Approach to the adult patient with anemiaAuthorStanley L Schrier, MDSection EditorWilliam C Mentzer, MDDeputy EditorStephen A Landaw, MD, PhDDisclosures: Stanley L Schrier, MD Nothing to disclose. William C Mentzer, MD Equity Ownership/Stock Options: Johnson & Johnson [Anemia (Erythropoietin)]. Stephen A Landaw, MD, PhDEmployee of UpToDate, Inc. Employee (Spouse): Mass Medical Society (New England Journal of Medicine).

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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: Mar 26, 2014.

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 obtained as a part of the complete blood count: hemoglobin concentration, hematocrit, or RBC count:

●Hemoglobin concentration (HGB) this is the concentration of hemoglobin, 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). Efforts are underway to determine HGB levels non-invasively, allowing continuous monitoring of this parameter [1,2].●Hematocrit (HCT) is the percent of a sample of whole blood occupied by intact red blood cells (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 or liter 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 introduction to the phenomenon of RBC destruction (hemolysis) and tests that may be used to provide a diagnosis of hemolytic anemia is presented separately. (See"Approach to the diagnosis of hemolytic anemia in the adult".)

Approaches to the older adult or child with anemia are presented separately. (See "Anemia in the older adult" and "Approach to the child with anemia".)

DEFINITIONS

Normal range — One set of "normal ranges" (95 percent confidence limits) for HGB, HCT, and RBC count is shown in the table (table 1). If anemia is defined as values that are more than two

standard deviations (SD) below the mean, then, by using these ranges, a HGB <13.5 g/dL (<135 g/L) or a HCT <41.0 percent represents anemia in men, and a value <12.0 g/dL (<120 g/L) 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 [3].●WHO criteria for anemia in men and women are <13 and <12 g/dL, respectively [4]. 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 [3].●The revised WHO/National Cancer Institute's criteria for anemia in men and women are <14 and <12 g/dL, respectively [5]. 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 (table 2) [3]. 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 that 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 [3].●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, older adults).  (See 'Special populations' below and "Approach to anemia in adults with heart failure", section on 'Evaluation'.)●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 [6]. However, in one report, 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 [7], suggesting that alternative criteria for anemia might be required for this group (table 2) [3]. (See "Anemia in the older adult", section on 'Defining anemia in the older adult'.)

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 for all three will be reduced if the RCM is decreased and/or if the plasma volume is increased [8]. Three common clinical examples will help make this point:

●Acute bleeding – 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 [9].●Late pregnancy – 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 (figure 1). However, according to the RBC mass, such women are polycythemic. The terms "physiologic" or "dilutional" anemia have been applied to this setting.●Volume depletion – 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 (table 1) may not be appropriate for all populations:

●Patients living at high altitude have values higher than those living at sea level [10]. (See "High altitude, air travel, 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 [11]. 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 [12], occasionally reaching polycythemic levels. (See "Diagnostic approach to the patient with polycythemia", section on 'Acquired secondary polycythemia'.)●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 [3,13-17]. Some, but not all, of these differences may be attributable to co-existing iron deficiency anemia and/or alpha thalassemia [18].●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'.)

Older adults — Anemia in older adults is discussed separately. (See "Anemia in the older adult".)

Athletes — Values in male and female endurance athletes may vary significantly from those in otherwise normal people [19-24]. Dilutional anemia secondary to an increased plasma volume [20,25], gastrointestinal bleeding [21], intravascular hemolysis (eg, march hemoglobinuria) [22], iron deficiency [26,27], as well as polycythemia [23,25] have all been reported as a consequence of strenuous sports, or the use of 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 "Use of androgens and other hormones to enhance athletic performance", section on 'Androgens'.)

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 (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 [28].

The reticulocyte retains its ribosomal network (and its staining characteristics) for approximately four days, of which three days are generally spent in the bone marrow and one day in the peripheral blood (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, primarily on the RBC membrane, through mechanisms that are poorly understood. (See "Red blood cell survival: Normal values and measurement".)

●Under steady state conditions, the rate of RBC production equals the rate of RBC loss. Assuming, for ease of calculation, a survival of mature RBC of 100 days, 1 percent of RBCs will be 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 (table 1). Since the normal RBC count is approximately 5 million/microL (5.0 x 1012/liter), 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 approximately fivefold in adults and seven- to eight-fold in children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as high as 250,000/microL (2.5 x 1011/liter) 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 (picture 2). The normal range (ie, percent of RBC with positive staining) in adults is 0.5 to 2.0 percent (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 (picture 3).

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 [29]. (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/orthe 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.

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 5 volumes percent (25 percent of the total) is normally removed by the tissues [30]. (See "Oxygen delivery and consumption" and "Genetic disorders of hemoglobin oxygen affinity", section on 'Mutations that decrease the affinity of hemoglobin for 2,3-BPG'.)

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 5 volumes percent can be maintained by enhanced extraction alone down to a hemoglobin concentration of 8 to 9 g/dL [31].

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 [32]. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Role of blood in oxygen delivery'.)

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 fatigability, lassitude, and muscle cramps. This can progress to postural dizziness, lethargy, syncope, and, in severe cases, to persistent hypotension, shock, and death. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)

Mortality — The development of anemia is a risk factor for increased mortality in a number of clinical settings. A few of the many examples are listed below:

●Chronic kidney disease (see "Anemia and left ventricular hypertrophy in chronic kidney disease", section on 'General cardiovascular outcomes')●Malignancy (see "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Effect on disease control and survival')●Heart failure (see "Approach to anemia in adults with heart failure", section on 'Prognosis')●The older adult (see "Anemia in the older adult", section on 'Increased mortality')●The hospitalized adult [33] (see "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Impact of anemia on morbidity and mortality')

Fatigue — Although anemia may be associated with 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 "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 [34].

Kinetic approach — Anemia can be caused by one or more of three independent mechanisms: decreased RBC production, increased RBC destruction, and blood loss [28].

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, myelodysplastic syndromes, tumor infiltration)●Bone marrow suppression (eg, drugs, chemotherapy, irradiation) (see "Hematologic consequences of malignancy: Anemia and bleeding")●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 [35,36]. (See"Treatment of orthostatic and postprandial hypotension", section on 'Erythropoietin'.)•Acquired inhibitors of EPO or the EPO receptor have also been described as causes of anemia [37]. (See "Pure red cell aplasia due to anti-erythropoietin antibodies".)

●The anemia of 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 [38]. (See "Red blood cell survival: Normal values and measurement".)

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 (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, malaria, paroxysmal nocturnal hemoglobinuria)

Blood loss — Iron deficiency in the United States and Western Europe is almost always due to blood loss, which may be obvious, occult, or underappreciated, as follows:

●Obvious bleeding (eg, trauma, melena, hematemesis, severe menometrorrhagia)●Occult bleeding (eg, slowly bleeding ulcer or carcinoma) (see "Evaluation of occult gastrointestinal bleeding")●Induced bleeding (eg, repeated diagnostic testing [39,40], hemodialysis losses, excessive blood donation)●Underappreciated menstrual blood loss. (See "Approach to abnormal uterine bleeding in nonpregnant reproductive-age women", section on 'Menstrual history'.)

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 (Lasthénie de Ferjol syndrome) [41-43]●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 [44]. 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 approximately 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 iron deficiency anemia in the adult".)

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 [45]. 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 (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. 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). (See "Mean corpuscular volume", section on 'Red blood cell distribution width'.)

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 that "flag" for the presence of abnormalities such as anisocytosis (cells of varying size), microcytosis, macrocytosis, and hypochromia (reduced hemoglobin content per cell) [46]. (See "Automated hematology instrumentation", section on 'Red cell distribution width'.)

Macrocytic anemia — Anemia is considered "macrocytic" when the MCV exceeds 100 fL (femtoliters) (table 5) Causes include the following. (See "Macrocytosis".)

●An increased MCV is a normal characteristic of reticulocytes (picture 3). 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 andhydroxyurea) may lead to macrocytosis and anemia●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 [47], while a study of 1784 randomly selected older adults living at home found macrocytosis in 6.3 percent of men and 3.3 percent of women [48]. The most common causes were alcoholism, liver disease, hypothyroidism, and the megaloblastic anemias (eg, folate or B12 deficiency).

Microcytic anemia — Anemia is considered "microcytic" when the MCV is less than 80 fl. Microcytosis is usually accompanied by a decreased hemoglobin content within the RBC (mean corpuscular hemoglobin, MCH), with a parallel reduction in MCV, producing a hypochromic (low MCH) as well as a microcytic (low MCV) appearance on the blood smear (picture 4 and 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 inflammation, copper deficiency●Acquired disorders of heme synthesis – Lead poisoning, acquired sideroblastic anemias●Reduced globin production – Thalassemic disorders, other hemoglobinopathies

●Rare congenital disorders including sideroblastic anemias, porphyria, and defects in iron absorption, transport, utilization, and recycling [49,50]

The three most common causes of microcytosis in clinical practice are iron deficiency, alpha or beta thalassemia minor, and (less often) the anemia of inflammation (anemia of chronic disease). 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 (table 6). For clinicians 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 iron deficiency anemia in the adult".)●Alpha or beta thalassemia minor – Adults with thalassemia are most often heterozygotes for the alpha or beta forms of this syndrome, and may be only minimally anemic. A family history is therefore often negative. Physical examination may reveal splenomegaly; the peripheral smear shows varying degrees of hypochromia, microcytosis, target cells (picture 5), tear-drop forms, and basophilic stippling (picture 6). The RBC count may actually be increased; 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 the alpha thalassemia variants [51]. (See "Laboratory diagnosis of the hemoglobinopathies".)●Anemia of 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 those 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 (ie, MCV between 80 and 100 fL) in patients with normocytic anemia (table 4). Approach to this extremely large category of patients 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 and 'Systemic disorders' below).

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, C-reactive protein, serum protein electrophoresis, WBC count and differential, and reduced (or increased) platelet counts. Anemia in older adults, which may be difficult to categorize, is discussed separately. (See "Anemia in the older adult".)

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'.)

Cardiorenal anemia syndrome — Cardiorenal anemia syndrome refers to the simultaneous presence of anemia, heart failure, and chronic renal disease [52]. This disorder complex is discussed separately. (See "Anemia and left ventricular hypertrophy in chronic kidney disease" and "Approach to anemia in adults with heart failure".)

Cancer-associated anemia — Anemia in patients with malignancy is often multi-factorial and related to the underlying malignancy as well as its treatment. (See"Hematologic consequences of malignancy: Anemia and bleeding".)

Acquired anemia in hospitalized patients — The development of anemia in a previously non-anemic patient subsequent to hospitalization (hospital-acquired anemia, HAA) is usually multifactorial and includes causes such as bleeding following an invasive procedure or surgery, large volumes of blood drawn for diagnostic studies, occult bleeding, hemodilution from intravenous fluid administration, as well as a blunted erythropoietic response associated with critical illness [40,53,54]. As examples:

●In one population study, among 188,447 hospitalizations, 74 percent developed HAA, which was correlated with increases in length of stay, hospital charges, and mortality [33].●In a separate study in patients with myocardial infarction, the risk of development of moderate to severe HAA was increased by 18 percent for every 50 mL of blood drawn for diagnostic purposes [39].

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 folate 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 that 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 [55]. (See "Introduction to hemoglobin

mutations" and "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 older adult 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 [56-59], 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 [58]. 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 (42.8 micromol/L) and by only 68 percent at a bilirubin concentration of 3.1 mg/dL (53.0 micromol/L) [60]. False positives were mostly attributable to medical students, while false negatives were not related to the level of training.

Other physical findings — 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 myeloid 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 adult 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 the RBC shapes (poikilocytosis). Some counters will "flag" for the presence of specific 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 [61]. (See 'Blood smear' below and "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) (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 the mean corpuscular volume (MCV) is 80 to 100 femtoliters (fL). The causes of anemia associated with a low (microcytosis) or high (macrocytosis) MCV are discussed above (table 4) (see 'Morphologic approach' above).

●Values of the MCV in excess of 115 fL are almost exclusively seen in vitamin B12 or folate deficiency.●Even higher values can occur as an artifact when cold agglutinins are present, which causes RBCs to go through the counting aperture in automated instruments in doublets or triplets [62]. 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 mean corpuscular hemoglobin (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 (340 g/L of RBCs). The 95 percent confidence limits for the MCHC have been variably given (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 desiccated (eg, sickle cell anemia, hemoglobin C disease, xerocytosis). (See "Hereditary spherocytosis: Clinical features, diagnosis, and treatment" and "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, other causes for bone marrow suppression) (see 'Multiple causes of anemia' below).●A low reticulocyte percentage accompanied by pancytopenia (ie, the combination of anemia, thrombocytopenia, and neutropenia) is suggestive of aplastic anemia, while an extremely low or zero reticulocyte percentage 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 "Acquired pure red cell aplasia in the adult".)

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 glucocorticoids

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 (picture 7). This peripheral smear finding, along with macroovalocytic red cells (picture 8), is classically associated with impaired DNA synthesis, as seen in disorders of vitamins B12 and folate. (See "Etiology and clinical manifestations of vitamin B12 and folate 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 [63]. 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 fibrosis or replacement with tumor cells (picture 9).

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 4173 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 [64]. 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 the presence of a myeloproliferative neoplasm, 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 diagnosis considerably, and includes disorders such as aplastic anemia, folate or cobalamin deficiency, hematologic malignancy (eg, acute myeloid leukemia, myelodysplasia), and marrow ablation from chemotherapy or radiation or replacement with fibrosis or tumor. Rare causes include anorexia nervosa and panhypopituitarism. (See "Anemias due to decreased red cell production", section on 'Normocytic anemia with pancytopenia' and "Approach to the adult with unexplained 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 (picture 10), microspherocytes in autoimmune hemolytic anemia, teardrop RBCs in myelofibrosis (picture 11), a leukoerythroblastic pattern with bone marrow replacement (picture 9), the "bite cells" in oxidative hemolysis (picture 12), or RBC parasites such as malaria or babesiosis (picture 13). (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 (table 6). (See "Causes and diagnosis of iron deficiency anemia in the adult".)

Evaluation for hemolysis — Hemolysis should be considered if the patient has experienced a rapid fall in hemoglobin concentration, reticulocytosis, and/or abnormally shaped RBC (especially spherocytes or fragmented RBCs) on the peripheral smear (table 3) in the absence of blood loss. 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 [65,66].

Intravascular hemolysis — Plasma and urinary 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 marrow had previously been considered the "gold standard" for the diagnosis of iron deficiency, this diagnosis is usually established by laboratory tests alone (table 6). (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Estimation of iron stores'.)

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 neoplasm. 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 older adults. Common examples are:

●A patient with gastrointestinal bleeding secondary to colon cancer may also have the anemia of inflammation (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 [67]. (See "Acquired pure red cell aplasia in the adult", section on 'Etiology and pathogenesis'.)●A patient with autoimmune hemolytic anemia may develop worsening anemia from gastrointestinal blood loss following treatment with glucocorticoids.●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 [68]. (See "Anemia and left ventricular hypertrophy in chronic kidney disease".)

Algorithms for diagnosing anemia (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 — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient information: Anemia of chronic disease (The Basics)")●Beyond the Basics topics (see "Patient information: Anemia caused by low iron (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — The initial approach to the patient with anemia is to perform a complete history and physical examination along with a review of the results of a complete blood count (CBC) with white blood cell differential, platelet count, reticulocyte count, and an examination of the peripheral blood smear (table 1). (See 'Evaluation of the patient' above.)

A HGB <13.5 g/dL (<135 g/L) or a HCT <41.0 percent represents anemia in men; a value <12.0 g/dL (<120 g/L) or <36.0 percent, respectively, represents anemia in women. Differences may also exist between races, in older adults, and in athletes. (See 'Definitions' above and 'Special populations' above.)

Diagnostic approach: morphology — According to the morphologic approach, the anemia is first classified via the red cell size (ie, mean corpuscular volume, MCV), which is part of the CBC (algorithm 1):

●Microcytic anemias are associated with an MCV below 80 fL. The most commonly seen causes are iron deficiency (table 4 and table 6), thalassemia, and the anemia of (chronic) inflammation (see 'Microcytic anemia' above and 'Evaluation for iron deficiency' above).●Macrocytic anemias are characterized by an MCV above 100 fL (table 4 and table 5). The most common causes include alcoholism, liver disease, folate and vitamin B12 deficiency, and myelodysplasia. (See "Macrocytosis", section on 'Evaluation'.)●The MCV is between 80 and 100 fL in patients with normocytic anemia (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, physical examination, or examination of the peripheral blood smear (eg, sudden onset of anemia, jaundice, splenomegaly, presence of spherocytes or schistocytes or other red cell shape changes) (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 (table 3). (See 'Evaluation for hemolysis' above and "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 (algorithm 1) suggests that the anemia is part of a more complex hematologic disorder (eg, leukemia, aplastic anemia, myelodysplastic syndrome, myeloproliferative neoplasm). Consultation with a hematologist would be appropriate at this point.●Anemia may be the first manifestation of a systemic disorder (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 or C-reactive protein.

Diagnostic approach: kinetics — According to the kinetic approach, the following three questions are asked in order to determine the mechanism(s) causing the anemia. (See 'Causes of anemia' above.)

●Is there evidence for decreased red cell production? (See 'Decreased RBC production' above.)●Is there evidence for increased red cell destruction (hemolysis)? (See 'Increased RBC destruction' above.)●Is there a history of bleeding? (See 'Blood loss' above.)

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