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Anemia: when is it not iron deficiency? (Primary Care Approaches).

Part 1 of this series, "Anemia: When is it Iron Deficiency?," presented an overview of red blood cell and hemoglobin physiology and specifically addressed iron deficiency anemia. Part II of this two part series will focus on additional causes of anemia in the infant and young child and present strategies for detection and management.

Definition of Anemia

Anemia refers to red blood cell (RBC) mass, amount of hemoglobin, and/or volume of packed RBCs less than normal, determined either as a hematocrit or hemoglobin concentration > 2 standard deviations below the normal mean for age (Abshire, 2001; Cohen, 1996; Korones & Cohen, 1997; Walters & Abelson, 1996). Application of reference normals for age is not always straightforward, however. Infants less than 2 months of age have not yet established steady state values for hemoglobin or hematocrit, hence reference ranges for normal are extensive. Those who meet the screening criteria by universal or targeted screening protocols will be identified. However, others may be functionally anemic despite having hematocrit and hemoglobin levels within the acceptable range. Chronic pulmonary or cardiac disease, for example, may create increased oxygen demands due to increased need for oxygen or impaired oxygen utilization; children with these conditions may, therefore, experience symptoms traditionally suggestive of anemia at hemoglobin and hematocrit levels above reference cutoffs (Segel, Hirsh, & Feig, 2002a).

Anemia may be mild, moderate, or severe in nature. Mild anemia, hemoglobin 9.5-11 g/dl, is often asymptomatic and frequently escapes detection. Moderate anemia, hemoglobin 8-9.5 g/dl, may present with other symptoms and warrants timely management to prevent long-term complications. Severe anemia, hemoglobin < 8 g/dl, will warrant investigation and prompt management. Dependent upon its etiology and the magnitude of the RBC deficit, it may be life threatening (Abshire, 2001; Lesperance, Wu, & Bernstein, 2002; Segel et al., 2002a; Tender & Cheng, 2002).

For anemia to be appropriately detected, hematocrit and/or hemoglobin values must be precisely obtained. Specimen reliability is affected by such factors as collection site and sample quantity. Venous blood samples are preferable, however appropriately obtained capillary specimens may be more practical in certain circumstances. For capillary sites to be used, as in a heelstick specimen in the neonate, the site must be warmed and the blood free flowing (Geaghan, 1999; Hermiston & Mentzer, 2002).

Significance of Childhood Anemia

Anemia is a common and often complex finding throughout childhood. As many as 20% of children in the U.S. and up to 80% in developing countries will be determined to be anemic at some point prior to the age of 18 years (Irwin & Kirchner, 2001). Iron deficiency anemia alone occurs in 3% of children older than two years of age and 1%-3% of adolescents (Tender & Cheng, 2002). Certain anemias are more common in select ethnic groups or specific geographic areas, which likely speaks to the multifactoral origin of many anemias. There is ethnic variation in the incidence of all types of anemia: African American children have an incidence rate of 24.6%; Hispanics, 18.4%; Caucasians, 15.2%, and Asian/Pacific Islanders, 15.1%. Geographic locale affects the distribution of other anemias. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is more common in those of Mediterranean descent, and iron deficiency anemia and lead poisoning more commonly affect children in urban settings (Crocetti, Hawit, & Kato, 2002; Hermiston & Mentzer, 2002).

Anemia may contribute to excess cardiovascular or respiratory work and generate such findings as decreased exercise tolerance, fatigue, shortness of breath, or congestive heart failure (Cohen, 1996). Worldwide, anemia in adults is responsible for lost productivity, premature deaths, and perinatal complications (Centers for Disease Control, 2002) and poor growth, developmental delays, and increased susceptibility to infection in children (Lesperance et al., 2002).

Physiology of Anemia

Normal erythrocyte numbers reflect an intricate balance between production and destruction. RBCs, whose major role is oxygen transport, are produced in response to low oxygen levels. Sufficiently low mixed venous oxygen saturation stimulates the kidney to produce and release erythropoietin, a hormone that directly prompts erythroid precursors to differentiate into mature cells. For appropriate RBC production to occur, there must be sufficiently available erythroid precursors in the bone marrow and adequate production and release of erythropoietin (Hermiston & Mentzer, 2002).

RBCs typically circulate in the blood stream for approximately 120 days before they are sequestered in the spleen and undergo programmed destruction. The heme and globulin components of hemoglobin are then recycled for future RBC production. Erythrocytes must be appropriately sized and shaped to remain in the bloodstream. RBCs with abnormal shapes (e.g., spherocytes or elliptocytes) or sizes (e.g., microcytes or macrocytes) may not remain active in the bloodstream for the full 120 days, but may become sequestered and destroyed earlier. If sufficient premature destruction occurs, the balance between production and destruction is upset (Cohen, 1996; Salsbury, 2001).

Anemia conceptually reflects an imbalance between RBC production and destruction and may be due to one of three mechanisms. Excess RBC loss, as occurs with hemorrhage, may create anemia as RBCs are depleted in addition to loss of intravascular volume. Excess or premature RBC destruction, such as from hemolysis, may create anemia as RBCs are lost from circulation prior to their normal turnover. A third mechanism, insufficient RBC production, may create anemia either from lack of stimulation of production or lack of RBC precursor availability (Cohen, 1996; Hermiston & Mentzer, 2002; Ioli, 2002).

Clinical Findings of Anemia

The clinical manifestations of anemia are frequently subtle and nonspecific. Symptoms, when they occur, will relate to the underlying etiology (loss, destruction, or underproduction of RBCs). Clinical findings will also depend upon the severity and duration of the RBC deficit (Green, 1998).

Anemia Due to Blood Loss

Anemia due to acute blood loss may present with symptoms of hypovolemia, including hypotension, poor perfusion, weak pulses, pallor, and tachycardia. These findings may develop in addition to symptoms such as cyanosis and tachypnea, reflecting impaired oxygen carrying capacity (Korones & Cohen, 1997). Of note, in cases of acute hemorrhage, the initial hematocrit or hemoglobin values may be normal and, hence, misleading until intravascular equilibration occurs and diminished RBC numbers become apparent.

Chronic blood loss may be compensated for over time, thus the infant or child will show fewer clinical findings suggesting diminished intravascular volume. Symptoms more typically will suggest impaired oxygen carrying capacity, such as pallor, cyanosis, irritability, or fatigue. A systolic murmur may be evident. Less common findings may include bony changes, such as frontal bossing and maxillary overgrowth due to bone marrow expansion (Abshire, 2001), nail bed changes due to increased capillary development to support oxygenation in the distal digits (Irwin & Kirchner, 2001), and generalized edema due to diminished colloid osmotic pressure (Manno & Cohen, 2002).

Anemia Due to Hemolysis

RBC hemolysis may occur acutely or chronically and be manifested as mild, moderate, or severe anemia. The degree of anemia will dictate the constellation of clinical findings, which may range from mild symptoms suggesting impaired oxygenation (e.g., pallor, fatigue, or cyanosis) to more overt findings suggesting hypovolemia. Jaundice may also be present, as bilirubin is liberated during the hemolytic process. Hepato-splenomegaly may be evident, indicating the effects of extramedullary hematopoiesis and RBC destruction (Irwin & Kirchner, 2001), and in severe cases, hydrops or congestive heart failure may develop (Manno & Cohen, 2002). Other reported symptoms include arthralgia and gastrointestinal findings such as nausea, vomiting, diarrhea, or abdominal pain (Green, 1998).

Anemia Due to RBC Underproduction

RBC underproduction may present solely with anemia or with additional findings suggesting diminished production of multiple cell lines. Certain congenital and inherited anemias may feature diminished white blood cell or platelet numbers, evident on the complete blood cell count, as a result of bone marrow supression. The presence of petechiae or bruising supports the diagnosis of bone marrow failure, as these findings often accompany low platelet counts. Additional physical findings suggesting congenital anemias or syndromes include forearm and hand abnormalities or cafe au lait spots, as seen in Fanconi's anemia, or a triphalangeal thumb, as seen in Diamond-Blackfan Syndrome (Abshire, 2001).

A unique anemia in the neonatal period, anemia of prematurity, is related to transient endogenous erythropoietin underproduction or insensitivity. Clinical findings may be subtle or reflect impairment of oxygen delivery, including such findings as pallor, cyanosis, apnea and bradycardia, tachycardia, and poor weight gain (Widness, 2000).

Chronic infection or inflammation may result in mild to moderate anemia, as a consequence of decreased RBC survival, impaired bone marrow RBC genesis, and limited iron supply. The diagnosis is supported by microcytosis in conjunction with historical findings suggesting specific infective, metaplastic, or autoimmune disorders. Lead poisoning may create a microcytic anemia due to interference with iron incorporation into the RBC and generate findings similar to those of iron deficiency anemia. Additionally, elevated lead levels may create an encephalopathic condition evidenced by malaise or behavioral changes (Korones & Cohen, 1997).

Symptoms of anemia due to nutritional causes will vary with its duration and severity. Iron deficiency, for example, may present with little or no symptoms in its early stages, yet eventually pallor, poor growth, fatigue, irritability, tachycardia, splenomegaly, and flow murmur may develop with progression of the iron deficit (Johnson & Oski, 1997; Lesperance et al., 2002). Other nutritional anemias, including folic acid and vitamin B12 deficiency may be asymptomatic or present with macrocytic anemia, poor growth, diarrhea, or anorexia. Both folic acid and vitamin B12 are critical factors in normal cell division, and long-standing deficiencies may result in ineffective hematopoiesis and neurologic sequelae from direct effects on the central and peripheral nervous systems (Ioli, 2002).

Diagnostic Approach to Anemia

Most children with anemia are asymptomatic, therefore the diagnosis is often prompted by historical features and aided by clinical assessment and laboratory followup. This makes thorough history taking an indispensible component of discovery and management. Age of onset, gender, and overall health status are important features to note in the child's history. Family history, including race and ethnicity, or presence of any hematologic disorders may provide supportive evidence for inherited disorders, which may be a cause of anemia. For example, a family history of anemia, Mediterranean or Southeast Asian ethnicity, and the clinical presence of microcytic anemia may suggest a hemolytic disorder such as thalassemia (Segel et al., 2002a). Dietary history may support the diagnosis of nutritional deficiencies, including iron, folic acid, and vitamin B12 deficiencies (Abshire, 2001). Table I depicts important features of history. These historical features considered along with specific clinical findings will aid in diagnosis and assist in developing appropriate management.

Many diagnostic approaches have been developed to identify the etiology of anemia and to aid in its management. Two common approaches include differential diagnosis of anemia based on etiology and differential diagnosis based on red cell characteristics or indices (Ioli, 2002)

Differential Diagnosis by Etiology

Anemia due to blood loss. In the neonatal period, anemia is commonly the result of blood loss (Abshire, 2001). Blood loss (hemorrhage) may occur acutely or chronically, and may originate from the infant or placental unit. Acute hemorrhage may occur from perinatal losses such as placental abruption or umbilical cord accidents. Sources of neonatal bleeding include ruptured viscus (e.g., liver or spleen), intracranial bleeding, hematomas or extensive bruising, and iatrogenic causes such as excess sampling for testing. Any of these conditions will result in both RBC and intravascular volume loss. As noted previously, initial assessment of hematocrit or hemoglobin may be misleading in cases of acute blood loss. However, once intravascular space equilibration has occurred, up to 24 hours after birth, the magnitude of the RBC deficit will become apparent (Green, 1998; Widness, 2000).

A more chronic blood loss may occur from fetal-maternal or twin-twin transfusion via anomalous placental vascular connections. In these circumstances, the "donor" infant will manifest symptoms suggesting anemia (Widness, 2000). In the older child, anemia created by blood loss is uncommon. However, occult sources such as ulcers or diverticuli in males and females and menstruation in females may contribute to anemia. Additionally, in select children, excess whole cow's milk consumption may create occult gastrointestinal blood loss, thereby creating or compounding iron deficiency and anemia (Abshire, 2001; Lesperance et al., 2002).

Anemia due to RBC hemolysis. Excess RBC destruction is another important cause of anemia presenting in the neonatal period. Pertinent factors in the history may include the presence of hyperbilirubinemia, which supports hemolysis, and gender and ethnicity, as certain anemias, such as G6PD deficiency, more commonly occur in select populations. Hemolysis may be due to factors externally affecting the RBC or inherent RBC defects. Blood group incompatibility, most commonly from Rh or ABO incompatibility between mother and infant, and intrauterine or postnatal infections are examples of extrinsic causes of hemolytic anemia (Altman, 2002). Intrinsic defects include structural or component malformations of the RBC itself, which render it more easily destroyed. G6PD deficiency, a defect of erythrocyte metabolism, and hereditary spherocytosis, an erythrocyte membrane disorder, both create RBCs that are more easily hemolyzed (Ioli, 2002). The thalassemias represent a group of hemoglobinopathies involving globulin synthesis, creating hemolytic anemia and most of which present beyond the neonatal period. Alpha-thalassemia may present in one of four ways depending on the amount of alpha chain deletion in structural hemoglobin. Mild to moderate anemia is created dependent upon the degree of alpha-globin synthesis; at its extreme, with no alpha chain synthesis, it leads to fetal hydrops and ultimately fetal/neonatal demise due to absent oxygen carrying capability. The presentation of beta-thalassemia is dependent upon the degree of beta-globin chain synthesis. Beta-thalassemia trait, its least extreme form, generates a mild hypochromic anemia, while beta- thalassemia major, the most extreme form, creates a severe, progressive anemia beyond the neonatal period. Progressive anemia occurs as diminishing fetal hemoglobin levels no longer compensate for the effects of the abnormally produced hemoglobin (Irwin & Kirchner, 2001; Johnson & Oski, 1997; Manno & Cohen, 2002; Segel et al., 2002a).

Anemia due to RBC underproduction. Anemia due to RBC underproduction is uncommon in the neonate. When it occurs it is due either to deficient bone marrow cell precursors or insufficient synthesis or release of erythropoietin. Children with renal failure may develop anemia either due to effects of chronic inflammation or as a consequence of impaired erythropoietin production or release (Fisher, 2003; Korones & Cohen, 1997). As noted previously, a unique anemia presenting in the neonatal period is anemia of prematurity, a transient disorder of diminished erythropoietin production or sensitivity. RBC production is insufficient, even in the face of significant anemia, until the infant approaches term gestation and erythropoietin bioavailability spontaneously increases (Salsbury, 2001; Widness, 2000).

Bone marrow failure, either congenital or acquired, will create anemia in infancy and childhood. True arregenerative (inability to produce cells) or hyporegenerative (inability to produce sufficient cells) anemias, often due to hereditary or congenital causes, are rare and manifest as an inability to produce RBCs or other cell lines due to insufficient precursors. Diamond-Blackfan Syndrome, a pure erythrocyte aplasia, presents before the sixth month of life and is notable for anemia, reticulocytopenia, and decreased erythroid precursors. Fanconi's anemia, a congenital aplastic anemia, affects all cell lines including erythrocytes and is notable for pancytopenia in addition to the clinical findings of short stature and microcephaly (Green, 1998; Walters & Abelson, 1996). Neoplasia infiltrating the bone marrow may inhibit RBC production, as well as other cell lines including platelets and white blood cells. Acute lymphoblastic leukemia, for example, may present as anemia with associated petechiae, splenomegaly, and lymphadenopathy (Ioli, 2002). Transient erythroblastopenia of childhood (TEC) is a temporary, acquired disorder that creates a normochromic, normocytic, reticulopenic anemia. The etiology is uncertain, the course is insidious, yet unlike most hyporegenerative anemias, spontaneous recovery is anticipated (Crocetti et al., 2002).

Nutritional deficiencies may create anemia due to decreased erythrocyte production, increased destruction, or both. Iron deficiency, for example, is a common cause of childhood anemia (The reader is referred to Part I of this series for a more thorough discussion of iron deficiency). Folic acid and vitamin B12 deficiencies may also create anemia during early childhood. Insufficient dietary intake, impaired intestinal absorption due to bowel disease, or inhibition due to anticonvulsant or chemotherapeutic agents may lead to diminished serum levels of folic acid. Anemia is generally mild, often asymptomatic, and responsive to folic acid administration. Vitamin B12 deficiency may develop from inadequate intake, lack of gastrointestinal secretion of critical protein cofactors, or absence of intestinal receptor sites. Dietary causes are rare, though strict vegan diets have been implicated for their insufficient vitamin B12 content. Breastfed infants of strict vegans or mothers with pernicious anemia may be at special risk. As in folic acid deficiency, once the diagnosis is established, supplementation with the appropriate element is generally sufficient to correct the deficiency (Hermiston & Mentzer, 2002; Johnson & Oski, 1997).

Differential Diagnosis of Anemia by RBC Indices and Biochemical Markers

Assessment of the complete blood count, RBC indices, and select biochemical markers will aid in determination of the etiology of most anemias. Figure 1 depicts an algorithm using RBC indices and markers in the discrimination of neonatal anemia.

[FIGURE 1 OMITTED]

The peripheral smear will reveal visible RBC characteristics, such as hypochromia or microcytosis, which will narrow the diagnostic possibilities for anemia (Abshire, 2001). If erythrocytes have been produced numerically and morphologically normal, as in cases of acute blood loss, the smear will be normal. On the other hand, hypochromia and microcytosis may be present on the peripheral smear in response to chronic blood loss, reflecting ongoing iron depletion (Manno & Cohen, 2002). The presence of numerous nucleated RBCs suggests active erythropoiesis, as may occur in hemolysis. Abnormal cell forms produced as a component of some anemias, such as Heinz bodies in G6PD deficiency or Howell-Jolly bodies in sickle cell disease, may additionally be identified on the smear and support those diagnoses (Abshire, 2001; Ioli, 2002). The peripheral smear may be notable for numerous nucleated RBCs suggesting active erythropoiesis; in cases of hemolysis related to abnormal RBC or hemoglobin morphology, abnormal cell forms may be evident as well (Abshire, 2001; Ioli, 2002; Korones & Cohen, 1997).

The reticulocyte count may assist in differentiating a hyporegenerative or arregenerative anemia from one due to RBC destruction (Irwin & Kirchner, 2001; Lesperance et al., 2002). An elevated reticulocyte count suggests premature release of immature RBCs into the circulation (Abshire, 2001) to replace losses from rapid destruction, as occurs in hemolytic disorders. Conversely, a low reticulocyte count in the face of anemia suggests decreased production or release of RBCs (Cohen, 1996), as may be found in bone marrow failure, iron deficiency, lead poisoning, and anemia of inflammation (Hermiston & Mentzer, 2002). Assessment of the reticulocyte count is particularly helpful in the diagnosis of anemia of prematurity, as it will be paradoxically decreased for the degree of anemia present. In addition to its diagnostic potential, the reticulocyte count may be used to guide response to anemia management, including nutritional support or exogenous erythropoietin administration (Abshire, 2001; Widness, 2000).

Mean corpuscular volume (MCV) is an indicator of RBC size and may discriminate between microcytic or macrocytic anemias (Abshire, 2001; Lesperance et al., 2002). Microcytosis, reflected in a low MCV, is due to defective hemoglobin production, either from ineffective heme or globin synthesis. For example, a low MCV, suggesting small RBCs (microcytosis), occurs in several childhood disorders including iron deficiency anemia, beta-thalassemia trait, lead poisoning, anemia from chronic illness, and rarely, in sideroblastic anemia (Hermiston & Mentzer, 2002). High MCV, suggesting macrocytosis, occurs with other nutritional anemias such as vitamin B12 and folate deficiency (Cohen, 1996; Neufeld, 2002). Megaloblastic (morphologically abnormal, enlarged cell) anemias due to certain chemotherapeutics, for example, may additionally yield a high MCV due to inappropriate bone marrow cellular production (Neufeld, 2002).

The source of most childhood anemias may be determined by the integration of findings of MCV, reticulocyte count, and peripheral smear. Anemia occurring with a normal MCV may be associated with a low, normal, or elevated reticulocyte count. A normal MCV associated with a low reticulocyte count suggests bone marrow failure or RBC aplasia. A normal reticulocyte count associated with a normal MCV suggests chronic inflammation. A normal MCV associated with an increased reticulocyte count suggests rapid RBC loss, as in hemolysis or acute blood volume loss (Abshire, 2001).

Anemia expressed as an increased MCV may be associated with either a low or elevated reticulocyte count. Causes of reticulocytosis include acute or chronic blood loss or hemolysis (Ioli, 2002; Lesperance et al., 2001). An increased MCV associated with a decreased reticulocyte count suggests that despite being normal in morphology, the overall number of RBCs generated is low. Hereditary hyporegenerative anemias, drug suppression, and nutritional anemias may account for these changes (Abshire, 2001; Hermiston & Mentzer, 2002; Lesperance et al., 2001).

Anemia associated with a low MCV suggests microcytic disorders as previously described and certain hemoglobinopathies. Low MCV coupled with an elevated reticulocyte count suggests beta-thalassemia (Ioli, 2002; Korones & Cohen, 1997; Lesperance et al., 2002). Table 2 lists causes of childhood anemia as determined by MCV and reticulocyte count.

Additional hematologic tests may be employed, as when hemolysis is suspected or to confirm specific deficiencies or disorders. The Coombs' test detects the presence of antibody and when positive suggests an immune etiology of anemia. Hemolytic anemia due to Rh isoimmunization is frequently Coombs' positive. Hemoglobin electropheresis, a test to analyze globin chains comprising hemoglobin, may be used to conclusively differentiate between hemoglobinopathies when these are suspected. Other specialized tests, such as osmotic fragility, may be used to confirm suspected select hereditary disorders, such as spherocytosis (Hermiston & Mentzer, 2002; Irwin & Kirchner, 2001).

Biochemical markers, though often nonspecific, may support specific diagnoses. Iron deficiency anemia, for example, may masquerade as other microcytic anemias, making the use of adjunctive tests such as serum ferritin (an indicator of iron storage) or iron sometimes useful (Abshire, 2001; Lesperance et al., 2002). Ferritin will be depressed in iron deficiency, normal in thalassemia, normal to high in lead poisoning, and high in anemia of inflammation, thus helping to discriminate between these causes of microcytosis (Hermiston & Mentzer, 2002). Free erythrocyte protoporphyrin (FEP), a marker of failed incorporation of iron into heme, may also be useful in this regard. FEP will be elevated in both iron deficiency and lead poisoning, yet normal in beta thalassemia trait (Hermiston & Mentzer, 2002). When used adjunctively with serum lead or iron levels, it will discriminate between iron deficiency and lead poisoning (Hermiston & Mentzer, 2002; Korones & Cohen, 1997). Nutritional anemias, such as vitamin B12 or folic acid deficiency may be detected and/or monitored through direct assessment of serum B12 and folate levels (Ioli, 2002), and enzymatic defects such as G6PD and pyruvate kinase deficiency may be identified by specific assay of these enzyme levels (Irwin & Kirchner, 2001). Suspected feto-maternai hemorrhage may be confirmed by detection of fetal RBCs in the maternal bloodstream by Kleihauer-Betke testing (Korones & Cohen, 1997).

Bone marrow assessment may determine the absence of erythroid and nonerythroid cell precursors, which will support the diagnosis of hyporegenerative or arregenerative disorders, such as Diamond-Blackfan anemia or Fanconi's anemia (Hermiston & Mentzer, 2002). Bone marrow assessment may also be used to diagnose and monitor management of chemotherapy in neoplastic conditions such as acute lymphoblastic anemia.

Management Approach to Anemia

Anemia due to acute blood loss or hemolysis. The management of anemia is directed at both the cause and the magnitude of associated symptoms. Anemia due to acute blood loss or hemolysis may present with symptoms attributable to deficient intravascular volume and, thus, can be predicted to respond to volume replacement. Transfusion with whole blood will replace volume, and packed red blood cells (PRBCs) will supplement the RBC deficit. Both may be indicated in the management of severe anemia. PRBC or other blood products must be used cautiously with consideration of associated risks, including transmission of blood borne infections and graft vs. host disease (Cohen, 1996).

The presence of hemolysis creates a management challenge. While the overall goal of boosting the RBC volume by transfusion exists, the presence of circulating antibody to donor cells may contraindicate this simplified approach. Additionally, if hyperbilirubinemia coexists, efforts to remove this toxic product may be as critical as remedying the anemia. In cases of severe neonatal anemia due to Rh or ABO incompatibility, this consideration is foremost. Thus, a double volume exchange utilizing allogenic whole blood or PRBCs suspended in fresh frozen plasma may be offered to manage both the anemia and excess bilirubin (Manno & Cohen, 2002).

Additional non-cellular therapies for severe and refractory anemias, including spherocytosis, elliptocytosis, and pyruvate kinase deficiency, may include partial or total splenectomy or bone marrow transplantation (Altman, 2002).

Anemia due to chronic blood loss or hemolysis. Chronic blood loss or hemolysis may be well compensated and, hence, not present with evidence of diminished intravascular volume. This makes immediate volume replacement unnecessary and possibly hazardous if there is any evidence of cardiac dysfunction or overload (Cohen, 1996). Hemoglobinopathies creating substantial ongoing hemolysis may necessitate chronic transfusion therapy. For example, red cell transfusion is the mainstay of treatment for severe cases of thalassemia, with a therapeutic goal of maintaining a hemoglobin level of 9.5-10.5 g/dl. This target will minimize iron overload, yet provide sufficient hemoglobin to support tissue oxygenation (Golden & Vichinsky, 2002; Johnson & Oski, 1997). Monthly transfusions may be used in sickle cell anemia with the goal of reducing the proportional sickle-hemoglobin concentration by 2/3 (Williams & Levine, 2002). More recently, treatments such as intrauterine transfusion and stem cell transplantation have been used in cases of severe hemolytic anemia such as alpha thalassemia (Segel et al., 2002a).

Anemia due to RBC underproduction. Many anemias of RBC underproduction offer minimal symptomatology and, hence, require observation only. Nutritional anemias, including iron, vitamin B 12, and folate deficiency, may simply require supplementation and nutritional counseling (Ioli, 2002; Lesperance et al., 2002; Segel et al., 2002a). Folic acid deficiency is a decreasingly common cause of nutritional anemia as a byproduct of mandated food product supplementation. Though intended to target pregnant women, supplementation has offered an advantage for the general population as well (Neufeld, 2002). A focused patient history may reveal non-nutritional causes including intestinal malabsorption from inflammation or degenerative intestinal disease or prescribed drugs such as anticonvulsants or chemotherapeutics (Johnson & Oski, 1997). Folic acid supplementation of 50 mcg/d for infants and 1 mg/d for children and adults is generally sufficient, coupled with dietary counseling to include folate containing foods. Adequate management is reflected by slight improvement in anemia, improved neurologic findings after I week of therapy, and ongoing improvement in growth and development (Ioli, 2002).

Vitamin B12 deficiency may occur due to failed absorption, as in gastrointestinal transport or enzyme defects. Rarely, it may be associated with dietary deficiency, as in strict vegan diets or in breastfeeding infants of vitamin B12 deficient mothers (Johnson & Oski, 1997). Generally, vitamin B12 deficiency will respond to supplementation initiated as daily cobalamin injections for 1 week and supplemental monthly injections of 250-500 micrograms B12. Ongoing nutritional guidance should include recommendations for dietary sources of vitamin B12. Successful management will be reflected in a decrease of MCV by 5 fl by the completion of 2 weeks of treatment (Ioli, 2002).

Recombinant human erythropoietin (Epotin Alfa, Epogen) may be utilized as a treatment for mild to moderate anemia. Generally given as a subcutaneous dose of 15-300 1U/kg 1-3 times per week, it offers all of the advantages of erythropoietin normally produced by the body. Exogenous erythropoietin will not suppress endogenous production, thus offering an advantage over transfusion in the management of anemia. To be effective, there must be sufficient erythroid precursors in the bone marrow. Additionally, to promote a normocytic, normochromic response, adequate iron stores and protein intake must be assured. Common clinical practice, therefore, is to administer 3-6 mg/kg/d of supplemental iron concurrently. Erythropoietin has demonstrated efficacy in the treatment of both anemia of prematurity and anemia due to renal failure, and has been suggested as a potential treatment for transient bone marrow suppression induced by chemotherapy (Fisher, 2003; Salsbury, 2001; Varan, Buyukpamukcu, Kutluk, & Akyuz, 1999; Widness, 2000).

Primary Care Assessment

Timely screening coupled with appropriate diagnostic testing will afford the most optimal identification and management of childhood anemia. Certain anemias, such as sickle cell and G6PD deficiency, may now be detected as part of state newborn screening programs. As many of these anemias are not clinically apparent in the immediate newborn period, early identification will assist with appropriate management and optimize outcome.

Iron deficiency anemia, by far the most common childhood anemia, remains an important primary care concern. Through appropriate screening and timely diagnostic testing, many cases will be detected and adequately managed. However, both universal and targeted screening protocols have limitations, and all cases, especially those with minimal symptomatology, may not be identified. Proactive nutritional counseling is indicated for all children. Once detected, this and other nutritional anemias generally respond to supplementation. Hemoglobin that fails to show improvement within 4-8 weeks or anemia that recurs despite adequate supplementation warrants further investigation (Segel et al., 2002a).

Severe anemias, especially hemoglobinopathies and arregenerative disorders, should be managed in consultation with a team of specialists. A pediatric hematologist is indicated to ensure appropriate, comprehensive management of these complex disorders. A dysmorphology or genetic consultant is indicated in cases of hereditary disorders to determine recurrence risk for the family with subsequent offspring. Newborns with a history of immune hemolytic anemia should have regular postdischarge followup, as anemia may persist in this group for many months due to persistence of maternally derived antibody in the infant's bloodstream. An increasing reticulocyte count is the most sensitive indicator of resolution of severe hemolytic anemia and can be followed serially while awaiting a parallel increase in hemoglobin or hematocrit (Widness, 2000).

Certain anemias are characterized by recurrent hemolytic crises following exposure to certain inciting agents or conditions. Sickle cell anemia, for example, is worsened by conditions that induce hypoxia or hypovolemia (Segel, Hirsh, & Feig, 2002b), and G6PD deficiency and pyruvate kinase deficiency may display recurrent hemolysis during oxidative stress created by certain medications or dietary sources (Irwin & Kirchner, 2001). Therefore, efforts to avoid or modify exposure to these stressors is warranted.

Children with sickle cell anemia and those who have undergone therapeutic splenectomy (e.g., hereditary spherocytosis or beta-thalassemia major) will require ongoing surveillance for opportunist infections. Up to 30% of children with sickle cell will develop pneumococcal sepsis (Johnson & Oski, 1997), and meningococcus, influenza, and hepatitis A and B pose substantial risks to those children with a partial or absent spleen. These children are, therefore, candidates for immunoprophylaxis as part of routine health supervision visits (Ioli, 2002; Johnson & Oski, 1997).

Summary

Anemia presents a challenge both in determination of cause and appropriate management. Careful history taking and appropriate screening in keeping with AAP recommendations will aid in identifying cases of anemia. Judicious use of laboratory testing will assist in achieving accurate diagnosis. Finally, appropriately timed and monitored treatment strategies will offer the most optimal outcome.
able 1
Pertinent Features of Child's History in
Childhood Anemia

Family History
  Ethnic origin
  Hematologic disorders (e.g., jaundice, coagulopathy,
    anemia)
  Transfusions
  Splenomegaly
  Gallstones
  Carcinoma

Maternal History
  Pregnancy or perinatal complications
  Substance use
  Anemia or other hematologic abnormality
  Pica

Child History
  Age
  Gender
  Hyperbilirubinemia (jaundice)
  Prematurity
  Medications
  Diet (type/quantity of milk; pica)
  Chronic or acute infections
  Hepatic dysfunction
  Gastrointestinal dysfunction
  Endocrine dysfunction
  Easy bruising or bleeding
  Activity level
  Heavy menstruation

Note: Adapted from Abshire, 2001; Hermiston & Mentzer
(2002); Ioli (2002); and Korones & Cohen (1997).

able 2
Childhood Anemias as Determined by MCV and
Reticulocyte Count

Normocytic Anemia (Normal MCV)
  * with normal or increased reticulocyte count
      blood loss (e.g., traumatic or occult bleeding)
      intrinsic hemolysis (e.g., spherocytosis,
        pyruvate kinase deficiency)
      extrinsic hemolysis (e.g., ABO incompatibility,
        sepsis)
  * with decreased reticulocyte count
      aplastic anemia (e.g., Fanconi's anemia)
      red cell aplasia (e.g., Diamond-Blackfan
        anemia, TEC)
      bone marrow replacement (e.g., leukemia)
      anemia of inflammation (normal or low
        reticulocyte count)
      erythropoietin deficiency (e.g., chronic renal
        failure, anemia of prematurity)

Microcytic Anemia (Low MCV)
  * with normal or increased reticulocyte count
      hemoglobinopathies
  * with decreased reticulocyte count
      iron deficiency anemia
      lead poisoning
      anemia of inflammation (normal or low
        reticulocyte count)

Macrocytic Anemia (High MCV)
  * with normal or increased reticulocyte count
      hemorrhage
      hemolysis
      hypersplenism
  * with decreased reticulocyte count
      folic acid deficiency
      vitamin B12 deficiency
      bone marrow failure (e.g., Fanconi or
        Diamond-Blackfan anemia)
      inborn errors of metabolism
      chronic liver disease
      hypothyroidism
      myelodysplasia

Note: Adapted from Crocetti, Hawit, & Kato (2002),
Korones & Cohen (1997), Irwin & Kirchner (2001), and
Neufeld (2002).


References

Abshire, T.C. (2001). Sense and sensibility: Approaching anemia in children. Contemporary Pediatrics, 18(9), 104-113.

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Annette Carley, MS, RN, NNP, PNP, is Assistant Clinical Professor, Department of Family Health Care Nursing, University of California, San Francisco, and Neonatal Nurse Practitioner, Pediatric Independent Contractors, San Francisco, CA.

The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families. If you are interested in author guidelines and/or assistance, contact Patricia L, Jackson Allen at Pat.jacksonallen@yale.edu
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