: Clinical features and diagnosis".)

Leukopenia, neutropenia, and/or thrombocytopenia may signify abnormal bone marrow function or increasedperipheral destruction of blood cells:

Blood smear — A review of the peripheral smear is an essential part of any anemia evaluation. Even if thepatient's RBC indices are normal, review of the blood smear may reveal abnormal cells that can help identifythe cause of anemia. (See "Evaluation of the peripheral blood smear".)

The following features should be noted:

Macrocytic anemia is defined as anemia with a high MCV value (ie, ≥97.5 percentile for age, race,and sex).

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Because reticulocytes have a greater MCV than do mature cells (picture 1), patients with significantdegrees of reticulocytosis may have elevated MCV values in the face of otherwise normocytic RBCs[16]. (See 'Macrocytic anemia' below and "Macrocytosis".)

Red cell distribution width (RDW) − The red cell distribution width (RDW) is a quantitative measure ofthe variability of RBC sizes in the sample (anisocytosis). Normal values vary little with age and aregenerally between 12 and 14 percent [11].

Mean corpuscular hemoglobin concentration (MCHC) − The mean corpuscular hemoglobinconcentration (MCHC) is a calculated index (MCHC = HGB/HCT), yielding a value of grams of HGB per100 mL of RBC. MCHC values vary depending upon the age (infants have higher values than olderchildren) and sex (males have slightly higher values than females) of the child. MCHC also increaseswith decreasing gestational age [15]. MCHC measurements may vary slightly based upon the technologyused and should be interpreted using the normal range for the specific laboratory.

Anemia can also be classified on the basis of MCHC:

Hypochromic anemia is defined as anemia with low MCHC (≤32 g/dL).•

Normochromic anemia is defined as anemia with MCHC values in the normal range (33 to 34 g/dL).•

Hyperchromic anemia is defined as anemia with high MCHC (≥35 g/dL).•

Hypochromia and hyperchromia usually can be appreciated on the peripheral smear (picture 2 and picture3) [17].

Causes of bone marrow suppression/failure include drugs or toxins, nutritional deficiency (eg, folic acid orvitamin B12 deficiency, and rarely iron deficiency), acute leukemia, or aplastic anemia.

Increased peripheral destruction of blood cells may be due to splenic hyperfunction ("hypersplenism"),microangiopathic hemolytic anemia (eg, hemolytic uremic syndrome), or Evans syndrome (a variant ofautoimmune hemolytic anemia).

RBC size – A normal RBC should have the same diameter as the nucleus of a small lymphocyte (picture4). This comparison will help the investigator identify the patient with microcytosis (picture 2) ormacrocytosis (picture 5).

Central pallor – The normal mature RBC is a biconcave disc (picture 6). As a result, RBCs on theperipheral smear demonstrate an area of central pallor, which, in normochromic RBCs, is approximatelyonethird the diameter of the cell (picture 4). Increased central pallor indicates hypochromic cells, whichmost often are seen in iron deficiency (picture 2) and thalassemia (picture 7). On the other hand,spherocytes (picture 3) and reticulocytes (picture 1) do not display central pallor, because they are not









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The appearance of the patient's leukocytes should also be noted:

Reticulocyte count — Reticulocytes are the youngest red cells in the circulation, and are identified by thepresence of residual RNA (picture 1 and picture 22). The reticulocyte is reported as a percentage of the RBCpopulation. After the first few months of life, the normal reticulocyte percentage is the same as that of theadult, approximately 1.5 percent [1].

In patients with anemia, the reticulocyte percentage must be interpreted in relation to the reduced number ofred blood cells. The simplest approach is to calculate the absolute reticulocyte count (ARC) as follows:

biconcave discs.

Fragmented cells – Although the patient's overall RBC indices may be normal, review of the bloodsmear may reveal the presence of small numbers of fragmented cells, indicating a microangiopathicprocess (picture 8). (See "Extrinsic nonimmune hemolytic anemia due to mechanical damage:Fragmentation hemolysis and hypersplenism" and "Overview of hemolytic anemias in children".)

Other features – Other anemias may be characterized by typical morphologic abnormalities, which maygo undetected without inspection of the peripheral smear; these include:

Sickle cells, as seen in sickle cell disease (picture 9). (See "Diagnosis of sickle cell disorders".)•

Elliptocytes, as seen in congenital elliptocytosis (picture 10). (See "Hereditary elliptocytosis:Clinical features, diagnosis, and treatment".)

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Stomatocytes, as seen in hereditary or acquired stomatocytosis (picture 11). (See"Stomatocytosis".)

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Pencil poikilocytes, which can be seen in iron deficiency anemia or thalassemia (picture 2).•

Target cells, as seen in the various hemoglobinopathies, including thalassemia, as well as in liverdisease, and postsplenectomy (picture 12 and picture 7). (See "Causes of spiculated cells(echinocytes and acanthocytes) and target cells".)

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Bite cells and Heinz bodies (picture 13) are seen in hemolytic anemia due to oxidant sensitivity,such as G6PD deficiency. (See "Diagnosis and treatment of glucose6phosphate dehydrogenasedeficiency".)

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The presence of numerous nucleated RBCs indicates rapid bone marrow turnover and is seen withhemolytic processes (picture 9 and picture 14).

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Red blood cell agglutination (picture 15) is seen in cold agglutinin hemolytic anemia. (See "Overviewof hemolytic anemias in children", section on 'Coldagglutinin hemolytic anemia'.)

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HowellJolly bodies (picture 16) are associated with absence or hypofunction of the spleen. (See"Approach to the adult patient with splenomegaly and other splenic disorders", section on'Hyposplenism and asplenia'.)

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Basophilic stippling (picture 17) is classically seen in lead poisoning and may also be present inthalassemia, sickle cell anemia, and sideroblastic anemia. (See "Childhood lead poisoning: Clinicalmanifestations and diagnosis".)

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Increases in circulating neutrophils, especially increased numbers of band forms or toxic changes (picture18), or the presence of atypical lymphocytes (picture 19) suggests the possibility of infectious orinflammatory conditions. (See "Approach to the patient with neutrophilia" and "Approach to the patientwith lymphocytosis or lymphocytopenia".)

Hypersegmented neutrophils (picture 20) suggest vitamin B12 or folate deficiency.

The presence of early white blood cell forms (eg, blasts) (picture 21) along with anemia should raise thesuspicion of leukemia or lymphoma. (See "Overview of the presentation and diagnosis of acutelymphoblastic leukemia in children and adolescents".)








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Absolute reticulocyte count = percent reticulocytes x red blood cell count/L

The ARC is calculated and reported by many automated cell counters. ARC is expected to increase in thepresence of anemia, although laboratories do not provide normal ranges adjusted for the level of anemia. In apatient with anemia, ARC values within the normal range (<100 x 10 /L) generally indicate an inappropriatelylow erythropoietic response [19]. The ARC is an indication of bone marrow erythropoietic activity and is usedto classify the bone marrow response to anemia (see 'Classification of anemia' below and "Approach to thediagnosis of hemolytic anemia in the adult", section on 'Reticulocyte response'):

These two categories are not mutually exclusive, however. Hemolysis or blood loss can be associated with alow reticulocyte count if there is a concurrent disorder that impairs RBC production (eg, infection).

In some cases, the reticulocyte count depends on the phase of the illness. As an example, the reticulocytecount is low in a child during the acute phase of transient erythroblastopenia of childhood or transient bonemarrow suppression caused by a viral illness. However, during the recovery phase from these disorders,children may have elevated reticulocyte counts, as the bone marrow recovers and responds to the anemia. Theabsence of scleral icterus, jaundice, and hepatosplenomegaly distinguishes this recovery process from ahemolytic process. (See "Anemia in children due to decreased red blood cell production", section on 'Transienterythroblastopenia of childhood (TEC)'.)

DIAGNOSTIC APPROACH — The history, physical examination, and initial laboratory tests are used tonarrow the diagnostic possibilities and guide further testing.

Abnormalities in other cell lines — The first step in narrowing the diagnostic possibilities is determiningwhether the patient has an isolated anemia or if other cell lines (ie, white blood cells [WBC] and platelets[PLT]) are also abnormal (algorithm 3):

Classification of anemia — Anemias are classified based upon red blood cell (RBC) size and the physiologicresponse of the bone marrow (ie, the reticulocyte response). Approaching the evaluation of an anemic patientusing these classification schemes helps to further narrow the diagnostic possibilities (algorithm 2).

Microcytic anemia — Microcytic anemia (picture 2) is defined as anemia with a low mean corpuscularvolume (MCV) (ie, ≤2.5 percentile for age, race, and sex) (table 1). (See 'RBC indices' above.)

The most common causes of microcytic anemia in children are iron deficiency and thalassemia (algorithm 2)

9

Anemia with a high ARC reflects an increased erythropoietic response to hemolysis or blood loss.

Anemia with a low or normal ARC reflects deficient production of RBCs (ie, a reduced marrow responseto the anemia).

Pancytopenia − Causes of pancytopenia in children include leukemia, infection, myelosuppressivemedications, aplastic anemia, and hypersplenism. (See "Aplastic anemia: Pathogenesis; clinicalmanifestations; and diagnosis" and "Overview of the presentation and diagnosis of acute lymphoblasticleukemia in children and adolescents" and "Approach to the child with an enlarged spleen".)

Anemia with thrombocytopenia − Causes of anemia associated with low PLT count include hemolyticuremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and Evans syndrome. (See"Overview of hemolytic uremic syndrome in children" and "Causes of thrombotic thrombocytopenicpurpurahemolytic uremic syndrome in adults" and "Clinical features and diagnosis of autoimmunehemolytic anemia: Warm agglutinins", section on 'Evans syndrome'.)

Anemia with thrombocytosis − Iron deficiency anemia is commonly associated with thrombocytosis[18].Other causes of anemia associated with elevated PLT count include postsplenectomy anemia andinfection or inflammation. (See "Iron deficiency in infants and young children: Screening, prevention,clinical manifestations, and diagnosis" and "Approach to the patient with thrombocytosis".)

Anemia with leukocytosis − Causes of anemia associated with elevated WBC count include leukemiaand infection. (See "Overview of the presentation and diagnosis of acute lymphoblastic leukemia inchildren and adolescents".)

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http://www.uptodate.com/contents/aplastic-anemia-pathogenesis-clinical-manifestations-and-diagnosis?source=see_link

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[14,20].

The red cell distribution width (RDW) can be helpful in differentiating iron deficiency from thalassemia.Anisocytosis (high RDW) is typical of iron deficiency whereas the RDW is usually normal in patients withthalassemia (though elevated RDW can occur). (See "Iron deficiency in infants and young children: Screening,prevention, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of thethalassemias".)

Normocytic anemia — Normocytic anemia is defined as anemia with a normal MCV (ie, between the 2.5and 97.5 percentile for age, race, and sex (table 1)). Common causes of normocytic anemia include hemolyticanemias, blood loss, infection, medication, and anemia of chronic disease. (See 'RBC indices' above.)

Macrocytic anemia — Macrocytic anemia (picture 5) is defined as anemia with a high MCV (ie, ≥97.5percentile for age, race and sex (table 1)). (See 'RBC indices' above.)

The most common cause of macrocytosis in children is exposure to certain medications (eg, anticonvulsants,zidovudine, and immunosuppressive agents) [20,21]. Other causes include vitamin B12 or folate deficiency,liver disease, DiamondBlackfan anemia, hypothyroidism, and aplastic anemia (algorithm 2).

Reticulocyte response — The reticulocyte count is especially helpful in evaluating children withnormocytic anemia (algorithm 2 and algorithm 3) (see 'Reticulocyte count' above):

Confirmatory testing — Once the diagnostic possibilities have been narrowed based upon the MCV andreticulocyte count, confirmatory testing is performed (algorithm 2 and algorithm 3).

If hemolytic anemia is suspected, testing should include serum indirect bilirubin, lactate dehydrogenase, andhaptoglobin levels. Testing for specific etiologies may include direct antiglobulin test, G6PD deficiencyscreening test, osmotic fragility, and/or hemoglobin electrophoresis. (See "Overview of hemolytic anemias inchildren".)

If iron deficiency is suspected, additional studies may include serum ferritin, iron, and total iron bindingcapacity (TIBC). Iron studies are not necessary in children <2 years old who present with a mild microcyticanemia and a suggestive dietary history. A therapeutic trial of iron may be used to confirm the diagnosis inthese children. (See "Iron deficiency in infants and young children: Screening, prevention, clinicalmanifestations, and diagnosis", section on 'Presumptive diagnosis and empiric trial'.)

Testing for other nutritional deficiencies and/or lead poisoning may include serum folate, B12, and lead levels.(See "Diagnosis and treatment of vitamin B12 and folate deficiency" and "Childhood lead poisoning: Clinicalmanifestations and diagnosis".)

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High reticulocyte count − A high reticulocyte count (>3 percent) reflects an increased erythropoieticresponse to blood loss or hemolysis (table 5). Common causes include: hemorrhage; autoimmunehemolytic anemia; membranopathies (eg, hereditary spherocytosis); enzymopathies (eg, glucose6phosphate dehydrogenase [G6PD] deficiency); hemoglobinopathies (eg, sickle cell disease); andmicroangiopathic hemolytic anemia (eg, hemolytic uremic syndrome) (algorithm 2 and algorithm 3). (See"Overview of hemolytic anemias in children".)

Low or normal reticulocyte count − A low or normal reticulocyte count reflects deficient production ofRBCs (ie, a reduced marrow response to the anemia).

Causes of inadequate marrow response include infections, lead poisoning, hypoplastic anemias, transienterythroblastopenia of childhood (TEC), DiamondBlackfan anemia (which typically presents withmacrocytic anemia), drugs (most drugs that decrease erythropoiesis affect other cell lines as well;cisplatin is an example of a medication that can cause isolated suppression of erythropoiesis), and kidneydisease (algorithm 2 and algorithm 3).

In addition, anemia due to acute blood loss can be associated with low absolute reticulocyte count (ARC)if there has not been time for the bone marrow to mount an appropriate reticulocyte response, whichtypically takes about one week.

http://www.uptodate.com/contents/iron-deficiency-in-infants-and-young-children-screening-prevention-clinical-manifestations-and-diagnosis?source=see_link&sectionName=Presumptive+diagnosis+and+empiric+trial&anchor=H19509670#H19509670








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Bone marrow aspirate and/or biopsy may be necessary to evaluate for leukemia or other diseases of bonemarrow failure (eg, aplastic anemia, DiamondBlackfan anemia).

SUMMARY

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REFERENCES

1. Gallagher PG. The neonatal erythrocyte and its disorders. In: Nathan and Oski's Hematology andOncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE, Look T, Lux SE, Ginsburg D, NathanDG (Eds), WB Saunders, Philadelphia 2015. p.52.

2. Kling PJ, Schmidt RL, Roberts RA, Widness JA. Serum erythropoietin levels during infancy:associations with erythropoiesis. J Pediatr 1996; 128:791.

3. Holland BM, Jones JG, Wardrop CA. Lessons from the anemia of prematurity. Hematol Oncol Clin North

The threshold for defining anemia is a hemoglobin (HGB) or hematocrit (HCT) that is ≤2.5 percentile forage, race, and sex (table 1). Hemoglobin levels are high (>14 g/dL) at birth and then rapidly decline,reaching a nadir of approximately 11 g/dL at six to nine weeks of age, which is called "physiologic anemiaof infancy" (figure 1). (See 'Definition of anemia' above.)

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The causes of anemia vary based upon the age at presentation. In neonates and young infants, immunehemolytic disease, infection, and hereditary disorders are most common (algorithm 1). In older children,acquired causes of anemia are more likely, particularly iron deficiency anemia (dietary or due to bloodloss). (See 'Age of patient' above and "Iron deficiency in infants and young children: Screening,prevention, clinical manifestations, and diagnosis" and "Overview of hemolytic anemias in children" and"Introduction to hemoglobin mutations".)

Key historical factors in the assessment of a child with anemia include the severity and onset ofsymptoms, evidence of jaundice or blood loss (gastrointestinal symptoms and menstrual history), drugand toxin exposure, chronic disease, and family history of anemias or hemoglobinopathy (table 2). (See'History' above.)

The physical examination should include a careful assessment for pallor, scleral icterus, jaundice,hepatomegaly, and splenomegaly (table 4). (See 'Physical examination' above.)

The laboratory examination should begin with a complete blood count, including red blood cell (RBC)indices, reticulocyte count, and review of the peripheral blood smear. (See 'Laboratory evaluation' above.)

Examination of the peripheral blood smear may reveal features that suggest a specific cause of anemia,and helps to evaluate the possibility of a hematologic malignancy. (See 'Blood smear' above.)

The mean corpuscular volume (MCV) provides a preliminary categorization of the anemia, which guidesadditional testing (algorithm 2 and algorithm 3). Common causes of microcytic (ie, low MCV) anemiainclude iron deficiency and thalassemia. Common causes of normocytic (ie, normal MCV) anemia includehemolytic anemias, blood loss, infection, medication, and anemia of chronic disease. Common causes ofmacrocytic (ie, high MCV) anemia include medications (eg, anticonvulsant drugs) and deficiency ofvitamin B12 or folate. (See 'Classification of anemia' above.)

The reticulocyte count distinguishes disorders resulting from rapid destruction or loss of RBCs (hemolysisor bleeding) from disorders resulting in an inability to adequately produce RBCs (ie, bone marrowdepression). Hemolysis and bleeding are usually associated with a high reticulocyte count (>3 percent),whereas bone marrow depression is associated with a low reticulocyte count (algorithm 2). (See'Reticulocyte count' above.)

Once the diagnostic possibilities have been narrowed based upon RBC indices and reticulocyteresponse, further confirmatory testing is performed (algorithm 2 and algorithm 3). (See 'Confirmatorytesting' above.)



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http://www.uptodate.com/contents/approachtothechildwithanemia?topicKey=PEDS%2F5927&elapsedTimeMs=0&source=search_result&searchTe… 10/54

Am 1987; 1:355.4. Matoth Y, Zaizov R, Varsano I. Postnatal changes in some red cell parameters. Acta Paediatr Scand

1971; 60:317.5. Sandoval C, Dong S, Visintainer P, et al. Clinical and laboratory features of 178 children with recurrent

epistaxis. J Pediatr Hematol Oncol 2002; 24:47.6. Geller J, Kronn D, Jayabose S, Sandoval C. Hereditary folate malabsorption: family report and review of

the literature. Medicine (Baltimore) 2002; 81:51.7. Kalter HD, Burnham G, Kolstad PR, et al. Evaluation of clinical signs to diagnose anaemia in Uganda

and Bangladesh, in areas with and without malaria. Bull World Health Organ 1997; 75 Suppl 1:103.8. Stoltzfus RJ, EdwardRaj A, Dreyfuss ML, et al. Clinical pallor is useful to detect severe anemia in

populations where anemia is prevalent and severe. J Nutr 1999; 129:1675.9. Montresor A, Albonico M, Khalfan N, et al. Field trial of a haemoglobin colour scale: an effective tool to

detect anaemia in preschool children. Trop Med Int Health 2000; 5:129.10. Hung OL, Kwon NS, Cole AE, et al. Evaluation of the physician's ability to recognize the presence or

absence of anemia, fever, and jaundice. Acad Emerg Med 2000; 7:146.11. Thomas WJ, Collins TM. Comparison of venipuncture blood counts with microcapillary measurements in

screening for anemia in oneyearold infants. J Pediatr 1982; 101:32.12. Daae LN, Hallerud M, Halvorsen S. A comparison between haematological parameters in 'capillary' and

venous blood samples from hospitalized children aged 3 months to 14 years. Scand J Clin Lab Invest1991; 51:651.

13. Bellamy GJ, Hinchliffe RF. Venous and skin puncture blood counts compared. Clin Lab Haematol 1988;10:329.

14. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and Oski'sHematology and Oncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE, Look T, Lux SE,Ginsburg D, Nathan DG, et AL (Eds), WB Saunders, Philadelphia 2015. p.293.

15. Christensen RD, Jopling J, Henry E, Wiedmeier SE. The erythrocyte indices of neonates, defined usingdata from over 12,000 patients in a multihospital health care system. J Perinatol 2008; 28:24.

16. d'Onofrio G, Chirillo R, Zini G, et al. Simultaneous measurement of reticulocyte and red blood cell indicesin healthy subjects and patients with microcytic and macrocytic anemia. Blood 1995; 85:818.

17. Walters MC, Abelson HT. Interpretation of the complete blood count. Pediatr Clin North Am 1996;43:599.

18. Sandoval C. Thrombocytosis in children with iron deficiency anemia: series of 42 children. J PediatrHematol Oncol 2002; 24:593.

19. Means RT, Glader B. Anemia: General Considerations. In: Wintrobe's Clinical Hematology, 12 ed, GreerJP, Foerster J, Rodgers GM, et al (Eds), Lippincott Williams and Wilkins, Philadelphia 2009. Vol 1,p.784.

20. Rapaport SI. Diagnosis of anemia. In: Introduction to hematology, JB Lippincott, Philadelphia 1987. p.15.21. Pappo AS, Fields BW, Buchanan GR. Etiology of red blood cell macrocytosis during childhood: impact of

new diseases and therapies. Pediatrics 1992; 89:1063.

Topic 5927 Version 20.0



















GRAPHICS

Normal values for hemoglobin, hematocrit, and mean corpuscularvolume in children

Age

Hemoglobin(g/dL)

Hematocrit(%)

MCV (fL)

50thpercentile

Lowerlimit*

50thpercentile

Lowerlimit*

50thpercentile

Lowerlimit*

Upperlimit*

1year

Caucasian 12.5 11 37 32 80 71 89

AfricanAmerican 12 11 36 31 77 63 88

2 to3years

Caucasian 12.6 11 37 33 82 74 89

AfricanAmerican 12 11 36 32 80 64 89

4 to6years

Caucasian 12.9 11.7 38 34 84 77 91

AfricanAmerican 12.5 11 37 33 83 67 91

7 to10years

Caucasian 13.5 12 40 35 85 78 91

AfricanAmerican 12.7 11.2 38 34 84 72 92

11 to14years

Caucasian Female 13.7 12.3 40 36 87 80 94

Male 14.3 12.6 42 36 87 80 94

AfricanAmerican

Female 12.9 10.6 38 33 86 71 95

Male 13.6 11.8 40 35 86 73 95

15 to18years

Caucasian Female 13.7 11.5 40 34 89 81 96

Male 15.4 13.7 46 40 89 81 96

AfricanAmerican

Female 12.8 10.7 38 32 87 71 96

Male 14.9 12.9 44 38 87 75 96

HGB: hemoglobin; HCT: hematocrit; MCV: mean corpuscular volume; fL: femtoliter; AAP: AmericanAcademy of Pediatrics.* Lower limits are defined as the 2.5th percentile for all values, except hemoglobin levels at 1 and 2to 3 years, which are based upon recommendations from the AAP. Upper limits are defined as the97.5th percentile for all values. ¶ Normal values for hemoglobin, hematocrit, and MCV change dramatically during the first year of life.Refer to topic on the approach to the child with anemia for a discussion of normal values in infants <1year old.

References: 1. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and

Oski's Hematology and Oncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE,Ginsburg D, et al (Eds), WB Saunders, Philadelphia 2015. p.293.

2. Cembrowski GS, Chan J, Cheng C. NHANES 19992000 data used to create comprehensivehealthassociated race, sex and agestratified pediatric reference intervals for the CoulterMAXM. Laboratory Hematol 2004; 10:245.

3. Baker RD, Greer FR, Committee on Nutrition American Academy of Pediatrics. Diagnosis andprevention of iron deficiency and irondeficiency anemia in infants and young children (03years of age). Pediatrics 2010; 126:1040.

¶



Graphic 101544 Version 1.0



Normal values for hematocrit and hemoglobinduring the first year of life in healthy term infants

Data from: 1. Jopling J, Henry E, Wiedmeier SE, et al. Reference ranges for hematocritand blood hemoglobin concentration during the neonatal period: data from amultihospital health care system. Pediatrics 2009; 123:e333.2. Oski FA, Naiman JL. Hematologic problems in the newborn, 2nd ed, WBSaunders, Philadelphia 1972; p.13.3. Saarinen UM, Siimes MA. Developmental changes in red blood cell countsand indices of infants after exclusion of iron deficiency by laboratory criteriaand continuous iron supplementation. J Pediatr 1978; 92:412.




Diagnostic approach to anemia in the newborn

HGB: hemoglobin; RBC: red blood cell; DAT: direct antiglobulin test; MCV: mean corpuscular volume; DIC:disseminated intravascular coagulation; PK: pyruvate kinase; G6PD: glucose6phosphate dehydrogenase;CMV: cytomegalovirus; HSV: herpes simplex virus.

Reproduced from: Gallagher PG. The neonatal erythrocyte and its disorders. In: Nathan and Oski'sHematology and Oncology of Infancy and Childhood, 8th Ed, Orkin SH, Fisher DE, Look AT, et al (Eds), WBSaunders, Philadelphia 2015. p.52. Illustration used with the permission of Elsevier Inc. All rights reserved.




The medical history in the child with anemia: Elements associatedwith specific causes of childhood anemia

Patientcharacteristics

Age:

In neonates and young infants, immune hemolytic disease, infection,and hereditary disorders are most commonAnemia detected at three to six months of age suggests ahemoglobinopathy

Nutritional iron deficiency is an unlikely cause of anemia before theage of six months in term infantsIn older children, acquired causes of anemia are more likely,particularly iron deficiency anemia (dietary or due to blood loss)

Sex:

Some inherited causes of anemia are Xlinked (eg, G6PD deficiencyand Xlinked sideroblastic anemia), and occur most commonly inmales

Race/ethnicity:

Hemoglobin S and C are most commonly seen in black and HispanicpopulationsThalassemia syndromes are more common in individuals ofMediterranean and Southeast Asian descent

G6PD deficiency is more common among Sephardic Jews, Filipinos,Greeks, Sardinians, Kurds, and black populations

Symptoms Changes in urine color, scleral icterus, or jaundice suggest a hemolyticdisorderBloody stools, hematemesis, severe epistaxis, or severe menstrualbleeding suggest anemia from blood loss and/or iron deficiency

Infectious symptoms (eg, fevers, cough) suggest an infectious etiology ofanemia

History ofanemia

Prior episodes of anemia suggest an inherited disorderAnemia in a patient with previously documented normal CBC suggestsan acquired etiology

Hyperbilirubinemia in the newborn period suggests a hemolytic etiology;microcytosis at birth suggests chronic intrauterine blood loss orthalassemia

Underlyingmedicalconditions

Underlying renal disease, malignancy, or inflammatory/autoimmunedisorders may be associated with anemia

Drugs andtoxin exposure

Anemia following exposure to oxidant drugs or fava beans suggests G6PDdeficiencyExposure to paint, home renovations, or use of imported or glazedceramics suggest lead toxicity

Family history Family members with jaundice, gallstones, or splenomegaly suggests aninherited hemolytic anemia

Dietary history In infants and young children, iron deficiency is suggested by the following:

Use of low iron formula



Introduction of unmodified cow's milk before the age of one yearExcessive milk intake (>24 ounces per day)

Poor intake of ironrich foods (meats or fortified infant cereal)

Travel history Travel to/from areas of endemic infection suggests infectious etiologysuch as malaria or tuberculosis

Developmentalhistory

Developmental delay is associated with iron deficiency, vitamin B12/folicacid deficiency, and Fanconi anemia

CBC: complete blood count; G6PD: glucose6phosphate dehydrogenase.




Partial list of medicines and other substances thought to beunsafe or safe in individuals with G6PD deficiency

Medicines and other substances likely to be UNSAFE in moderate tosevere G6PD deficiency (WHO classes I, II, and III*)

Antiinfectives

Dapsone

Nitrofurantoin and related, including nifuratel and nitrofurazone (nitrofural)

Primaquine

Miscellaneous

Dimercaprol

Methylene blue (methylthioninium chloride) [antidote, also contained in some urinary tractcombination products]

Phenazopyridine

Toluidine blue (tolonium chloride) [diagnostic agent]

Uricase (rasburicase, pegloticase)

Chemical exposures and foods likely to be UNSAFE in moderate to severe G6PDdeficiency (WHO classes I, II, and III)

Aniline dyes

Naphthalene (mothballs, lavatory deodorant)

Henna compounds (black and red Egyptian) and related dyes used for hair and tattoos

Fava beans

Some prefer to avoid red wine, legumes, blueberries, soya, and tonic water

Medicines previously considered unsafe, but PROBABLY SAFE given inusual therapeutic doses in G6PD deficiency (WHO classes II and III);NOTE: safety in WHO Class I G6PD deficiency is generally notknown

Analgesics

Acetaminophen (paracetamol)

Antipyrine (phenazone)

Aspirin (acetylsalicylic acid)

Aminophenazone and related NSAIDs (dipyrone , metamizole )

Antiinfectives

Antimalarials: chloroquine, mepacrine, quinine

Fluoroquinolones : ciprofloxacin, levofloxacin, nalidixic acid, norfloxacin, ofloxacin

Sulfonamides: cotrimoxazole , sulfacetamide (topical), sulfanilamide , sulfisoxazole,sulfamethoxazole , trimethoprimsulfamethoxazole

Other antiinfectives: chloramphenicol, furazolidone , isoniazid, mepacrine

Miscellaneous

Ascorbic acid (vitamin C)

[13]

¶ ¶

Δ

[4]

[2]

¶ ¶ ¶

Δ

Δ◊ Δ ΔΔ◊ Δ◊

Δ



Glyburide (glibenclamide)

Hydroxychloroquine (see chloroquine)

Isosorbide dinitrate

Mesalamine (mesalazine)

Quinine

Succimer (dimercaptosuccinic acid)

Sulfasalazine

Medicines GENERALLY CONSIDERED SAFE in usual therapeutic dosesin G6PD (WHO classes II and III); NOTE: safety in WHO class I G6PDdeficiency is generally not known

Some agents listed are associated with nonhemolytic anemias unrelated to G6PDdeficiency. For additional information, please refer to individual drug monographs.

Colchicine

Diphenhydramine

Doxorubicin

Levodopa, levodopacarbidopa

Paraaminosalicylic acid (aminosalicylic acid)

Paraaminobenzoic acid (PABA)

Phenacetin

Phenylbutazone

Probenecid

Procainamide

Pyrimethamine

Streptomycin

Sulfadiazine

Tripelennamine

Vitamin K, Vitamin K synthetic derivatives

Please consult the G6PD deficiency favism association website for additional informationon this subject: http://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISSit.

G6PD: glucose6phosphate deficiency; WHO: World Health Organization; NSAIDs: nonsteroidalantiinflammatory drugs.* There is marked variability in reports of drugs that are unsafe in patients with G6PD deficiency. Thislist is based on evidence supporting a clear association with druginduced hemolysis. Individualcharacteristics (ie, degree of G6PD deficiency, dose, presence of infection) will determine actual safetyor injury. Medicines known to be unsafe in G6PD deficiency that are no longer in clinical use areexcluded from this list.¶ Not available in the United States. Available in other countries.Δ Conflicting reports. Considered unsafe for all degrees of G6PD deficiency according to somereferences. ◊ Sulfamethoxazole may produce a modest shortening in the survival of G6PDdeficient red cells. Foradditional detail, please refer to UpToDate topic on clinical manifestations of glucose6phosphatedehydrogenase.§ There are reports of hemolytic episodes after administration of sulfasalazine (of which mesalamine

Δ

Δ§

Δ§

[2]

¶

¶

Δ

Δ[3]

Δ

[3]

http://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it



is a component) in G6PDdeficient patients as well as numerous reports of anemia with theappearance of Heinz bodies in patients who received sulfasalazine who were not G6PD deficient.

References:1. Cappellini MD, Fiorelli G. Glucose6phosphate dehydrogenase deficiency. Lancet 2008;

371:64.2. Youngster I, Arcavi L, Schechmaster R. Medications and glucose6phosphate dehydrogenase

deficiency. Drug Saf 2010; 33:713.3. Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenetics with ongoing

clinical implications. Br J Haematol 2014; 164:469.4. G6PD deficiency favism association website:

http://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISSit (Accessed January 29,2014).


http://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it



Physical findings as clues to the etiology of anemia in children

Finding Possible etiology

Skin

Hyperpigmentation Fanconi anemia

Petechiae, purpura Autoimmune hemolytic anemia with thrombocytopenia,hemolyticuremic syndrome, bone marrow aplasia, bonemarrow infiltration

Carotenemia Suspect iron deficiency in infants

Jaundice Hemolytic anemia, hepatitis, and aplastic anemia

Cavernous hemangioma Microangiopathic hemolytic anemia

Ulcers on lower extremities Sickle cell disease (S and C hemoglobinopathies), thalassemia

Facies

Frontal bossing,prominence of the malarand maxillary bones

Congenital hemolytic anemias, thalassemia major, severe irondeficiency

Eyes

Microcornea Fanconi anemia

Tortuosity of theconjunctival and retinalvessels

Sickle cell disease (S and C hemoglobinopathies)

Microaneurysms of retinalvessels

Sickle cell disease (S and C hemoglobinopathies)

Cataracts Glucose6phosphate dehydrogenase deficiency, galactosemiawith hemolytic anemia in newborn period

Vitreous hemorrhages S hemoglobinopathy

Retinal hemorrhages Chronic, severe anemia

Edema of the eyelids Infectious mononucleosis, exudative enteropathy with irondeficiency, renal failure

Blindness Osteopetrosis

Mouth

Glossitis Vitamin B12 deficiency, iron deficiency

Angular stomatitis

Chest

Unilateral absence of thepectoral muscles

Poland's syndrome (increased incidence of leukemia)

Shield chest DiamondBlackfan syndrome

Hands

Triphalangeal thumbs Red cell aplasia

Hypoplasia of the thenareminence

Fanconi anemia



Spoon nails Iron deficiency

Spleen

Enlargement Congenital hemolytic anemia, leukemia, lymphoma acuteinfection, portal hypertension

Reproduced with permission from: Oski FA, Brugnara G, Nathan DG. A diagnostic approach to theanemia patient. In: Nathan and Oski's Hematology of Infancy and Childhood. WB Sauders,Philadelphia. 1998. p.378.




Diagnostic approach to isolated anemia in children: Morphologic classification



HGB: hemoglobin; RBC: red blood cell; MCV: mean corpuscular volume; RDW: red cell distribution width; TIBC: total iron binding capacity; TEC: transient erythroblastopenia of childhood; G6PD:glucose6phosphate dehydrogenase; HUS: hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulation; DAT: direct antiglobulin test;PMNs: polymorphonuclear cells; LDH: lactate dehydrogenase.* Hemoglobin levels vary considerably by age, race, and sex; when diagnosing anemia, hemoglobin values should be compared with age, race, and sexadjusted norms. Mild anemia occurring at sixto nine weeks of life is consistent with "physiologic anemia" and is not pathologic. Falsely elevated hemoglobin values may occur when measured using capillary samples (eg, finger or heel "sticks"),particularly when using microhematocrit measurements. Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis, or high immunoglobulin levels.¶ The RDW can be helpful in differentiating thalassemia from iron deficiency. High RDW is typical of iron deficiency whereas the RDW is usually normal in patients with thalassemia (though elevatedRDW can occur).Δ Anemia of chronic disease typically presents as a normocytic anemia, but can have low MCV.◊ In children with mild microcytic anemia and dietary history that is suggestive of iron deficiency, serum iron studies (ie, ferritin, iron, and TIBC levels) are generally not necessary. In these children,a therapeutic trial of iron can be used to confirm the diagnosis.§ Evidence of hemolysis includes jaundice, indirect hyperbilirubinemia, elevated lactate dehydrogenase, and/or elevated haptoglobin.￥ Findings on blood smear may suggest an underlying etiology of anemia but they are generally not diagnostic. Further confirmatory testing should be carried out to confirm the diagnosis.

References:1. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and Oski's Hematology and Oncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE, Ginsburg

D, et al (Eds), WB Saunders, Philadelphia 2015. p.293.2. Rapaport SI. Diagnosis of anemia. In: Introduction to hematology, JB Lippincott, Philadelphia 1987. p.15.




Diagnostic approach to the child with anemia and abnormalities of othercell lines

HGB: hemoglobin; HUS: hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; DIC:disseminated intravascular coagulation; PMNs: polymorphonuclear cells; TIBC: total iron binding capacity; LDH:lactate dehydrogenase; DAT: direct antiglobulin test; WBC: white blood cell; PLT: platelets.* Hemoglobin levels vary considerably by age, race, and sex; when diagnosing anemia, hemoglobin values should becompared with age, race, and sexadjusted norms. Mild anemia occurring at six to nine weeks of life is consistentwith "physiologic anemia" and is not pathologic. Falsely elevated hemoglobin values may occur when measuredusing capillary samples (eg, finger or heel "sticks"), particularly when using microhematocrit measurements.Spurious results may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis, orhigh immunoglobulin levels.¶ Findings on blood smear may suggest an underlying etiology of anemia, but they are generally not diagnostic.Further confirmatory testing should be performed to confirm the diagnosis.Δ In children with mild microcytic anemia and dietary history that is suggestive of iron deficiency, serum iron



studies (ie, ferritin, iron, and TIBC levels) are generally not necessary. In these children, a therapeutic trial of ironcan be used to confirm the diagnosis.

References:1. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and Oski's

Hematology and Oncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE, Ginsburg D, et al (Eds), WBSaunders, Philadelphia 2015. p.293.

2. Rapaport SI. Diagnosis of anemia. In: Introduction to hematology, JB Lippincott, Philadelphia 1987. p.15.




Polychromatophilia due to increased reticulocytes

Peripheral blood smear taken from a patient with increasedreticulocytes. Unlike mature red cells (thin black arrows), which havecentral pallor and are the same size as the nucleus of a smalllymphocyte (thick arrow), reticulocytes (blue arrows) are larger, havea blue tint, and lack central pallor because they are not biconcavediscs. (WrightGiemsa stain).

Courtesy of Stanley Schrier, MD.


Normal peripheral blood smear

High power view of a normal peripheral blood smear. Severalplatelets (black arrows) and a normal lymphocyte (blue arrow) canalso be seen. The red cells are of relatively uniform size andshape. The diameter of the normal red cell should approximate thatof the nucleus of the small lymphocyte; central pallor (red arrow)should equal onethird of its diameter.

Courtesy of Carola von Kapff, SH (ASCP).



Microcytic hypochromic red cells in iron deficiencyanemia

Peripheral smear at two different magnifications from a patient withiron deficiency shows small (microcytic) red cells with a thin rim ofpink hemoglobin (hypochromic); occasional "pencil" shaped cells arealso present. Normal red cells are similar in size to the nucleus of asmall lymphocyte (arrow) and central pallor should equal about onethird of its diameter; thus, many hypochromic and microcytic cells arepresent in this smear.

Kindly supplied by Dr. German Pihan, Department of Pathology, Beth IsraelDeaconess Medical Center, Boston, MA.





Spherocytes

Peripheral blood smear shows multiple spherocytes which are small,dark, dense hyperchromic red cells without central pallor (arrows).These findings are compatible with hereditary spherocytosis orautoimmune hemolytic anemia.










High power view of a normal peripheral blood smear. Several platelets(black arrows) and a normal lymphocyte (blue arrow) can also beseen. The red cells are of relatively uniform size and shape. Thediameter of the normal red cell should approximate that of thenucleus of the small lymphocyte; central pallor (red arrow) shouldequal onethird of its diameter.





Macroovalocytes in vitamin B12 deficiency

Peripheral smear shows marked macroovalocytosis in a patient withvitamin B12 deficiency. In this case teardrop cells are an advancedform of macroovalocytes.

Courtesy of Stanley L Schrier, MD.








Normal red blood cell

Scanning electron microphotograph of a normal adult human red bloodcell. Note the biconcave disc shape, which gives the cell more surfacearea than a sphere of identical volume. The normal red cell is thinnestin the center, resulting in the central pallor seen on the peripheralsmear.





Beta thalassemia trait

Peripheral smear from a patient with beta thalassemia trait. The fieldshows numerous hypochromic and microcytic red cells (thin arrows),some of which are also target cells (blue arrows).

Courtesy of Stanley Schrier, MD








Peripheral smear in microangiopathic hemolyticanemia showing presence of schistocytes

Peripheral blood smear from a patient with a microangiopathichemolytic anemia with marked red cell fragmentation. The smearshows multiple helmet cells (small black arrows), other fragmentedred cells (large black arrow); microspherocytes are also seen (bluearrows). The platelet number is reduced; the large platelet in thecenter (red arrow) suggests that the thrombocytopenia is due toenhanced destruction.








Peripheral blood smear in sickle cell anemia

Peripheral blood smear from a patient with sickle cell anemia. Thissmear shows multiple sickle cells (blue arrows). There are alsofindings consistent with functional asplenia, including a nucleated redblood cell (upper left), a red blood cell containing a HowellJolly body(black arrow), and target cells (red arrow).









Elliptical red cells in hereditary elliptocytosis

Peripheral blood smear from a patient with hereditary elliptocytosisshows multiple elliptocytes.









Stomatocytosis

Peripheral blood smear showing multiple stomatocytes characterizedby a mouthshaped area of central pallor.









Target cells

Peripheral smear shows multiple target cells which have an area ofcentral density surrounded by a halo of pallor (arrows). These cellsare characteristic of liver disease and certain hemoglobinopathies(most notably hemoglobin C disease).









Peripheral smear in Heinz body hemolytic anemiashowing Heinz bodies and bite cells

Split screen view of a peripheral smear from a patient with Heinz bodyhemolytic anemia. Left panel: red cells with characteristic bitelikedeformity (arrows). Right panel: Heinz body preparation which revealsthe denatured hemoglobin precipitates.









Peripheral blood smear in beta thalassemiaintermedia

Peripheral smear from a patient with beta thalassemia intermediapostsplenectomy. This field shows target cells, hypochromic cells,microcytic cells, red cell fragments, red cells with bizarre shapes, anda single nucleated red cell (arrow).

Courtesy of Stanley Schrier, MD.




Red blood cell agglutination due to a coldagglutinin

Peripheral blood smear from a patient with cold agglutinin hemolyticanemia shows marked red blood cell agglutination into irregularclumps.









HowellJolly bodies following splenectomy

This peripheral blood smear shows two red blood cells (RBC) thatcontain HowellJolly bodies (black arrows). HowellJolly bodies areremnants of RBC nuclei that are normally removed by the spleen.Thus, they are seen in patients who have undergone splenectomy (asin this case) or who have functional asplenia (eg, from sickle celldisease). Target cells (blue arrows) are another consequence ofsplenectomy.









Basophilic stippling of red cells in lead poisoning

Peripheral blood smear shows basophilic stippling in several red cellsfrom a patient with lead poisoning. The granules represent ribosomalprecipitates. A similar picture can be seen in a number of otherconditions including thalassemia, megaloblastic anemia, sickle cellanemia, and sideroblastic anemia.









Toxic granulations and Döhle bodies ininfection/inflammation

Left panel: Peripheral blood smear shows neutrophils with toxic granulations,which are dark coarse granules. A Döhle body is also seen (arrow). Rightpanel: A neutrophil with toxic granulations, vacuoles (another toxic change),and a Döhle body (arrow). These abnormalities are characteristic of toxicsystemic illnesses.




High power view of a normal peripheral blood smear. Severalplatelets (black arrows) and a normal lymphocyte (blue arrow) canalso be seen. The red cells are of relatively uniform size and



shape. The diameter of the normal red cell should approximate thatof the nucleus of the small lymphocyte; central pallor (red arrow)should equal onethird of its diameter.





Atypical lymphocytes in infectious mononucleosis

Peripheral smear from a patient with infectious mononucleosis showsthree atypical lymphocytes with generous cytoplasm.





Megaloblastic blood picture

Peripheral blood smear showing a hypersegmented neutrophil (sevenlobes) and macroovalocytes, a pattern that can be seen withcobalamin or folate deficiency.









Lymphoblasts in acute lymphoblastic leukemia FABL1 morphologic type

Blood smear showing small lymphoblasts with rare nucleoli andvacuoles, as seen in acute lymphocytic leukemia (ALL) of the FrenchAmerican British (FAB) L1 morphologic type.

Courtesy of Robert Baehner, MD.




Reticulocytes after supravital staining

Supravital stain of a peripheral blood smear shows bluestainedresidual reticulin (ribosomal RNA) in reticulocytes.









Causes of hemolytic anemia in children

Intrinsic red blood cell defects

Enzyme deficiencies (eg, G6PD or pyruvate kinase deficiencies)

Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable hemoglobins)

Membrane defects (eg, hereditary spherocytosis, elliptocytosis)

Extrinsic red blood cell defects

Autoimmune hemolytic anemia (AIHA)

WarmreactiveColdreactive (paroxysmal cold hemoglobinuria or cold agglutinin disease)

Liver disease (eg, cirrhosis, hypersplenism, acquired disorders of the red cell membrane)*

Hypersplenism

Oxidant agents (eg, dapsone, nitrites, aniline dyes)

Microangiopathies

Hemolyticuremic syndrome (HUS)Disseminated intravascular coagulation (DIC)

Artificial heart valvesKasabachMerritt phenomena (destruction of platelets and red blood cells within avascular tumor)

Paroxysmal nocturnal hemoglobinuria (PNH)

Wilson disease

Drugs

G6PD: glucose6phosphate deficiency.* Refer to UpToDate topic review on extrinsic nonimmune hemolytic anemia due to systemic disease.¶ Refer to UpToDate topic review on extrinsic nonautoimmune hemolytic anemia due to drugs andtoxins.

Courtesy of Michael Recht, MD, PhD.


¶

aoriximacion del niño con anemia

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