Approach to the child with anemiaAuthorClaudio Sandoval, MDSection EditorsDonald H Mahoney, Jr, MDMartin I Lorin, MDDeputy EditorAlison G Hoppin, MD

Disclosures: Claudio Sandoval, MD Nothing to disclose. Donald H Mahoney, Jr, MD Nothing to disclose. Martin I Lorin, MD Nothing to disclose. Alison G Hoppin, MD Employee of UpToDate, Inc.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2014. | This topic last updated: Sep 25, 2013.

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

A systematic approach to the examination of the peripheral blood smear and bone marrow is discussed separately. (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 blood hemoglobin concentration. In practice, anemia most commonly is defined by reductions in one or both of the following:

●Hematocrit (HCT) — The hematocrit is the fractional volume of a whole blood sample occupied by red blood cells (RBCs), expressed as a percentage. As an example, the normal HCT in a child age 6 to 12 years is approximately 40 percent.●Hemoglobin (HGB) — This is a measure of the concentration of the RBC pigment hemoglobin in whole blood, expressed as grams per 100 mL (dL) of whole blood. The normal value for HGB in a child age 6 to 12 years is approximately 13.5 g/dL (135 g/L).

The threshold for defining anemia is a HGB or HCT that is more than two standard deviations below the mean for the reference population. Normal ranges for HGB and HCT vary substantially with age; thus, it is particularly important to use age and sex adjusted norms when evaluating a pediatric patient for anemia (table 1). In addition, there is racial variation, with healthy black children having average hemoglobin values 0.5 g/dL below that of white children of the same age and sex [1].

OVERVIEW OF ERYTHROPOIESIS — Fetal erythropoiesis begins with primitive megaloblastic erythropoiesis in the yolk sac; these cells can be identified at approximately four to five weeks gestation [2]. A transition is made to normoblastic erythropoiesis at approximately six weeks gestation. At this time, blood formation begins in the liver, which is the primary organ of hematopoiesis from the third to sixth month of gestation [2]. At approximately the third month of

gestation, hematopoiesis begins in the spleen, thymus, and lymph nodes. The liver and spleen continue to produce blood cells into the first week of postnatal life [2].

Bone marrow hematopoiesis begins around the fourth month of gestation and increases throughout intrauterine development. After birth, further marrow volume expansion occurs. Throughout gestation, hematopoiesis is primarily under fetal control and is only partially influenced by maternal factors [2]. (See "Structure and function of normal human hemoglobins".)

Erythropoiesis decreases dramatically after birth. RBC production decreases by a factor of 2 to 3 in the first few days of life and by a factor of 10 in the week following birth, resulting in the “physiologic anemia of infancy” [2]. This decrease is initiated by the increase in tissue oxygen level that occurs at birth and is accompanied by a decrease in erythropoietin production [2,3]. Erythropoietin levels in term infants are lowest at one month and highest at two months of age [3]. RBC production is at a minimum during the second week after birth and subsequently rises to maximum values at approximately three months. The net result of these changes is a hemoglobin level that typically reaches a nadir at six to nine weeks of age (sometimes referred to as "physiologic anemia") (figure 1) [4,5].

Low hemoglobin levels in preterm infants may be more pronounced because of the shorter life span of preterm RBCs. The mean half-life of RBCs for term infants is 23.3 days, as compared with 16.6 days in preterm infants, and 26 to 35 days in adults [2]. (See "Red blood cell survival: Normal values and measurement", section on 'Red blood cell half-time' and "Anemia of prematurity".)

Infants presenting with RBC membrane abnormalities, such as hereditary spherocytosis, may develop anemia in the neonatal period because of the combination of decreased erythropoiesis that follows birth, the concomitant increase (normalization) in splenic filtration and phagocytosis [6], and a shorter red cell life span. (See"Hereditary spherocytosis: Clinical features, diagnosis, and treatment", section on 'Signs and symptoms according to age'.)

CLASSIFICATIONS OF ANEMIA — Anemias may be classified on either a physiologic or a morphologic basis. Approaching the evaluation of an anemic patient using one or both of these classification schemes helps to narrow the diagnostic possibilities.

Physiologic classification — Anemia may be classified in two broad categories based on the reticulocyte count, which serves as a marker of whether erythropoiesis is suppressed or active (algorithm 1).

●Disorders resulting in an inability to adequately produce red blood cells (ie, bone marrow depression). These disorders are generally associated with a lower than expected reticulocyte response.●Disorders resulting in rapid RBC destruction (hemolysis) or RBC losses from the body (bleeding). These disorders are generally associated with a robust reticulocyte response.

Reticulocyte response — Reticulocytes are the youngest red cells in the circulation, and are identified by the presence of residual RNA, which gives them a blue tint on standard Wright-Giemsa stains (picture 1). They are quantitated by staining with vital dyes, such as new methylene blue or thiazole orange, and are reported as a percentage of the red blood cell population (picture 2). After the first few months of life, the mean reticulocyte percentage is the same as that of the adult, approximately 1.5 percent [2].  

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

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

The ARC is calculated and reported by many automated cell counters. In a patient with anemia, ARC values within the normal range (less than 100 x 109/L) generally indicate an inappropriately low erythropoietic response [7]. Other reticulocyte indices (the corrected reticulocyte count and the reticulocyte production index) are sometimes used to correct for the degree of anemia, as described separately. (See "Approach to the diagnosis of hemolytic anemia in the adult", section on 'Reticulocyte response'.)

The ARC is an indication of bone marrow erythropoietic activity. Thus, anemia with an elevated ARC suggests active erythropoiesis in response to hemolysis, acute blood loss, or recent institution of replacement therapy (eg, successful treatment of iron or folic acid deficiency), or recovery from a transient episode of erythroblast suppression. By contrast, anemia with a normal or low ARC indicates a suboptimal bone marrow response and is suggestive of marrow aplasia, infiltration with malignant cells, depression caused by infection or other toxic agents, or suboptimal production of erythropoietin [8]. (See "Approach to the adult patient with anemia", section on 'Reticulocyte count'.)

These two categories are not mutually exclusive, however. Although patients generally have one major etiology for their anemia, hemolysis or blood loss may co-exist with bone marrow suppression. As an example, a child with sickle cell disease will have life-long hemolysis, anemia, and a brisk reticulocyte response. However, during times of infection, the child’s bone marrow may be suppressed, as evidenced by a reduction in the reticulocyte response and a consequent worsening of the anemia. In other cases, the reticulocyte count depends on the phase of the illness. As an example, the reticulocyte count is low in a child during the acute phase of transient erythroblastopenia of childhood or transient bone marrow 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. (See "Anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood (TEC)'.)

Morphologic classification — Anemias also may be classified according to RBC morphology, reflected by indices of RBC size (mean corpuscular volume, MCV), hemoglobin content (mean corpuscular hemoglobin, MCH), or hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC) (table 1). The etiology of the anemia may be elucidated by using these indices, the white blood cell (WBC) and platelet counts (PLT), and the reticulocyte count (algorithm 1).

Mean corpuscular volume — The mean corpuscular volume (MCV) is the most useful RBC parameter used in the workup of anemia. It is measured directly by automated blood cell counters and represents the mean value (in femtoliters, fL) of the volume of individual RBCs in the blood sample.  

As with the HGB and HCT, normal values for MCV vary based upon age (table 2). In particular, infants have an increased MCV compared to older children. MCV values also increase with decreasing gestational age so that a preterm infant with a gestational age of 25 weeks will have a MCV of 119 fL compared to a value of 106 fL in a term infant [9]. Microcytosis is defined as an MCV

values less than 2 SC below the mean (or <80 fL in adults); macrocytosis is defined as an MCV values more than 2 SD above the mean (or >100 fL in adults). MCV values within two standard deviations of the mean are considered normocytic.

The most common cause of macrocytosis in children is the use of certain medications (eg, anti-convulsants, zidovudine, and immunosuppressive agents) [10]. Other factors include vitamin B12 or folate deficiency, liver disease, or aplastic anemia. Because reticulocytes have a greater MCV than do mature cells (picture 1), patients with significant degrees of reticulocytosis may have elevated MCV values in the face of otherwise normocytic RBCs [11]. (See "Macrocytosis".)

Factors that reduce the MCV include iron deficiency, lead intoxication, anemia of chronic disease, and hemoglobinopathies, but not sickle cell anemia.

Mean corpuscular hemoglobin concentration — The MCHC is a calculated index (MCHC = HGB/HCT), yielding a value of grams of HGB per 100 mL of RBC. Values in the normal range (33 to 34 g/dL), indicate that cells are normochromic, whereas values lower than normal indicate the presence of hypochromia. MCHC values vary depending upon the age of the child (table 1) with infants having a higher value than older children. MCHC also increases with decreasing gestational age [9].

The MCHC is low in the same conditions that generate low values for MCV and MCH. Increased values for MCHC can be caused by congenital or acquired spherocytosis or other congenital hemolytic anemias in which RBCs are abnormally desiccated. This is because the RBC’s hemoglobin concentration is relatively increased when the RBC loses membrane surface area and/or water. The hyperchromia usually can be appreciated on the peripheral smear (picture 3) [12].  

Red cell distribution width — The red cell distribution width (RDW) is a quantitative measure of the variability of RBC sizes in the sample (anisocytosis). The RDW is a function of MCV and, therefore, normal values vary slightly with age. However, normal values generally are between 12 and 14 percent [13]. The RDW is especially helpful in differentiating iron deficiency from thalassemia in the pediatric patient with microcytic anemia. Patients with a RDW greater than 20 are more likely to have iron deficiency, whereas patients with normal RDW values are more likely to have thalassemia or the anemia of chronic disease [14].

HISTORY AND PHYSICAL EXAMINATION — The clinical signs and symptoms of anemia vary based on the age of the child and the etiology and chronicity of the anemia. As with most other disorders in medicine, a thorough history and physical examination are important factors in evaluating the child with anemia.

History — Patients with inherited etiologies often present in childhood. Thus, when evaluating the history of an anemic patient, one must not only review the symptoms of the patient, but also ask pointed questions regarding family history. In addition, the birth history and neonatal course may provide important etiologic clues.

In addition to the age and sex of the child, the following components should be part of the history when evaluating an anemic child:

●Severity and initiation of symptoms — Common symptoms of anemia include lethargy, tachycardia, and pallor. Anemic infants may present with irritability and poor oral intake.

Because of the body's compensatory abilities, patients with chronic anemia may have few or no symptoms, in contrast to patients with acute anemia with similar hemoglobin values.●Questions relating to hemolytic episodes — Specific questions regarding changes in urine color, scleral icterus, or jaundice associated with the symptoms of anemia should be asked. Hemolytic episodes that occur only in male family members may indicate the presence of a sex-linked disorder, such as glucose-6-phosphate dehydrogenase deficiency. (See "Overview of hemolytic anemias in children" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia"and "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase deficiency".)●Prior CBCs, therapy or anemic episodes — Prior complete blood counts (CBCs), anemic episodes, duration, etiology, and resolution, as well as all prior therapy for anemia, should be reviewed. Prior episodes of anemia may indicate inherited forms, whereas anemia in a patient with previously documented normal blood counts suggests an acquired etiology. Patients with hemoglobinopathies resulting in the production of small (microcytic) and pale (hypochromic) RBCs, such as Hb E or the various thalassemias, may have a history of treatment on multiple occasions for an erroneous diagnosis of iron deficiency anemia, in which the RBCs are also hypochromic and microcytic. (See 'Blood smear' below and "Clinical manifestations and diagnosis of the thalassemias".)●Questions about possible blood loss — Specific questions related to bleeding from the gastrointestinal tract, including changes in stool color, the identification of blood in stools, and history of bowel symptoms, should be reviewed. Teenagers may have excessive menstrual losses without realizing it. Therefore, information regarding the menstrual history including duration of periods, flow, quantitation, and saturation of tampons or pads, should be obtained. Severe or chronic epistaxis also may result in anemia from blood and iron deficiency. Indeed, epistaxis and menorrhagia may be the result of an underlying bleeding disorder [15]. In patients who appear to have excessive blood loss, it is important to determine whether there is a family history of inflammatory bowel disease, polyps, colorectal cancer, hereditary hemorrhagic telangiectasia, von Willebrand disease, platelet disorders, and hemophilia. (See "Approach to the child with bleeding symptoms", section on 'Von Willebrand disease'.)

A very common cause of anemia in children living in low and middle income countries is the presence of intestinal nematode infection (eg, hookworm, whipworm). (See"Enterobiasis and trichuriasis" and "Hookworm infection".)●Underlying medical conditions — A careful past medical history and review of symptoms should be obtained to 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. Recent illnesses should be reviewed, and possible infectious etiologies for the anemia should be explored. As an example, a mild drop in hemoglobin concentration of 1 to 1.5 g/dL is not uncommon in the presence of active infection.●Prior drug or toxin exposure — Prior medications as well as environmental toxin exposure, including the use of well water containing nitrates, should be reviewed. Any history of oxidant-induced hemolysis should be obtained. Inquiries regarding type and duration of homeopathic or herbal medications should be undertaken because children receiving these preparations may be at risk for exposure to lead and other toxins. In addition, when evaluating a child with microcytic anemia, one should ask specific questions regarding environment, housing, paint

exposure, cooking materials, and use of poorly glazed ceramic pots in order to evaluate for possible lead exposure. (See "Screening tests in children and adolescents", section on 'Lead poisoning'.)●Questions relating to diet — Questions should be primarily aimed at determining iron content in the diet and, to a lesser degree, folate and B12 content. The type of diet, type of formula (if iron fortified), and age of infant at the time of discontinuation of formula or breast milk should be documented. In addition, the amount and type of milk the patient is drinking should be determined. The presence of pica (particularly pagophagia, the eating of ice) is a useful clue to a diagnosis of lead poisoningand/or iron deficiency (see "Childhood lead poisoning: Clinical 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").●Birth history — A birth and neonatal history including infant and mother's blood type, any history of exchange or intrauterine transfusion, and a history of anemia in the early neonatal period should be obtained. Gestational age at birth is important, because premature infants may have iron or vitamin E deficiencies resulting in anemia. The presence of jaundice or need for phototherapy may signify the presence of an inherited hemolytic anemia. A prolonged newborn hospitalization is usually associated with multiple blood tests, which lead to decreased future iron stores. Microcytosis at birth should alert the physician to consider chronic intrauterine blood loss and alpha thalassemia.●Developmental milestones — Parents should be asked questions to determine if the child has reached age-appropriate developmental milestones. Loss of milestones or developmental delay in infants with megaloblastic anemia may signify abnormalities in the cobalamin pathway and folic acid malabsorption [16].●Family history, race, and ethnicity — Any family history of anemia should be pursued in depth. Family members with jaundice, gallstones, or splenomegaly should be identified. Asking if family members have undergone cholecystectomy or splenectomy may aid in the identification of additional individuals with inherited hemolytic anemias. Race and ethnic background are helpful in guiding the workup for hemoglobinopathies and enzymopathies. For example, thalassemia syndromes are more common in individuals of Mediterranean and Southeast Asian descent; Hemoglobin S and C are most commonly seen in Black and Hispanic populations.

Physical examination — The physical exam also may provide important clues as to the etiology of the anemia. Areas of particular importance on the physical examination include: the skin, eyes, mouth, facies, chest, hands, and abdomen (table 3).  

Pallor should be assessed by examining sites where capillary beds are visible (eg, conjunctiva, palm, and nail beds). Pallor in these locations is predictive of severe anemia, but mild and even severe anemia may be overlooked when relying solely on this physical finding [8,17]. As an example, in a field study of 535 preschool children, clinical pallor in the conjunctiva, palm, and nail beds was detected in only 20 percent of those with HGB <11.0 g/dL and 61 percent of those with severe anemia (HGB <7.0 g/dL)[18].

Patients with hemolytic processes resulting in anemia may present with signs of scleral icterus, jaundice, and hepatosplenomegaly resulting from increased red cell destruction. However, as with the clinical detection of anemia through evaluation of pallor, clinical detection of jaundice often is

poor. As an example, in an emergency department setting, the clinical detection of jaundice was found to have sensitivity and specificity of only approximately 70 percent [19]. Reticulocytosis in the absence of scleral icterus, jaundice, and hepatosplenomegaly should raise the suspicion of a recovering process such as transient erythroblastopenia of childhood instead of a hemolytic process. (See "Anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood (TEC)'.)

Other findings of the physical examination may indirectly lead to the explanation for the anemia. As an example, a report described two infants with anemia and auscultatory findings of borborygmi in the left lower lung fields [20]. These findings led to the diagnosis and treatment of hiatal hernias, and the iron deficiency resolved.  

LABORATORY EXAMINATION — The laboratory examination should begin with a complete blood count including red blood cell indices, a reticulocyte count, and a review of the peripheral blood smear. Normal ranges for HGB and HCT vary substantially with age, so it is important to use age and sex adjusted norms (table 1 and figure 1). These tests will allow for morphologic evaluation of the cells, classification of the anemia based on red blood cell size, and aid in the identification of the physiologic basis for the anemia [21]. Measurement of total and direct bilirubin and LDH may aid in diagnosing hemolytic conditions. After the evaluation of these parameters, precise laboratory tests may be obtained to identify and confirm the etiology of the anemia.

In the pediatric population, many blood samples obtained for anemia screening are capillary samples such as finger or heel "sticks." Although these means of sampling are acceptable, one must keep in mind that HGB and HCT values may be slightly elevated in such samples as compared to venous samples when using automated counting methods [22,23]. This difference may be more pronounced when using microhematocrit measurements from capillary samples [13]. Although the likelihood of masking significant anemia is low, borderline low values may be "normalized" using the capillary collection and processing method.

Blood smear — A review of the peripheral smear is an essential part of any anemia evaluation. The following features should be noted: (See "Evaluation of the peripheral blood smear".)

RBC size – A normal RBC should have the same diameter as the nucleus of a small lymphocyte (picture 4). This comparison will help the investigator identify the patient with microcytosis (picture 5) or macrocytosis (picture 6).

Central pallor – The normal mature RBC is a biconcave disc (picture 7). As a result, RBCs on the peripheral smear demonstrate an area of central pallor, which, in normochromic RBCs, is approximately one-third the diameter of the cell (picture 4). Increased central pallor indicates hypochromic cells, which most often are seen in iron deficiency (picture 5) and thalassemia (picture 8). On the other hand, spherocytes (picture 3) and reticulocytes (picture 1) do not display central pallor, because they are not biconcave discs.

Fragmented cells – Although the patient's overall RBC indices may be normal, review of the blood smear may reveal the presence of small numbers of fragmented cells, indicating a microangiopathic process (picture 9). (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 such as:

●Sickle cells, as seen in sickle cell disease (picture 10). (See "Diagnosis of sickle cell disorders".)●Elliptocytes, as seen in congenital elliptocytosis (picture 11). (See "Hereditary elliptocytosis: Clinical features and diagnosis".)●Stomatocytes, as seen in hereditary or acquired stomatocytosis (picture 12). (See "Stomatocytosis".)●Pencil poikilocytes, which can be seen in iron deficiency anemia or thalassemia (picture 5).●Target cells, as seen in the various hemoglobinopathies including thalassemia, in liver disease, and post-splenectomy (picture 13 and picture 8). (See "Spiculated cells (echinocytes and acanthocytes) and target cells".)●Bite cells, as seen in Heinz body hemolytic anemia (picture 14). (See "Extrinsic nonautoimmune hemolytic anemia due to drugs and toxins".)●The presence of numerous nucleated red blood cells indicates rapid bone marrow turnover and is seen with hemolytic processes (picture 10 and picture 15). These findings may go undetected without inspection of the peripheral smear.

Increases in circulating neutrophils (neutrophilia), especially in the presence of a "left shift" (increased numbers of band forms) or toxic changes (picture 16), or the presence of atypical lymphocytes (picture 17) suggests the possibility of infectious or inflammatory conditions. The presence of early white blood cell forms (eg, blasts) (picture 18) along with anemia should raise the suspicion of leukemia or lymphoma. (See "Approach to the patient with neutrophilia" and "Approach to the patient with lymphocytosis or lymphocytopenia" and "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children".)  

Red blood cell indices — The red blood cell indices MCV, MCH, and MCHC are an integral part of the evaluation of the anemic child. Interpretation of these indices is discussed above. (See 'Morphologic classification' above.)

White blood count and platelet count — In the patient with anemia, the presence of leukopenia (low total white blood cell count), neutropenia (low total number of neutrophils), and/or thrombocytopenia (low platelet count) may signify abnormal bone marrow function or increased peripheral destruction of blood cells.

●Bone marrow hypoplasia may be caused by drugs or toxins, acute leukemia, or aplastic anemia. Folic acid or vitamin B12 deficiency are characterized by ineffective erythropoiesis, and may be associated with reduced WBC and platelet counts, or hypersegmented WBC forms.●Increased peripheral destruction reduces WBC and platelet counts in the setting of splenic hyperfunction ("hypersplenism"), microangiopathic hemolytic anemia (eg, hemolytic-uremic syndrome) or Evans syndrome (a variant of autoimmune hemolytic anemia). Iron deficiency can result in either thrombocytosis (common) [24] or thrombocytopenia (uncommon) [25].

SUMMARY

●The threshold for defining anemia is a hemoglobin (HGB) or hematocrit (HCT) that is more than two standard deviations below the mean for the age- and sex-specific reference population (table 1 and figure 1). (See 'Definition of anemia' above.)●Major causes of anemia seen in children are iron deficiency (dietary or due to blood loss), hemolysis (drug-induced, hereditary, or due to hypersplenism), hemoglobinopathies, and bone marrow suppression. (See "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" and "Anemia in children due to decreased red blood cell production".)●Key historical factors in the assessment of a child with anemia include the severity and onset of symptoms, evidence of jaundice or blood loss (gastrointestinal symptoms and menstrual history), drug and toxin exposure, chronic disease, and family history of anemias or hemoglobinopathy. (See 'History' above.)●The physical examination should include a careful assessment for pallor, scleral icterus, jaundice, hepatomegaly, and splenomegaly. (See 'Physical examination'above.)●Disorders resulting in an inability to adequately produce red blood cells (ie, bone marrow depression) are usually associated with a low reticulocyte count (<3 percent). Disorders resulting in rapid destruction or loss of red blood cells (hemolysis or bleeding) are usually associated with an elevated reticulocyte count. (See 'Physiologic classification' above.)●Anemias also may be classified also according to RBC size (mean corpuscular volume, MCV), hemoglobin content (mean corpuscular hemoglobin, MCH), or hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC). (See 'Morphologic classification' above.)●Normal values for MCV are high at birth and decrease with age (table 1 and table 2). Factors that increase MCV include certain medications (eg, anticonvulsant drugs) vitamin B12 or folate deficiency, and reticulocytosis. Factors that reduce the MCV include iron deficiency, lead intoxication, and hemoglobinopathies. (See 'Mean corpuscular volume' above.)●The laboratory examination should begin with a complete blood count, including red blood cell indices, and a reticulocyte count. The MCV and reticulocyte count often provide a preliminary categorization of the anemia, which guides additional testing (algorithm 1). However, multiple factors may contribute to the anemia, and not all patients can be neatly categorized. (See 'Physiologic classification' above and 'Mean corpuscular volume' above.)●Review of the peripheral blood smear is essential. The findings may support or refute the conclusions suggested by the RBC indices, or reveal features that suggest a specific cause of anemia, and helps to evaluate the possibility of a hematologic malignancy. The clinician must critically examine all blood cells and not just the red cells. (See 'Blood smear' above.)

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