Anemia

Official reprint from UpToDate® Back | Print www.uptodate.com Approach to the adult patient with anemia Author Section Editor Deputy Editor Stanley L Schrier, MD William C Mentzer, MD Stephen A Landaw, MD, PhD Last literature review version 17.1: January 2009 | This topic last updated: December 31, 2008 (More) INTRODUCTION — Although anemia can be defined as a reduced absolute number of circulating red blood cells (ie, a reduced red blood cell mass as determined by a blood volume study), such studies are not practical, cost-effective, or generally available. As a result, anemia has been defined as a reduction in one or more of the major red blood cell (RBC) measurements: hemoglobin concentration, hematocrit, or RBC count: Hemoglobin concentration (HGB) measures the concentration of the major oxygen-carrying pigment in whole blood. Values may be expressed as grams of hemoglobin per 100 mL of whole blood (g/dL) or per liter of blood (g/L) Hematocrit (HCT) is the percent of a sample of whole blood occupied by intact red blood cells ( show picture 1 ). RBC count is the number of red blood cells contained in a specified volume of whole blood, usually expressed as millions of red blood cells per microL of whole blood. This topic review will provide an approach to the anemic patient. The first portion is devoted to an understanding of the basic aspects of erythropoiesis and a review of the causes and clinical consequences of anemia. The second portion is devoted to the clinical and laboratory evaluation of the anemic patient. An approach to the child with anemia is presented separately. ( See "Approach to the child with anemia" ). An introduction to the phenomenon of RBC destruction (hemolysis) and tests which may be used to provide a diagnosis of hemolytic anemia is presented separately. ( See "Approach to the diagnosis of hemolytic anemia in the adult" ). DEFINITIONS Normal range — One set of "normal ranges" (95 percent confidence limits) for HGB, HCT, and RBC count is shown in the table ( show table 1 ). If anemia is defined as values which are more than two standard deviations (SD) below the mean, then, by using these ranges, a HGB <13.5 g/dL or a HCT <41.0 percent represents anemia in men and a value <12.0 g/dL or <36.0 percent, respectively, represents anemia in women. Normal ranges other than the above have been proposed: Other authors have proposed different lower limits of normal, ranging from 13.0 to 14.2 g/dL for men and 11.6 to 12.3 g/dL for women [ 1] . WHO criteria for anemia in men and women are <13 and <12 g/dL, respectively [ 2] . These criteria were meant to be used within the context of international nutrition studies, and were not initially designed to serve as "gold standards" for the diagnosis of anemia [ 1] .

diagnosis of anemia [ 1] . The revised WHO/National Cancer Institute's criteria for anemia in men and women are <14 and <12 g/dL, respectively [ 3] . These values are meant to be used for evaluation of anemia in patients with malignancy. Other lower limits according to sex, age, and race, based on data from NHANES III and Scripps-Kaiser studies, have been proposed ( show table 2 ) [ 1] . These values are as low as 12.7 g/dL for black men >60 years of age and 11.5 g/dL for black women >20 years of age. There are a number of immediate limitations to this approach: The above ranges may be "two-tailed" to be used for defining both anemia and polycythemia. In such cases, 2.5 percent of normal adults will have values which are more than 2 standard deviations below whatever "normal range" has been selected, and will be considered anemic. On the other hand, some ranges are "one-tailed", such that 5 percent of normal subjects will have levels below the stated lower limit of normal [ 1] . The normal range for HGB and HCT is so wide that, for example, a male patient with a baseline HCT of 49 percent may lose up to 15 percent of his RBC mass and still have a HCT within the normal range. "Normal" ranges may not apply to special populations (eg, high altitude living, smokers, athletes, elderly, use of ACE inhibitors). ( See "Special populations" below and see "Impact of anemia in patients with heart failure" , section on Etiology). Setting a lower limit of normal for hemoglobin does not imply that such levels are "optimal" in terms of morbidity and mortality. One study has suggested that the lower limits of an optimal hemoglobin level, as assessed by all-cause mortality data, are 13.0 and 14.0 g/dL for elderly women and men, respectively [ 4] . However, in one study, older black subjects classified as anemic by WHO criteria did not appear to be at risk for adverse events such as mortality and mobility disability [5] , suggesting that alternative criteria for anemia are indeed required for this group ( show table 2 ) [ 1] . Volume status — HGB, HCT, and RBC count are all concentrations and dependent on the red blood cell mass (RCM) as well as the plasma volume. As a result, values will be reduced if the RCM is decreased and/or if the plasma volume is increased [ 6] . Three common clinical examples will help make this point: A 70 kg adult with a bleeding peptic ulcer who had a 750 mL hematemesis (ie, 15 percent of a normal total blood volume) within the past 30 minutes may have postural hypotension due to acute volume depletion, but will have normal values for HGB and HCT. Over the ensuing 36 to 48 hours, most of the total blood volume deficit will be repaired by the movement of fluid from the extravascular into the intravascular space. Only at these later times will the HGB and HCT reflect blood loss. However, if the total blood volume deficit is not fully repaired and the patient remains hypovolemic, the HGB and HCT will underestimate the degree of blood loss [7] . In the third trimester of pregnancy the RBC mass and plasma volume are expanded by 25 and 50 percent, respectively, resulting in reductions in HGB, HCT, and RBC count, often to anemic levels ( show figure 1 ). However, according to the RBC mass, such women are polycythemic. The terms "physiologic" or "dilutional" anemia have been applied to this setting.

Patients admitted to the hospital in a volume depleted state may not show abnormally low HGB/HCT values on initial testing. An underlying anemia may become apparent only after the volume depletion has been corrected. Special populations — Normal ranges ( show table 1 ) may not be appropriate for all populations: Patients living at high altitude have values higher than those living at sea level [ 8] . ( See "High altitude and heart disease" , section on Long-term altitude exposure). A study of blood donors who smoke found a significant and direct correlation between the patients' blood carboxyhemoglobin and HGB values [ 9] . The same study also found a significant relationship, although of lesser magnitude, between HGB values and the degree of environmental air pollution with carbon monoxide in nonsmoking blood donors. Thus, patients who smoke or have significant exposure to secondary smoke or other sources of carbon monoxide may have hematocrits higher than normal [ 10 ] , occasionally reaching polycythemic levels. ( See "Diagnostic approach to the patient with polycythemia" , section on Acquired secondary erythrocytosis). Values for HGB in African-Americans of both sexes and all ages are 0.5 to 1.0 g/dL lower than values in comparable Caucasian populations [ 1,11-15 ] . Some, but not all, of these differences may be attributable to co-existing iron deficiency anemia and/or alpha thalassemia [ 16 ] . Normal values for a population with a high incidence of chronic disease may be skewed toward anemic levels. Thus, anemia may be difficult to define in countries in which malnutrition, infection (eg, tuberculosis, malaria), and/or congenital hematologic disorders (eg, thalassemia) are common. ( See "Community public health issues and the thalassemic syndromes: Lessons from other countries" , section on Introduction). The elderly — Values for HGB and HCT in apparently healthy older adults are generally lower than those in younger adults, and differences between males and females in HGB and HCT that are seen in younger adults are lessened with aging [ 17-19 ] . The prevalence of anemia in adults >65 and ≥ 85 years of age has been estimated at 10 and >20 percent, respectively [ 20,21 ] . As an example, anemia as defined by the WHO criteria, was present in 26 percent of a cohort of 85 year old adults [ 22 ] . Although low hemoglobin concentrations are common in older adults, it has been suggested that the elderly should NOT be presumed to have a lower "normal" range, for fear of missing a serious underlying disorder [ 20,23-28 ] . A number of large studies have shown the adverse effects (eg, decline in physical performance, morbidity, mortality) of anemia in elderly patients [ 4,14,25,26,29-31 ] . Three of these are outlined below: In 686 community-dwelling women ≥ 65 with self-reported disabilities, HGB levels progressively lower than 11.0 g/dL were associated with increasingly higher risks for all-cause mortality than levels of 12.0 g/dL, whereas HGB levels of 13.0 and 14.0 g/dL were associated with a lower risk of death [ 29 ] . A study of 755 subjects >85 years of age showed that a HGB <13.0 g/dL in males and <12.0 g/dL in females was associated with an increased relative risk of mortality of 1.6 in males (95% CI 1.2-2.1) and 2.3 in females (95% CI 1.6-3.3) [26 ] . Disorders such as malignancy, peptic ulcer, and infection were more common in the anemic patients. However, the mortality risk in elderly anemic patients without obvious clinical disease was also increased to more than twice that of nonanemic patients.

nonanemic patients. It was concluded that anemia in older patients is due to disease and not aging, and that further investigation is warranted if an older person's HGB is below normal, even if no clinical disease is immediately apparent. A study in community dwelling elderly adults (age 71 to 82 years) confirmed the adverse effect of anemia, as defined by the WHO criteria, on mortality and mobility disability in white men and women [ 30 ] . Older blacks classified as anemic by WHO criteria were not at risk for adverse events, indicating, as noted above, that alternative criteria for anemia may be warranted for blacks ( show table 2 and see "Normal range" above ). The causes of anemia in the elderly were evaluated in a study of the noninstitutionalized United States population in the third National Health and Nutrition Examination Survey (NHANES III) [ 20 ] . Overall, 10 to 11 percent of men and women ≥ 65 years of age were anemic, with a higher rate (28 percent) in non-Hispanic blacks. The anemia was generally mild, with only 2 to 3 percent of men and women having a hemoglobin level <11.0 g/dL. The causes for anemia were estimated as follows: One-third were related to presence of a nutritional deficiency (eg, iron, folate, B12). Iron deficiency, alone or in combination with folate or B12 deficiency, constituted more than one-half of this group. One-third were related to chronic kidney disease and/or other chronic disorders (eg, arthritis, diabetes, increased serum C-reactive protein, or a positive rheumatoid factor). ( See "Anemia of chronic disease (anemia of chronic inflammation)" ). Anemia in the remaining one-third was unexplained, although 17 percent of these patients (6 percent of the entire patient population) satisfied one or more criteria for the diagnosis of the myelodysplastic syndrome (eg, macrocytosis, thrombocytopenia, neutropenia). ( See "Clinical manifestations and diagnosis of the myelodysplastic syndromes" , section on Making the diagnosis). In this and other studies in elderly anemic patients, 23 to 45 percent had anemia that remained unexplained [ 17,20,28 ] . The mechanism(s) underlying "unexplained" anemia in the elderly may include age-related decline in renal function [ 32 ] , altered erythropoietin sensing and response, loss of hematopoietic stem cell reserve with increasing age [ 33 ] , low testosterone levels, as well as undiagnosed myelodysplastic syndrome [ 20,34-38 ] . Despite these uncertainties, the most reasonable approach to the anemic elderly patient consists of ruling out the major identifiable causes, such as bleeding disorders, nutritional deficiencies, renal disease, inflammatory disorders, and the myelodysplastic syndrome [37 ] . The value of erythropoietin for the treatment of chronic unexplained (undiagnosed) anemia in the elderly patient is unclear [ 39 ] . One small exploratory, randomized, placebo-controlled, crossover study indicated that such treatment was associated with an increase in hemoglobin level of >2 g/dL in two-thirds of the patients, along with improvements in fatigue and quality of life [ 40 ] . Athletes — Values in male and female endurance athletes may vary significantly from those in otherwise normal people [ 41-46 ] . Dilutional anemia secondary to an increased plasma volume [ 42,47 ] , gastrointestinal bleeding [ 43 ] , intravascular hemolysis (eg, march hemoglobinuria) [ 44 ] , iron deficiency [ 48,49 ] , as well as polycythemia [ 45,47 ] have all been reported as a consequence of strenuous sports, or the use of performance-enhancing agents, such as androgens and erythropoietin . ( See "Extrinsic

performance-enhancing agents, such as androgens and erythropoietin . ( See "Extrinsic nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism" , section on Mechanical trauma and see "Use of androgens and other drugs by athletes" , section on Androgens and section on Erythropoietin). THE RBC LIFE CYCLE Overview — Erythropoiesis in the adult takes place within the bone marrow under the influence of the stromal framework, cytokines, and the erythroid specific growth factor, erythropoietin (EPO). EPO is a true endocrine hormone produced in the kidney by cells that sense the adequacy of tissue oxygenation relative to the individual's metabolic activity ( show figure 2 ). ( See "Regulation of erythropoiesis" ). EPO enhances the growth and differentiation of the two erythroid progenitors: burst forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) into normoblasts of increasing maturity. When the normoblast extrudes its nucleus to form a red blood cell, it still has a ribosomal network which, when stained supravitally, identifies it as a reticulocyte, a cell still capable of a limited amount of hemoglobin and protein synthesis [ 50 ] . The reticulocyte retains its ribosomal network (and its staining characteristics) for about four days, of which three days are generally spent in the marrow and one day in the peripheral blood ( show figure 3 ). The resulting mature RBC circulates for 110 to 120 days, after which it is removed from the circulation by macrophages that detect senescent signals, through mechanisms that are poorly understood. Under steady state conditions, the rate of RBC production equals the rate of RBC loss. Assuming, as a first approximation, survival of mature RBC of 100 days, 1 percent of RBCs are removed from the circulation each day. To achieve a constant RBC mass, RBC losses must be replaced with an equal number of reticulocytes during the same time period. Reticulocytes normally survive in the circulation for one day; after this time they lose their reticulum (RNA) and become mature red blood cells. Under steady-state conditions reticulocytes will represent approximately 1 percent of total circulating RBC ( show table 1 ). Since the normal RBC count is approximately 5 million/microL, the bone marrow must produce approximately 50,000 reticulocytes/microL of whole blood each day in order to achieve a stable RBC mass. Lesser rates of RBC production, if persistent, lead to anemia. The rate of red cell production increases markedly under the influence of high levels of erythropoietin (EPO). A normal bone marrow replete with iron, folate, and cobalamin can increase erythropoiesis in response to EPO about 5-fold in adults and 7- to 8-fold in children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as high as 250,000/microL are possible in the adult. Reticulocytes — Reticulocytes can be enumerated manually after supravital staining of a blood sample with dyes such as new methylene blue (show blood smear 1 ). The normal range (ie, percent of RBC with positive staining) in adults is 0.5 to 1.5 percent ( show table 1). Reticulocytes can be appreciated on a standard blood smear stained with Wright Giemsa as RBC with a blue tint (polychromatophilia) that are larger than mature RBC, with irregular borders and a lack of central pallor ( show blood smear 2 ). Reticulocytes can be counted with more accuracy via automated blood counters after staining with a fluorescent dye such as thiazole orange, which binds to the RNA of reticulocytes [ 51 ] . ( See "Automated hematology instrumentation" , section on Automated counting of reticulocytes). The utility of reticulocyte counting in some settings can be improved by determination of the absolute reticulocyte count, the corrected absolute reticulocyte count, and/or the reticulocyte production index. This subject is discussed separately. ( See "Approach to the

reticulocyte production index. This subject is discussed separately. ( See "Approach to the diagnosis of hemolytic anemia in the adult" , section on Reticulocyte response). CLINICAL CONSEQUENCES — The signs and symptoms induced by anemia are dependent upon the degree of anemia and the rate at which it has evolved, as well as the oxygen demands of the patient. Symptoms are much less likely with anemia that evolves slowly, because there is time for multiple homeostatic forces to adjust to a reduced oxygen carrying capacity of blood. Before discussing these issues, it is helpful to first review the normal function of red cells. Normal red cell function — RBCs carry oxygen linked to hemoglobin from the lungs to tissue capillaries. Oxygen is then released from hemoglobin according to the characteristics of the oxyhemoglobin dissociation curve, with each gram of hemoglobin carrying 1.3 mL of oxygen. Thus, approximately 20 mL/dL (or 20 volumes percent) can be carried by 15 g/dL of hemoglobin at full saturation. Approximately five volumes percent (25 percent of the total) is normally removed by the tissues [ 52 ] . ( See "Oxygen delivery and consumption" and see "Genetic disorders of hemoglobin oxygen affinity" , section on Mutations that decrease the affinity of hemoglobin for 2,3-DPG). Symptoms — Symptoms related to anemia can result from two factors: decreased oxygen delivery to tissues, and, in patients with acute and marked bleeding, the added insult of hypovolemia. There is some reduction in blood volume but not plasma volume after acute severe hemolysis, due to the fall in RBC mass. In comparison, total blood volume remains normal in anemia due to chronic, low-grade bleeding, since there is ample time for equilibration with the extravascular space and renal retention of salt and water. Symptoms of impaired oxygen delivery reflect the fall in hemoglobin concentration. The extraction of oxygen by the tissues can increase from a baseline of 25 percent to a maximum of about 60 percent in the presence of anemia or hypoperfusion. Thus, normal oxygen delivery of five volumes percent can be maintained by enhanced extraction alone down to a hemoglobin concentration of 8 to 9 g/dL [ 53 ] . When the added compensation of increases in stroke volume and heart rate (and therefore cardiac output) are included, oxygen delivery can be maintained at rest at a hemoglobin concentration as low as 5 g/dL (equivalent to a hematocrit of 15 percent), assuming that the intravascular volume is maintained [ 54 ] . ( See "Indications for red cell transfusion in the adult" , section on Physiology of anemia). Symptoms will occur when the hemoglobin concentration falls below this level at rest, at higher hemoglobin concentrations during exertion, or when cardiac compensation is impaired because of underlying heart disease. The primary symptoms include exertional dyspnea, dyspnea at rest, varying degrees of fatigue, and signs and symptoms of the hyperdynamic state, such as bounding pulses, palpitations, and "roaring in the ears". More severe anemia may lead to lethargy and confusion and potentially life-threatening complications such as congestive failure, angina, arrhythmia, and/or myocardial infarction. ( See "High-output heart failure" ). Anemia induced by acute bleeding is associated with the added complication of intracellular and extracellular volume depletion. The earliest symptoms include easy fatiguability, lassitude, and muscle cramps. This can progress to postural dizziness, lethargy, syncope, and, in severe cases, to persistent hypotension, shock, and death. (See "Clinical manifestations and diagnosis of volume depletion in adults" ). Fatigue — Although anemia may be associated with complaints of fatigue, this complaint is non-specific, may be present in a number of other conditions, and may be multi-factorial. This subject is discussed in depth separately. ( See "Approach to the adult patient with fatigue" and see "Cancer-related fatigue: Prevalence, screening and clinical assessment" ).

CAUSES OF ANEMIA — There are two general approaches one can use to help identify the cause of anemia: A kinetic approach, addressing the mechanism(s) responsible for the fall in hemoglobin concentration A morphologic approach categorizing anemias via alterations in RBC size (ie, mean corpuscular volume) and the reticulocyte response [ 55 ] . Kinetic approach — Anemia can be caused by one or more of three independent mechanisms: decreased RBC production, increased RBC destruction, and blood loss [ 50 ] . Decreased RBC production — Anemia will ultimately result if the rate of RBC production is less than that of RBC destruction. ( See "Anemias due to decreased red cell production" ). The more common causes for reduced (effective) RBC production include: Lack of nutrients, such as iron, B12, or folate. This can be due to dietary lack, malabsorption (eg, pernicious anemia, sprue), or blood loss (iron deficiency) Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia, tumor infiltration) Bone marrow suppression (eg, drugs, chemotherapy, irradiation). ( See "Hematologic consequences of malignancy: Anemia" ). Low levels of trophic hormones which stimulate RBC production, such as EPO (eg, chronic renal failure), thyroid hormone (eg, hypothyroidism), and androgens (eg, hypogonadism). A rare cause of anemia due to reduced EPO production has been described in patients with autonomic dysfunction and orthostatic hypotension [56,57 ] . ( See "Treatment of orthostatic and postprandial hypotension" , section on Erythropoietin ). The anemia of chronic disease/inflammation, associated with infectious, inflammatory, or malignant disorders, is characterized by reduced availability of iron due to decreased absorption from the gastrointestinal tract and decreased release from macrophages, a relative reduction in erythropoietin levels, and a mild reduction in RBC lifespan. ( See "Anemia of chronic disease (anemia of chronic inflammation)" ). Increased RBC destruction — A RBC life span below 100 days is the operational definition of hemolysis [ 58 ] . ( See "Red blood cell survival: Normal values and measurement" ). Hemolytic anemia will ensue when the bone marrow is unable to keep up with the need to replace more than about 5 percent of the RBC mass per day, corresponding to a RBC survival of about 20 days. ( See "Approach to the diagnosis of hemolytic anemia in the adult" ). Examples include ( show table 3 ): Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease, thalassemia major) Acquired hemolytic anemias (eg, Coombs'-positive autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, malaria) Blood loss — Iron deficiency in the United States and Western Europe is almost always due to blood loss. Blood loss is the most common cause of anemia and may take any one of a number of forms: Obvious bleeding (eg, trauma, melena, hematemesis, menometrorrhagia)

Occult bleeding (eg, slowly bleeding ulcer or carcinoma). ( See "Evaluation of occult gastrointestinal bleeding" ). Induced bleeding (eg, repeated diagnostic testing, hemodialysis losses, excessive blood donation) There are a number of situations in which blood loss can occur and not be easily recognized. These include: Factitious bleeding, secondary to surreptitious blood drawing by the patient Bleeding during or after surgical procedures may be extremely difficult to quantitate, and is often underestimated Bleeding into the upper thigh and/or retroperitoneal space can often be significant, but may not be clinically obvious. Such patients may, however, have associated symptoms of abdominal pain or mass, groin or hip pain, leg paresis, or hypotension [ 59 ] . This complication may be more common in patients taking anticoagulants, even when results of coagulation tests are within the therapeutic range. CT imaging of the abdomen and thigh is often helpful if this is suspected. In addition to the loss of RBCs from the body, which the bone marrow must replace, loss of the iron contained in these cells will ultimately lead to iron deficiency, once tissue stores of iron have been depleted. This usually occurs in males and females after losses of ≥ 1200 mL and ≥ 600 mL, respectively. However, since about 25 percent of menstruant females have absent iron stores, any amount of bleeding will result in anemia in this subpopulation. ( See "Causes and diagnosis of anemia due to iron deficiency" ). Since availability of iron is normally rate-limiting for RBC production, iron deficiency associated with chronic bleeding leads to a reduced marrow response, worsening the degree of anemia. Morphologic approach — The causes of anemia can also be classified according to measurement of RBC size, as seen on the blood smear and as reported by automatic cell counter indices [ 60 ] . The normal RBC has a volume of 80 to 96 femtoliters (fL, 10[-15] Liter) and a diameter of approximately 7 to 8 microns, equal to that of the nucleus of a small lymphocyte. Thus, RBCs larger than the nucleus of a small lymphocyte on a peripheral smear are considered large or macrocytic, while those that appear smaller are considered small or microcytic ( show table 4 ). ( See "Evaluation of the peripheral blood smear" , section on Red blood cells). Automatic cell counters estimate RBC volume cell by cell, sampling millions of RBCs in the process. ( See "Mean corpuscular volume" ). Machine output is a value for the mean corpuscular volume of the sample (MCV), as well as an estimate of the dispersion of values about this mean. The latter value is usually given as the coefficient of variation of RBC volumes or RBC distribution width (RDW). An increased RDW indicates the presence of cells of widely differing sizes, but it is not diagnostic of any particular disorder. However, some automatic cell counters have computer programs which "flag" for the presence of abnormalities such as anisocytosis (cells of varying size), microcytosis, macrocytosis, and hypochromia (reduced hemoglobin content per cell) [ 61 ] . ( See "Automated hematology instrumentation" , section on Red cell distribution width). Macrocytic anemia — Macrocytic anemias are characterized by an MCV above 100 fL (femtoliters) ( show table 5 ). ( See "Macrocytosis" ). An increased MCV is a normal characteristic of reticulocytes ( show blood smear 2 ). Any condition causing marked reticulocytosis will be associated with an increased

Any condition causing marked reticulocytosis will be associated with an increased MCV. Abnormal nucleic acid metabolism of erythroid precursors (eg, folate or cobalamin deficiency and drugs interfering with nucleic acid synthesis, such as zidovudine and hydroxyurea ). Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, LGL leukemia). Other common causes include alcohol abuse, liver disease, and hypothyroidism. A report from a family practice group found macrocytosis in 2 to 4 percent of patients [ 62 ] , while a study of 1,784 randomly selected elderly people living at home found macrocytosis in 6.3 percent of men and 3.3 percent of women [ 63 ] . The most common causes were alcoholism, liver disease, hypothyroidism, and the megaloblastic anemias. Microcytic anemia — Microcytic anemias are characterized by the presence of "small" RBCs (ie, MCV below 80 fL). Microcytosis is usually accompanied by a decreased hemoglobin content within the RBC, with parallel reductions in MCV and MCH, producing a hypochromic (low MCH) as well as a microcytic (low MCV) appearance on the blood smear (show blood smear 3 , show table 4 ). ( See "Mean corpuscular volume" , section on Causes of microcytosis). The following pathologic processes lead to the production of hypochromic microcytic red cells: Reduced iron availability — severe iron deficiency, the anemia of chronic disease, copper deficiency Reduced heme synthesis — lead poisoning, congenital or acquired sideroblastic anemia Reduced globin production — thalassemic states, other hemoglobinopathies The three most common causes of microcytosis in clinical practice are iron deficiency, alpha or beta thalassemia minor, and (less often) the anemia of chronic disease (anemia of chronic inflammation). Since all may have hypochromic and microcytic RBCs, other tests must be used to establish the diagnosis. Iron deficiency anemia — Important discriminating features are a low serum ferritin concentration, an increased total iron binding capacity (transferrin), and low serum iron concentration ( show table 6 ). For some physicians, proof of this diagnosis requires a clinical response (ie, increase in HGB or HCT) to treatment with iron. For physicians making this diagnosis, it is mandatory to determine the cause of the iron deficient state (eg, occult colonic carcinoma, excessive menstrual losses). ( See "Causes and diagnosis of anemia due to iron deficiency" ). Alpha or beta thalassemia minor — Adults with thalassemia are most often heterozygotes for the alpha or beta forms of this syndrome, and may not be anemic. A family history is therefore often negative. Physical examination may reveal splenomegaly; the peripheral smear shows varying degrees of hypochromia, microcytosis, target cells ( show blood smear 4 ), tear-drop forms, and basophilic stippling ( show blood smear 5 ). The RBC count may actually be increased and uncomplicated patients have normal or increased iron stores. ( See "Clinical manifestations and diagnosis of the thalassemias" ). The diagnosis of beta thalassemia trait can often be made by demonstrating increased levels of hemoglobin A2 on hemoglobin electrophoresis or liquid chromatography (HPLC), while molecular methods are usually required for the diagnosis of mild alpha thalassemia variants [ 64 ] . ( See "Molecular diagnosis of inherited hemoglobin disorders" ).

variants [ 64 ] . ( See "Molecular diagnosis of inherited hemoglobin disorders" ). Anemia of chronic disease (inflammation) — The hallmarks of this condition include a low serum iron, low total iron binding capacity (transferrin), and a normal to increased serum ferritin concentration. Although hypochromic and microcytic red cells can be found in these patients, a low MCV is most frequently seen only in patients with hepatoma or renal cell carcinoma. ( See "Anemia of chronic disease (Anemia of chronic inflammation)" ). Normocytic anemia — By definition, the mean RBC volume is normal (MCV between 80 and 100 fL) in patients with normocytic anemia ( show table 4 ). Approach to this extremely large and amorphous category can be narrowed somewhat by examination of the blood smear to determine if there is a subpopulation of RBCs with distinctive size or shape abnormalities which would place the patient in one of the above categories (ie, early microcytic or macrocytic anemia), or by use of the kinetic approach to determine the mechanism(s) underlying the anemia ( see "kinetic approach" above ). Systemic disorders — Anemia may be the first manifestation of a systemic disorder, along with other nonspecific complaints such as fever, weight loss, anorexia, and malaise. Simple laboratory tests may give additional clues toward the underlying disease process. These include abnormalities on the urinalysis or routine chest x-ray, liver or renal function tests, erythrocyte sedimentation rate, serum protein electrophoresis, WBC count and differential, and reduced (or increased) platelet counts. Anemia in the elderly is discussed separately ( see "The elderly" above ). Anemia of chronic renal disease — Anemia is a common complication of renal disease, and may be multifactorial. This subject is discussed in detail separately. ( See "Overview of the management of chronic kidney disease in adults" , section on Anemia and see "Anemia and left ventricular hypertrophy in chronic kidney disease" ). EVALUATION OF THE PATIENT Initial approach — Anemia is one of the major signs of disease. It is never normal and its cause(s) should always be sought. The history, physical examination, and simple laboratory testing are all useful in evaluating the anemic patient. The workup should be directed towards answering the following questions concerning whether one or more of the major processes leading to anemia may be operative: Is the patient bleeding (now or in the past)? Is there evidence for increased RBC destruction (hemolysis)? Is the bone marrow suppressed? Is the patient iron deficient? If so, why? Is the patient deficient in folic acid or vitamin B12 ? If so, why? History — There are a number of important components to the history in the setting of anemia: Is there a history of, or symptoms related to, a medical condition which is known to result in anemia (eg, tarry stools in a patient with ulcer-type pain, rheumatoid arthritis, renal failure)? Is the anemia of recent origin, subacute, or lifelong? Recent anemia is almost always an acquired disorder, while lifelong anemia, particularly if accompanied by a positive family history, is likely to be inherited (eg, the hemoglobinopathies, hereditary spherocytosis). The patient's ethnicity and country of origin may be helpful, as the thalassemias and other hemoglobinopathies are particularly common in patients from the Mediterranean littoral, Middle East, sub-Saharan Africa, and South East Asia [ 65 ] . ( See "Introduction to

littoral, Middle East, sub-Saharan Africa, and South East Asia [ 65 ] . ( See "Introduction to hemoglobin mutations" and see "Community public health issues and the thalassemic syndromes: Lessons from other countries" ). The use of medications, both prescribed as well as over-the-counter, should be examined in some detail. Specific questions should be asked about the use of alcohol, aspirin , and nonsteroidal antiinflammatory drugs. ( See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity" ). A past history of blood transfusions, liver disease, treatment of the patient (or other family members) with iron or other hematinics, herbal preparations, and exposure to toxic chemicals in the workplace or environment should also be obtained. An assessment of nutritional status is especially important in the elderly and alcoholics. Physical examination — The major aim on physical examination is to find signs of organ or multisystem involvement and to assess the severity of the patient's condition. Thus, the presence or absence of tachycardia, dyspnea, fever, or postural hypotension should be noted. While evaluation for jaundice and pallor is a standard part of the physical examination, such signs may be misinterpreted, and are not as reliable indicators of anemia as once thought. Pallor — The sensitivity and specificity for pallor in the palms, nail beds, face, or conjunctivae as a predictor for anemia varies from 19 to 70 percent and 70 to 100 percent, respectively [ 66-69 ] , with wide interobserver differences and widely differing conclusions as to the clinical value of the presence or absence of this finding. Jaundice — Jaundice may be difficult to detect under artificial (nonfluorescent) lighting conditions [ 68 ] . Even under optimal conditions, it may be missed. As an example, in a double blind study involving 62 medical observers at various levels of training, the presence of scleral icterus was detected by 58 percent at a total serum bilirubin concentration of 2.5 mg/dL and by only 68 percent at a bilirubin concentration of 3.1 mg/dL [ 70 ] . False positives were mostly attributable to medical students, while false negatives were not related to the level of training. Other items to search for on physical examination include the presence or absence of lymphadenopathy, hepatosplenomegaly, and bone tenderness, especially over the sternum. Bone pain may signify expansion of the marrow space due to infiltrative disease, as in chronic myelogenous leukemia, or lytic lesions as in multiple myeloma or metastatic cancer. It is also important to look for signs of other hematologic abnormalities, including petechiae due to thrombocytopenia, ecchymoses, and other signs of bleeding due to abnormalities of coagulation. ( See "Approach to the patient with a bleeding diathesis" , section on Disorders of platelets or blood vessels). One should also look for signs and symptoms of recurrent infections secondary to neutropenia or immune deficiency states. Stool obtained during the examination should always be tested for the presence of occult blood. ( See "Evaluation of occult gastrointestinal bleeding" ). LABORATORY EVALUATION — Initial testing of the anemic patient should include a "complete" blood count (CBC). This routinely includes HGB, HCT, RBC count, RBC indices, and white blood cell (WBC) count. A WBC differential, platelet count, and reticulocyte count are not part of the routine CBC in some medical centers; these may have to be ordered separately. Thus, to avoid confusion, the clinician should specifically request a CBC with platelets, WBC differential, and reticulocytes. Many automated blood counters report a RBC distribution width (RDW), a measure of the degree of variation in red cell size ( red cell volume, see "Morphologic approach" above ). However, the RDW alone does not indicate why the RBC size varies (anisocytosis) or what the RBC shapes are (poikilocytosis). Some counters will "flag" for the presence of specific RBC changes, such as hypochromia or microcytosis, which can be confirmed by

RBC changes, such as hypochromia or microcytosis, which can be confirmed by examination of the peripheral smear. ( See "Automated hematology instrumentation" ). Accordingly, the blood smear should always be reviewed by an experienced examiner, since many important changes may be missed by the inexperienced observer and may not be detected by automated blood counters [ 71 ] . ( See "Blood smear" below and see "Evaluation of the peripheral blood smear" ). Red blood cell indices — Three RBC indices are usually measured by automated blood counters: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) ( show table 1 ). The values for MCH and MCHC generally parallel the information obtained from the MCV (ie, larger or smaller RBCs tend to have higher or lower values for MCH, respectively). Mean corpuscular volume — The normal range for MCV is from 80 to 100 femtoliters (fL). The causes of anemia associated with a low (microcytosis) or high (macrocytosis) MCV are discussed above ( show table 4 , see "Morphologic approach" above ). Values in excess of 115 fL are almost exclusively seen in vitamin B12 or folic acid deficiency. Even higher values can occur as an artifact when cold agglutinins are present, which causes RBCs to go through the counting aperture in doublets or triplets [ 72 ] . Warming the specimen (and reagents) to body temperature prior to a repeat count should return the MCV to normal, and confirm the presence of a cold agglutinin. ( See "Mean corpuscular volume" ). Mean corpuscular hemoglobin — The normal MCH ranges from 27.5 to 33.2 picograms of hemoglobin per RBC. Low values are seen in iron deficiency and thalassemia, while increased values occur in macrocytosis of any cause. Mean corpuscular hemoglobin concentration — The mean normal value for the MCHC is 34 grams of hemoglobin per dL of RBCs. The 95 percent confidence limits for the MCHC have been variably given ( show table 1 ), with lower and upper limits of 31 to 33 and 35 to 36, respectively. Low values occur in the same conditions that generate low values for MCV and MCH, while increased values occur almost exclusively in the presence of congenital or acquired spherocytosis or in other congenital hemolytic anemias in which red cells are abnormally dessicated (eg, sickle cell anemia, hemoglobin C disease, xerocytosis). ( See "Hereditary spherocytosis: Clinical features; diagnosis; and treatment" and see "Xerocytosis" ). Reticulocyte count — The reticulocyte count, either as a percentage of all RBCs, the absolute reticulocyte count, the corrected absolute reticulocyte count, or as the reticulocyte production index, helps to distinguish among the different types of anemia: Anemia with a high reticulocyte count reflects an increased erythropoietic response to continued hemolysis or blood loss ( see "Reticulocytes" above ). A stable anemia with a low reticulocyte count is strong evidence for deficient production of RBCs (ie, a reduced marrow response to the anemia). ( See "Anemias due to decreased red cell production" ). Hemolysis or blood loss can be associated with a low reticulocyte count if there is a concurrent disorder that impairs RBC production (eg, infection, prior chemotherapy; see "Multiple causes of anemia" below ). A low reticulocyte percentage accompanied by pancytopenia is suggestive of aplastic anemia, while a reticulocyte percentage of zero with normal white blood cell and platelet counts suggests a diagnosis of pure red cell aplasia. ( See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis" and see "Acquired pure red cell aplasia" ).

White blood cell count and differential — A low total white blood cell (WBC) count (leukopenia) in a patient with anemia should lead to consideration of bone marrow suppression or replacement, hypersplenism, or deficiencies of cobalamin or folate. In comparison, a high total WBC count (leukocytosis) may reflect the presence of infection, inflammation, or a hematologic malignancy. Clues to the specific abnormality present may be obtained from the WBC differential, which, in conjunction with the total WBC may show increased or decreased absolute numbers of the various cell types in the circulation. Examples include: An increased absolute neutrophil count in infection An increased absolute monocyte count in myelodysplasia An increased absolute eosinophil count in certain infections A decreased absolute neutrophil count following chemotherapy A decreased absolute lymphocyte count in HIV infection or following treatment with corticosteroids Neutrophil hypersegmentation — Neutrophil hypersegmentation (NH) is defined as the presence of >5 percent of neutrophils with five or more lobes and/or the presence of one or more neutrophils with six or more lobes ( show blood smear 6 ). This peripheral smear finding, along with macroovalocytic red cells ( show blood smear 7 ), is classically associated with impaired DNA synthesis, as seen in disorders of vitamins B12 and folic acid . ( See "Etiology and clinical manifestations of vitamin B12 and folic acid deficiency" , section on Clinical manifestations). However, in one study of 100 subjects with normal values for red cell folate and serum cobalamin, NH (as defined above) was seen in 62 and 4 percent of 50 iron deficient and 50 normal subjects, respectively [ 73 ] . The mechanism for NH in iron deficiency is unknown. Circulating nucleated red blood cells — Nucleated RBCs (NRBCs) are not normally found in the circulation. They may be present in patients with known hematologic disease (eg, sickle cell disease, thalassemia major, various hemolytic anemias after splenectomy), or as a part of the leukoerythroblastic pattern seen in patients with bone marrow replacement ( show blood smear 8 ). In patients without known hematologic disease, NRBCs may reflect the presence of a life-threatening disease, such as sepsis or severe heart failure. In one study of 4,173 patients seen at a university clinic, NRBCs were seen at least once in 7.5 percent of all patients; the highest incidence (20 percent) occurred in patients from the general surgery and trauma intensive care unit [ 74 ] . In-hospital mortality was 1.2 and 21.1 percent in those without or with NRBCs, respectively, and increased with increasing concentration of NRBCs. In patients who died, nucleated RBCs were detected for the first time at a median of 13 days before death. Platelet count — Abnormalities in the platelet count often provide important diagnostic information. Thrombocytopenia occurs in a variety of disorders associated with anemia, including hypersplenism, marrow involvement with malignancy, autoimmune platelet destruction (either idiopathic or drug-related), sepsis, or folate or cobalamin deficiency. High platelet counts, in comparison, may reflect myeloproliferative disease, chronic iron deficiency, and inflammatory, infectious, or neoplastic disorders. ( See "Approach to the patient with thrombocytosis" ). Changes in platelet morphology (giant platelets, degranulated platelets) also may be important, suggesting myeloproliferative or myelodysplastic disease. Pancytopenia — The combination of anemia, thrombocytopenia, and neutropenia is termed pancytopenia. The presence of severe pancytopenia narrows the differential

termed pancytopenia. The presence of severe pancytopenia narrows the differential diagnosis to disorders such as aplastic anemia, folate or cobalamin deficiency, or hematologic malignancy (eg, acute myelogenous leukemia). ( See "Approach to the adult patient with thrombocytopenia" ). Mild degrees of pancytopenia may be seen in patients with splenomegaly and splenic trapping of circulating cellular elements. ( See "Extrinsic nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and hypersplenism" , section on Extravascular nonimmune hemolysis due to hypersplenism). Blood smear — Many clinicians rely on the above RBC parameters and the RDW in evaluating a patient with anemia. However, the RDW is, as noted above, of limited utility, and examination of the peripheral blood smear provides information not otherwise available. ( See "Evaluation of the peripheral blood smear" ). As examples, the automated counter may miss the red cell fragmentation ("helmet cells", schistocytes) of microangiopathic hemolysis ( show blood smear 9 ), microspherocytes in autoimmune hemolytic anemia, teardrop RBCs in myeloid metaplasia (show blood smear 10 ), a leukoerythroblastic pattern with bone marrow replacement (show blood smear 8 ), the "bite cells" in oxidative hemolysis ( show blood smear 11 ), or RBC parasites such as malaria or babesiosis ( show blood smear 12 ). ( See "Evaluation of the peripheral blood smear" ). Serial evaluation of hemoglobin and hematocrit — Measuring the rate of fall of the patient's HGB or HCT often provides helpful diagnostic information. Suppose the HGB concentration has fallen from 15 to 10 g/dL in one week. If this were due to total cessation of RBC production (ie, a reticulocyte count of zero) and if the rate of RBC destruction were normal (1 percent/day), the HGB concentration would have fallen by 7 percent over seven days, resulting a decline of 1.05 g/dL (0.07 x 15). The greater fall in HGB in this patient (5 g/dL) indicates that marrow suppression cannot be the sole cause of the anemia and that blood loss and/or increased RBC destruction must be present. Evaluation for iron deficiency — More complete evaluation for iron deficiency is indicated when the history (menometrorrhagia, symptoms of peptic ulcer disease) and preliminary laboratory data (low MCV, low MCH, high RDW, increased platelet count) support this diagnosis. In this setting, the plasma levels of iron, iron binding capacity (transferrin), transferrin saturation, and ferritin should be measured ( show table 6 ). ( See "Causes and diagnosis of anemia due to iron deficiency" ). Evaluation for hemolysis — Hemolysis should be considered if the patient has a rapid fall in hemoglobin concentration, reticulocytosis, and/or abnormally shaped RBC (especially spherocytes or fragmented RBCs) on the peripheral smear ( show table 3 ). The usual ancillary findings of hemolysis are an increase in the serum lactate dehydrogenase (LDH) and indirect bilirubin concentrations and a reduction in the serum haptoglobin concentration. ( See "Approach to the diagnosis of hemolytic anemia in the adult" ). The combination of an increased LDH and reduced haptoglobin is 90 percent specific for diagnosing hemolysis, while the combination of a normal LDH and a serum haptoglobin greater than 25 mg/dL is 92 percent sensitive for ruling out hemolysis [ 75,76 ] . Intravascular hemolysis — Serum or plasma hemoglobin and urinary hemosiderin should be measured if intravascular hemolysis is a consideration, as with paroxysmal nocturnal hemoglobinuria. ( See "Approach to the diagnosis of hemolytic anemia in the adult" , section on Testing for intravascular hemolysis). Bone marrow examination — Examination of the bone marrow generally offers little additional diagnostic information in the more common forms of anemia. If erythropoiesis is increased in response to the anemia, the bone marrow will show erythroid hyperplasia, a nonspecific finding. Similarly, although the absence of stainable iron in the bone

a nonspecific finding. Similarly, although the absence of stainable iron in the bone marrow had previously been considered the "gold standard" for the diagnosis of iron deficiency, this diagnosis is usually established by laboratory tests alone ( show table 6 ). (See "Causes and diagnosis of anemia due to iron deficiency" , section on Diagnosis). Indications for examination of the bone marrow in anemic patients include pancytopenia or the presence of abnormal cells in the circulation, such as blast forms. Such patients may have aplastic anemia, myelodysplasia, marrow replacement with malignancy, or a myeloproliferative disease. Other findings that may be seen in the marrow in anemic patients include megaloblastic erythropoiesis (folate or cobalamin deficiency), absence of recognizable RBC precursors (pure RBC aplasia), vacuolization of RBC precursors (alcohol or drug-induced anemia), and increased iron-laden RBC precursors (the sideroblastic anemias). ( See "Evaluation of bone marrow aspirate smears" ). Multiple causes of anemia — It is common in pediatric practice for anemia to be caused by a single identifiable disorder. In comparison, multiple causes are frequently present in adults, particularly the elderly. Common examples are: A patient with gastrointestinal bleeding secondary to colon cancer may also have the anemia of chronic disease, leading to a blunted reticulocyte response. ( See "Anemia of chronic disease (Anemia of chronic inflammation)" ). A patient with a chronic hemolytic anemia (eg, sickle cell anemia, hereditary spherocytosis) may develop worsening anemia following acute infection, particularly with parvovirus B19, which may blunt or temporarily ablate erythropoiesis and the reticulocyte response [ 77 ] . ( See "Acquired pure red cell aplasia" , section on Etiology and pathogenesis). A patient with autoimmune hemolytic anemia may develop worsening anemia from gastrointestinal blood loss following treatment with corticosteroids . Anemia, renal failure, and congestive failure are often found together, a condition that has been termed "cardio-renal anemia syndrome." Treatment of the anemia may improve both the renal failure and heart failure [ 78 ] . ( See "Anemia and left ventricular hypertrophy in chronic kidney disease" ). Algorithms for diagnosing anemia ( show algorithm 1 ) generally fail in the presence of more than one cause. Under such circumstances, the clinician is advised to obtain answers separately to each of the questions outlined above ( see "Initial approach" above ), to examine the peripheral blood smear for abnormal red blood cell populations (eg, microcytes, macrocytes, spherocytes, schistocytes), and proceed from that point. INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. ( See "Patient information: Iron deficiency anemia" ). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients , which includes this and other topics. RECOMMENDATION — The initial approach to the diagnosis of anemia is to review the results of a complete blood count (CBC) with WBC differential, platelet count, and reticulocyte count ( show table 1 ). A HGB <13.5 g/dL or a HCT <41.0 percent represents anemia in men; a value <12.0 g/dL or <36.0 percent, respectively, represents anemia in women. It is also critical to obtain values for prior CBCs in order to detect trends, disease progression, and to establish the date of disease onset. The anemia is first classified via the mean corpuscular volume (MCV), which is part of the CBC ( show algorithm 1 ): Microcytic anemias are associated with an MCV below 80 fL. The most commonly seen causes are iron deficiency ( show table 4 and show table 6 ), thalassemia, and

seen causes are iron deficiency ( show table 4 and show table 6 ), thalassemia, and the anemia of chronic disease ( see "Microcytic anemia" above and see "Evaluation for iron deficiency" above ). Macrocytic anemias are characterized by an MCV above 100 fL ( show table 4 and show table 5 ). The most common causes include alcoholism, liver disease, folic acid and vitamin B12 deficiency, and myelodysplasia. ( See "Macrocytosis" , section on Evaluation). The MCV is between 80 and 100 fL in patients with normocytic anemia ( show table 4). This is an extremely large and amorphous category, which can be narrowed somewhat by examination of the blood smear to determine if there is a small population of red cells with distinctive size or shape abnormalities which would place the patient in one of the above categories (ie, EARLY microcytic or macrocytic anemia), or would raise suspicion of an acute or chronic hemolytic state (eg, spherocytes, sickle forms, ovalocytes). Hemolysis may have been suspected from the patient's history and physical examination (eg, sudden onset of anemia, jaundice, splenomegaly; see "Evaluation of the patient" above ). It is confirmed by the finding of increased levels of indirect bilirubin and lactate dehydrogenase, and low levels of haptoglobin ( show table 3 ). ( See "Evaluation for hemolysis" above and see "Approach to the diagnosis of hemolytic anemia in the adult" , section on Diagnostic approach). The presence of abnormal cells in the circulation (eg, nucleated RBCs, blasts, atypical mononuclear cells) and/or abnormal increases or decreases in absolute counts for granulocytes, lymphocytes, monocytes, or platelets ( show algorithm 1 ) suggests that the anemia is part of a more complex hematologic disorder (eg, leukemia, aplastic anemia, myelodysplastic syndrome, myeloproliferative disorder). Consultation with a hematologist would be appropriate at this point. Anemia may be the first manifestation of a systemic disorder ( show table 4 ), along with other nonspecific complaints such as fever, weight loss, anorexia, and malaise. Simple laboratory tests may give additional clues toward the underlying disease process. These include abnormalities on the urinalysis or routine chest x-ray, elevated serum creatinine, abnormal liver function tests, and increased erythrocyte sedimentation rate. Use of UpToDate is subject to the Subscription and License Agreement . REFERENCES 1. Beutler, E, Waalen, J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?. Blood 2006; 107:1747. 2. World Health Organization. Nutritional anaemias: Report of a WHO scientific group. Geneva, Switzerland: World Health Organization; 1968. 3. Rodgers, GM, Becker, PS, Bennett, CL, et al. Cancer- and chemotherapy-induced anemia. J Natl Compr Canc Netw 2008; 6:536. 4. Culleton, BF, Manns, BJ, Zhang, J, et al. Impact of anemia on hospitalization and mortality in older adults. Blood 2006; 107:3841. 5. Patel, KV, Harris, TB, Faulhaber, M, et al. Racial variation in the relationship of anemia with mortality and mobility disability among older adults. Blood 2007; :. 6. Jacob, G, Raj, SR, Ketch, T, et al. Postural pseudoanemia: posture-dependent change in hematocrit. Mayo Clin Proc 2005; 80:611. 7. Valeri, CR, Dennis, RC, Ragno, G, et al. Limitations of the hematocrit level to

7. Valeri, CR, Dennis, RC, Ragno, G, et al. Limitations of the hematocrit level to assess the need for red blood cell transfusion in hypovolemic anemic patients. Transfusion 2006; 46:365. 8. Ruiz-Arguelles, GJ, Beutler, E, Waalen, J. Altitude above sea level as a variable for definition of anemia. Blood 2006; 108:2131. 9. Stewart, RD, Baretta, ED, Platte, LR, et al. Carboxyhemoglobin levels in American blood donors. JAMA 1974; 229:1187. 10. Nordenberg, D, Yip, R, Binkin, NJ. The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA 1990; 264:1556. 11. Garn, SM, Ryan, AS, Abraham, S, Owen, G. Suggested sex and age appropriate values for "low" and "deficient" hemoglobin levels. Am J Clin Nutr 1981; 34:1648. 12. Reed, WW, Diehl, LF. Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks. Arch Intern Med 1991; 151:501. 13. Perry, GS, Byers, T, Yip, R, Margen, S. Iron nutrition does not account for the hemoglobin differences between blacks and whites. J Nutr 1992; 122:1417. 14. Denny, SD, Kuchibhatla, MN, Cohen, HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med 2006; 119:327. 15. Robins, EB, Blum, S. Hematologic reference values for African American children and adolescents. Am J Hematol 2007; 82:611. 16. Beutler, E, West, C. Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. Blood 2005; 106:740. 17. Nilsson-Ehle, H, Jagenburg, R, Landahl, S, et al. Haematological abnormalities and reference intervals in the elderly. A cross-sectional comparative study of three urban Swedish population samples aged 70, 75 and 81 years. Acta Med Scand 1988; 224:595. 18. Nilsson-Ehle, H, Jagenburg, R, Landahl, S, et al. Decline of blood haemoglobin in the aged: a longitudinal study of an urban Swedish population from age 70 to 81. Br J Haematol 1989; 71:437. 19. Patel, KV. Epidemiology of anemia in older adults. Semin Hematol 2008; 45:210. 20. Guralnik, JM, Eisenstaedt, RS, Ferrucci, L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004; 104:2263. 21. Beghe, C, Wilson, A, Ershler, WB. Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature. Am J Med 2004; 116 Suppl 7A:3S. 22. den Elzen, WP, Westendorp, RG, Frolich, M, et al. Vitamin B12 and folate and the risk of anemia in old age: the Leiden 85-Plus Study. Arch Intern Med 2008; 168:2238. 23. Baldwin, JG. Hematopoietic function in the elderly. Arch Intern Med 1988; 148:2544. 24. Balducci, L. Epidemiology of anemia in the elderly: information on diagnostic evaluation. J Am Geriatr Soc 2003; 51:2. 25. Penninx, BW, Guralnik, JM, Onder, G, et al. Anemia and decline in physical performance among older persons. Am J Med 2003; 115:104. 26. Izaks, GJ, Westendorp, RGJ, Knook, DL. The definition of anemia in older persons. JAMA 1999; 281:1714. 27. Nissenson, AR, Goodnough, LT, Dubois, RW. Anemia: not just an innocent bystander?. Arch Intern Med 2003; 163:1400. 28. Artz, AS, Fergusson, D, Drinka, PJ, et al. Mechanisms of unexplained anemia in the nursing home. J Am Geriatr Soc 2004; 52:423. 29. Chaves, PH, Xue, QL, Guralnik, JM, et al. What constitutes normal hemoglobin concentration in community-dwelling disabled older women?. J Am Geriatr Soc 2004; 52:1811.

52:1811. 30. Patel, KV, Harris, TB, Faulhaber, M, et al. Racial variation in the relationship of anemia with mortality and mobility disability among older adults. Blood 2007; 109:4663. 31. Herzog, CA, Muster, HA, Li, S, Collins, AJ. Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare population. J Card Fail 2004; 10:467. 32. Adamson, JW. Renal disease and anemia in the elderly. Semin Hematol 2008; 45:235. 33. Gazit, R, Weissman, IL, Rossi, DJ. Hematopoietic stem cells and the aging hematopoietic system. Semin Hematol 2008; 45:218. 34. Ble, A, Fink, JC, Woodman, RC, et al. Renal function, erythropoietin, and anemia of older persons: the InCHIANTI study. Arch Intern Med 2005; 165:2222. 35. Ferrucci, L, Maggio, M, Bandinelli, S, et al. Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med 2006; 166:1380. 36. Ferrucci, L, Guralnik, JM, Bandinelli, S, et al. Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol 2007; 136:849. 37. Steensma, DP, Tefferi, A. Anemia in the elderly: How should we define it, when does it matter, and what can be done?. Mayo Clin Proc 2007; 82:958. 38. Makipour, S, Kanapuru, B, Ershler, WB. Unexplained anemia in the elderly. Semin Hematol 2008; 45:250. 39. Agarwal, N, Prchal, JT. Erythropoietic agents and the elderly. Semin Hematol 2008; 45:267. 40. Agnihotri, P, Telfer, M, Butt, Z, et al. Chronic anemia and fatigue in elderly patients: results of a randomized, double-blind, placebo-controlled, crossover exploratory study with epoetin alfa. J Am Geriatr Soc 2007; 55:1557. 41. Dufaux, B, Hoederath, A, Streitberger, I, et al. Serum ferritin, transferrin, haptoglobin and iron in middle-and long-distance runners, elite rowers and professional racing cyclists. Int J Sports Med 1981; 2:43. 42. Shaskey, DJ, Green, GA. Sports haematology. Sports Med 2000; 29:27. 43. Rudzki, SJ, Hazard, H, Collinson, D. Gastrointestinal blood loss in triathletes: Its etiology and relationship to sports anaemia. Aust J Sci Med Sport 1995; 27:3. 44. Selby, GB, Eichner, ER. Endurance swimming, intravascular hemolysis, anemia and iron depletion. Am J Med 1986; 81:791. 45. Berglund, B. High-altitude training. Aspects of haematological adaptation. Sports Med 1992; 14:289. 46. Kehat, I, Shupak, A, Goldenberg, I, Shoshani, O. Long-term hematological effects in Special Forces trainees. Mil Med 2003; 168:116. 47. Sawka, MN, Convertino, VA, Eichner, ER, et al. Blood volume: importance and adaptations to exercise training, environmental stresses, and trauma/sickness. Med Sci Sports Exerc 2000; 32:332. 48. Greydanus, DE, Patel, DR. The female athlete. Before and beyond puberty. Pediatr Clin North Am 2002; 49:553. 49. Beard, J, Tobin, B. Iron status and exercise. Am J Clin Nutr 2000; 72:594S. 50. Hillman, RS, Ault, KA (Eds). Clinical approach to anemia. In: Hematology in Clinical Practice, McGraw-Hill, New York 2001. p.29. 51. Erslev, AJ. Reticulocyte enumeration. In: Williams' Hematology, 5th ed, Beutler, E, Lichtman, MA, Coller, BS, et al (Eds), McGraw-Hill, New York 1995. p.L28. 52. Hillman, RS, Ault, KA (Eds). Normal erythropoiesis. In: Hematology in Clinical Practice, McGraw-Hill, New York 2001. p.3. 53. Jones, J. Transfusion in oligemia. In: Blood Transfusion in Clinical Medicine, 8th ed,

53. Jones, J. Transfusion in oligemia. In: Blood Transfusion in Clinical Medicine, 8th ed, Mollison, PL, Engelfriet, CP, Contreras, M (Eds), Blackwell, Oxford 1987. p.41. 54. Weiskopf, RB, Viele, MK, Feiner, J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279:217. 55. Tefferi, A. Anemia in adults: A contemporary approach to diagnosis. Mayo Clin Proc 2003; 78:1274. 56. Gomes, ME, Deinum, J, Timmers, HJ, Lenders, JW. Occam's razor; anaemia and orthostatic hypotension. Lancet 2003; 362:1282. 57. Perera, R, Isola, L, Kaufmann, H. Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res 1995; 5:211. 58. Mohandas, N, Schrier, SL. Mechanisms of red cell destruction in hemolytic anemias. In: The Hereditary Hemolytic Anemias, Mentzer, WC, Wagner, GM (Eds), Churchill Livingstone, New York 1989. p.391. 59. Gonzalez, C, Penado, S, Llata, L, et al. The clinical spectrum of retroperitoneal hematoma in anticoagulated patients. Medicine (Baltimore) 2003; 82:257. 60. Bull, BS, Breton-Gorius, J. Morphology of the erythron. In: Williams' Hematology, 5th ed, Beutler, E, Lichtman, MA, Coller, BS, Kipps, TJ (Eds), McGraw-Hill, New York. p.349. 61. Morris, MW, Williams, WJ, Nelson, DA. Automated blood cell counting. In: Williams' Hematology, 5th ed, Beutler, E, Lichtman, MA, Coller, BS, et al (Eds), McGraw-Hill, New York 1995. p.L3. 62. Davenport, J. Macrocytic anemia. Am Fam Physician 1996; 53:155. 63. Inelmen, EM, D'Alessio, M, Gatto, MR, et al. Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: some results of an Italian multicentric study. Aging (Milano) 1994; 6:81. 64. Bergstrome Jones, AK, Poon, A. Evaluation of a single-tube multiplex polymerase chain reaction screen for detection of common alpha-thalassemia genotypes in a clinical laboratory. Am J Clin Pathol 2002; 118:18. 65. Steensma, DP, Hoyer, JD, Fairbanks, VF. Hereditary red blood cell disorders in Middle Eastern patients. Mayo Clin Proc 2001; 76:285. 66. Nardone, DA, Roth, KM, Mazur, DJ, et al. Usefulness of physical examination in detecting the presence or absence of anemia. Arch Intern Med 1990; 150:201. 67. Gjorup, T, Bugge, PM, Hendriksen, C, Jensen, AM. A critical evaluation of the clinical diagnosis of anemia. Am J Epidemiol 1986; 124:657. 68. 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. 69. Sheth, TN, Choudhry, NK, Bowes, M, Detsky, AS. The relation of conjunctival pallor to the presence of anemia. J Gen Intern Med 1997; 12:102. 70. Ruiz, MA, Saab, S, Rickman, LS. The clinical detection of scleral icterus: Observations of multiple examiners. Mil Med 1997; 162:560. 71. Williams, WJ, Morris, MW, Nelson, DA. Examination of the blood. In: Williams' Hematology, 5th ed, Beutler,E, Lichtman, MA, Coller, BS, et al (Eds), McGraw-Hill, New York, 1995, p. 8. 72. Weiss, GB, Bessman, JD. Spurious automated red cell values in warm autoimmune hemolytic anemia. Am J Hematol 1984; 17:433. 73. Westerman, DA, Evans, D, Metz, J. Neutrophil hypersegmentation in iron deficiency anaemia: a case-control study. Br J Haematol 1999; 107:512. 74. Stachon, A, Sondermann, N, Imohl, M, Krieg, M. Nucleated red blood cells indicate high risk of in-hospital mortality. J Lab Clin Med 2002; 140:407. 75. Marchand, A, Galen, RS, Van Lente, F. The predictive value of serum haptoglobin in

75. Marchand, A, Galen, RS, Van Lente, F. The predictive value of serum haptoglobin in hemolytic disease. JAMA 1980; 243:1909. 76. Galen, RS. Application of the predictive value model in the analysis of test effectiveness. Clin Lab Med 1982; 2:685. 77. Serjeant, GR, Serjeant, GE, Thomas, PW, et al. Human parvovirus infection in homozygous sickle cell disease. Lancet 1993; 341:1237. 78. Silverberg, DS, Wexler, D, Iaina, A, Schwartz, D. The interaction between heart failure and other heart diseases, renal failure, and anemia. Semin Nephrol 2006; 26:296. GRAPHICS Manual hematocrit This photo shows two anticoagulated blood-filled Wintrobe hematocrit tubes following high speed centrifugation. The tube on the left is from a normal subject, with a hematocrit of 38 percent (blue arrow). The tube on the right is from a 19-year-old female with essential thrombocytosis and a platelet count of 5,000,000/ L. The extreme degree of thrombocytosis can be appreciated by the presence of a marked increase in the size of the "buffy coat" (white arrow). When the Wintrobe tube is filled to near capacity (upper arrows), the platelet count can be estimated by the thickness of this layer, with each mm being equivalent to one million platelets/ L. In normal subjects, the buffy coat, which is comprised of white blood cells and platelets, is only minimally visible. Courtesy of Stephen A Landaw, MD, PhD.

visible. Courtesy of Stephen A Landaw, MD, PhD. Normal values for red blood cell parameters in men and women Adult Adult Red cell parameter men women Hemoglobin, g/dL 15.7 ± 1.7 13.8 ± 1.5 Hematocrit, percent 46.0 ± 4.0 40.0 ± 4.0 RBC count, million/µL 5.2 ± 0.7 4.6 ± 0.5 Reticulocytes, percent 1.6 ± 0.5 1.4 ± 0.5 88.0 ± Mean corpuscular volume, fL 8.0 30.4 ± Mean cell hemoglobin, pg/RBC 2.8 Mean cell hemoglobin concentration, g/dL 34.4 ± of RBC 1.1 Red cell volume distribution width, percent 13.1 ± (RDW) 1.4 Values are mean ± 2 standard deviations. Adapted from Williams' Hematology, 6th ed, Beutler, E, Lichtman, MA, Coller, BS, et al (Eds), McGraw-Hill, New York, 2001. Proposed lower limits of normal for hemoglobin concentration of the blood for white and black adults Group Hemoglobin, g/dL White men, y 20-59 13.7 60+ 13.2 White women, y 20-49 12.2 50+ 12.2 Black men, y 20-59 12.9 60+ 12.7

Black women, y 20-49 11.5 50+ 11.5 Based on Scripps-Kaiser data for the 5th percentiles given in Table 2. NHANES data are considered to be confirmatory. To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10. Reproduced from: Beutler, E, Waalen, J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006; 107:1747. Copyright ©2006 The American Society of Hematology. Physiologic anemia of pregnancy Schematic representations of the increases in intravascular volume that occur during pregnancy. Plasma volume increases more than the total red cell volume (50 versus 25 percent), resulting in a 40 percent rise in blood volume and a dilutional fall in the hematocrit.

Serum erythropoietin levels in anemia This graph indicates the exponential relationship between serum erythropoietin levels (EPO, milliUnits/mL) and venous hematocrit (percent) in normal and anemic subjects without renal or chronic diseases. EPO was assayed either by bioassay or radioimmunoassay. Data from Erslev, AJ, et al. J Lab Clin Med 1987; 109:429.

Reticulocyte shift with anemia With worsening anemia and increasing erythropoietin stimulation, bone marrow reticulocytes (left) leave the marrow at an earlier stage in their maturation. This prolongs the maturation time in the circulation from one day to as long as 2.5 days (right). Adapted from Hillman, RS, Ault, KA (Eds). Normal erythropoiesis, in: Hematology in Clinical Practice, McGraw-Hill, New York, p. 29. Reticulocytosis in peripheral blood Supravital stain of a peripheral blood smear shows blue-stained residual reticulin (ribosomal RNA) in reticulocytes. Courtesy of Stanley L Schrier, MD. Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Polychromatophilia Peripheral blood smear taken from a patient with increased reticulocytes. Unlike mature red cells (thin black arrows), which have central pallor and are the same size as the nucleus of a small lymphocyte (thick arrow), reticulocytes (blue arrows) are larger, have a blue tint, and lack central pallor because they are not biconcave discs. (Wright-Giemsa stain). Courtesy of Stanley Schrier, MD.

Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Common causes of hemolytic anemia in the adult Extravascular destruction of red blood cells 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 Liver disease Hypersplenism Infections (eg, bartonella, babesia, malaria) Oxidant agents (eg, dapsone, nitrites, aniline dyes) Other agents (eg, lead, snake and spider bites) Microangiopathic (eg, DIC, TTP-HUS) Autoimmune hemolytic anemia (warm- or cold-reacting, drugs)

Intravenous immune globulin infusion Large granular lymphocyte leukemia Intravascular destruction of red blood cells Microangiopathy (eg, aortic stenosis, prosthetic valve leak) Transfusion reactions (eg, ABO incompatibility) Infection (eg, clostridial sepsis, severe malaria) Paroxysmal cold hemoglobinuria Paroxysmal nocturnal hemoglobinuria Following intravenous infusion of Rho(D) immune globulin Following intravenous infusion with hypotonic solutions Snake bites Differential diagnosis of the anemic adult Low mean corpuscular volume (microcytic anemia: MCV <80 fL) Iron deficiency anemia Thalassemic disorders Anemia of chronic disease (late; uncommon) Sideroblastic anemia (eg, congenital, lead, alcohol, drugs; uncommon) Copper deficiency, zinc poisoning (rare) Normal mean corpuscular volume (normocytic anemia: MCV 80 to 100 fL) Acute blood loss Iron deficiency anemia (early) Anemia of chronic disease (eg, infection, inflammation, malignancy) Bone marrow suppression (may also be macrocytic) Bone marrow invasion (eg, leukoerythroblastic blood picture) Acquired pure red blood cell aplasia Aplastic anemia Chronic renal insufficiency Endocrine dysfunction

Hypothyroidism Hypopituitarism Increased mean corpuscular volume (macrocytic anemia: MCV >100 fL) Ethanol abuse Folic acid deficiency Vitamin B12 deficiency Myelodysplastic syndromes Acute myeloid leukemias (eg, erythroleukemia) Reticulocytosis Hemolytic anemia Response to blood loss Response to appropriate hematinic (eg, iron, B12, folate) Drug-induced anemia (eg, Hydroxyurea, AZT, chemotherapeutic agents) Liver disease This list is not meant to be exhaustive; only the most common causes are mentioned. In addition, two or more of these conditions may be present (eg, combined iron and folic acid deficiencies), resulting in a misleadingly normal mean corpuscular volume. Causes and mechanisms of macrocytosis Abnormalities of DNA metabolism Vitamin B12 (cobalamin) deficiency Folate deficiency Drugs Hydroxyurea Zidovudine Cytosine arabinoside Methotrexate Azathioprine or 6-mercaptopurine Cladribine Capecitabine Imatinib, sunitinib Shift to immature or stressed red cells

Reticulocytosis Action of erythropoietin - skip macrocytes, stress erythrocytosis Aplastic anemia/Fanconi anemia Pure red cell aplasia Primary bone marrow disorders Myelodysplastic syndromes Congenital dyserythropoietic anemias Large granular lymphocyte leukemia Lipid abnormalities Liver disease Hypothyroidism Hyperlipidemia Mechanism unknown Alcohol abuse Multiple myeloma and other plasma cell disorders Microcytic hypochromic red cells Peripheral smear from a patient with iron deficiency shows pale small red cells with just a scant rim of pink hemoglobin; occasional "pencil" shaped cells are also present. Normal red cells are similar in size to the nucleus of a small lymphocyte

cells are similar in size to the nucleus of a small lymphocyte (arrow); thus, many microcytic cells are present in this smear. Thalassemia can produce similar findings. Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Laboratory tests in iron deficiency of increasing severity Fe Fe Severe Fe deficiency deficiency deficiency without with mild with severe Normal anemia anemia anemia Marrow reticulo- 2+ to 3+ None None None endothelial iron Serum iron, µg/dL 60 to 150 60 to 150 <60 <40 Iron binding capacity 300 to 300 to 390 350 to 400 >410 (transferrin), 360 µg/dL Saturation 20 to 50 30 <15 <10 (SI/TIBC), percent

Hemoglobin, g/dL Normal Normal 9 to 12 6 to 7 Normal or Red cell Hypochromia Normal Normal slight morphology and microcytosis hypochromia Plasma or serum 40 to 200 <40 <20 <10 ferritin, ng/mL Erythrocyte protoporphyrin, 30 to 70 30 to 70 >100 100 to 200 ng/mL RBC Nail and Other tissue None None None epithelial changes changes Note: Test results outlined in bold type are the ones most likely to define the various stages of iron deficiency. Thus, the presence or absence of iron stores (marrow reticuloendothelial iron) in a non-anemic patient serves to distinguish normal subjects from those with iron deficiency without anemia, respectively. Beta thalassemia trait Peripheral smear from a patient with beta thalassemia trait. The field shows numerous hypochromic and microcytic red cells (thin arrows), some of which are also target cells (blue arrows). Courtesy of Stanley Schrier, MD Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Basophilic stippling Peripheral blood smear shows basophilic stippling in several red cells from a patient with lead poisoning. The granules represent ribosomal precipitates. A similar picture can be seen in a number of other conditions including thalassemia, megaloblastic anemia, sickle cell anemia, and sideroblastic anemia. Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear

Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Hypersegmented neutrophil Blood smear from a patient with megaloblastic anemia, showing a neutrophil with an increased number of nuclear lobes. At least six discrete lobes are present; normal neutrophils have five lobes or less. Courtesy of Stephen A. Landaw, MD, PhD. Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Megaloblastic blood picture Peripheral blood smear showing a hypersegmented neutrophil (7 lobes) and macroovalocytes, a pattern that can be seen with cobalamin or folate deficiency. Courtesy of Stanley L Schrier, MD. Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Leukoerythroblastic smear Leukoerythroblastic peripheral blood smear showing the presence of nucleated red cells and immature white cells. This pattern occurs with marrow replacement, usually due to fibrosis that may be idiopathic (eg, myelofibrosis with agnogenic myeloid metaplasia) or reactive to conditions such as metastatic cancer. Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Microangiopathic smear Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with marked red cell fragmentation. The smear shows multiple helmet cells (small black arrows), other fragmented red cells (large black arrow); microspherocytes are also seen (blue arrows). The platelet number is reduced; the large platelet in the center (red arrow) suggests that the thrombocytopenia is due to enhanced destruction. Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear

Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Teardrop cells This peripheral smear from a patient with bone marrow fibrosis shows numerous teardrop-shaped red cells (arrows). Note that the teardrops are pointed in several different directions, ruling out an artifact due to preparation of the smear. Courtesy of Carola von Kapff, SH (ASCP).

Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Heinz body hemolytic anemia Split screen view of a peripheral smear from a patient with Heinz body hemolytic anemia. Left panel: red cells with characteristic bite-like deformity (arrows). Right panel: Heinz body preparation which reveals the denatured hemoglobin precipitates. Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear

Normal peripheral blood smear High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP). Malaria Peripheral smear from a patient with malaria shows intraerythrocytic ring forms (trophozoites) (arrows). Courtesy of Carola von Kapff, SH (ASCP). Normal peripheral blood smear

High power view of a normal peripheral blood smear. Several platelets (black arrows) and a normal lymphocyte (blue arrow) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (red arrow) should equal one-third of its diameter. Courtesy of Carola von Kapff, SH (ASCP).

Anemia algorithm Adapted from Nathan, DG, Oski, FA. Hematology of Infancy and Childhood, 4th ed, WB Saunders, Philadelphia, PA 1993. p. 352. © 2009 UpToDate, Inc. All rights reserved. | Subscription and License Agreement Licensed to: felipe vergara

Anemia

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Anemia

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