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Diagnostic approach to anemia in adults
Authors: Robert T Means, Jr, MD, MACP, Robert A Brodsky, MD
Section Editor: William C Mentzer, MD
Deputy Editors: Jennifer S Tirnauer, MD, Lisa Kunins, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2022. | This topic last updated: Apr 25, 2022.
INTRODUCTION
Evaluation for anemia is one of the most common problems in clinical practice. The evaluation may be straightforward in an otherwise
healthy individual with a single cause of anemia, but in many cases the cause is not readily apparent and multiple conditions may be
contributing.
An approach to the evaluation of the adult with anemia is presented here. Diagnosis of specific conditions is discussed in separate topic
reviews referenced below. Evaluation of anemia in children is discussed separately. (See "Approach to the child with anemia".)
BASIC PRINCIPLES
Anemia definitions — Anemia is defined for patient care as a reduction in one or more of the major red blood cell (RBC) measurements
obtained as a part of the complete blood count (CBC): hemoglobin concentration, hematocrit, or RBC count. A low hemoglobin
concentration and/or low hematocrit are the parameters most widely used to diagnose anemia.
● Hemoglobin – Hemoglobin is reported as the concentration of hemoglobin in whole blood. Values may be expressed as grams of
hemoglobin per 100 mL (g/dL) or per liter (g/L). To convert to mmol/L, the hemoglobin in g/dL can be multiplied by 0.62. Hemoglobin
can be reported non-invasively by continuous monitoring [1-3].
● Hematocrit – Hematocrit (HCT), also called packed cell volume (PCV), is the percentage of blood volume occupied by RBCs. It can be
measured directly following centrifugation of a blood sample (
picture 1 and
picture 2).
When measured by an electronic cell counter, HCT is calculated from the RBC count (in millions/microL) and the mean corpuscular
volume (MCV; in femtoliters [fL]): HCT = ([RBC x MCV]/10).
● RBC count – RBC count is the number of RBCs contained in a specified volume of whole blood, usually expressed as millions of cells
per microL of whole blood.
One set of normal ranges for hemoglobin, HCT, and RBC count is shown in the table (
table 1). Other normal ranges have been
proposed. World Health Organization (WHO) criteria for anemia in men and women are hemoglobin <13 and <12 g/dL, respectively [4].
However, these criteria were intended for use within the context of international nutrition studies and were not initially designed to serve
as "gold standards" for diagnosing anemia [5].
Normal ranges for laboratory tests are defined as the range of values centered at the median that includes 95 percent of an apparently
healthy population. For that reason, normal values of hemoglobin, HCT, and RBC count may differ depending on the population tested.
Since hemoglobin is measured and HCT calculated (HCT = MCV x RBC count/10), hemoglobin is likely to be more accurate. (See 'Caveats for
normal ranges' below.)
Some reports have described lower values for hemoglobin in Black Americans than in White Americans (approximately 0.5 to 1 g/dL lower
for Black Americans) [5-9]. It is not clear whether this difference is due to health disparities such as greater frequency of iron deficiency, to
a higher presence of alpha thalassemia in individuals of African ancestry, or to other causes [10]. We use the same hemoglobin and HCT
thresholds for evaluating anemia in all racial and ethnic groups (we do not assume that a slightly lower value in a Black American is
normal).
The increased frequency of anemia seen with aging has led to suggestions that a different standard for the normal hemoglobin should be
used in older adults [5]. Review of data from the National Health and Nutrition Examination Survey (NHANES) indicates that the mean
hemoglobin values for men and women over 70 is within the usual normal range (14.5 g/dL and 13.4 g/dL, respectively), while the 5th
percentile is below the normal range (11.7 g/dL for men and 10.9 g/dL for women) [11]. This lower boundary may reflect an increased
prevalence of comorbidities, especially chronic kidney disease [12]. Another study that used survey data to try to identify a lower normal
hemoglobin in older individuals concluded that the World Health Organization (WHO) definitions are applicable in older adults [13]. Thus,
rather than seeking to define a lower limit for the reference range for older individuals as a population, we prefer to focus on determining
the appropriate evaluation of a low hemoglobin in each person and to individualize the approach to each person's circumstances, with an
informed discussion and shared decision-making. (See 'Older adults' below.)
In individuals with anemia, hemoglobin and HCT decrease in parallel, although the HCT/hemoglobin ratio (approximately 3 in most cases)
may vary according to the volume (size) of the cells. The RBC count also usually parallels the hemoglobin and HCT, except in cases of
extreme microcytosis such as thalassemia, in which the RBC count may be increased despite the presence of anemia. The RBC count is less
commonly used to diagnose anemia for this reason. A finding of high RBC count in an individual with anemia suggests thalassemia. (See
"Diagnosis of thalassemia (adults and children)", section on 'CBC and hemolysis testing'.)
For research, anemia can be defined as a reduced RBC mass, expressed in mL/kg, as determined via blood volume studies. However, blood
volume studies are not practical, cost-effective, or generally available.
Caveats for normal ranges — The "normal" ranges specified in the table (
table 1) may not apply in certain settings:
● Causes of lower values
• Intense physical activity – Values in endurance athletes may vary significantly from those in other healthy individuals. Various
causes may contribute, including dilutional anemia from increased plasma volume, iron deficiency, and/or "march" hemolysis.
(See "Exercise-related gastrointestinal disorders", section on 'Gastrointestinal bleeding' and "Non-immune (Coombs-negative)
hemolytic anemias in adults", section on 'Foot strike or hand strike'.)
• Pregnancy – During a healthy pregnancy, maternal red cell mass increases, but plasma volume increases to a greater degree,
causing a relative decrease in hemoglobin and HCT [14]. By the criterion of RBC mass, the individual is not anemic, but
hemoglobin, HCT, and RBC count frequently decrease to anemic levels (
figure 1). The terms "physiologic" or "dilutional" anemia
have been applied to this setting, although these individuals are not actually anemic and do not require evaluation as long as
their hemoglobin remains ≥11 g/dL in the first trimester, ≥10.5 g/dL in the second trimester, and ≥10.5 g/dL in the third trimester.
(See "Anemia in pregnancy".)
• Older age – Values for hemoglobin and HCT in apparently healthy older adults are generally lower than those in younger adults,
and differences between males and females that are seen in younger adults are lessened with aging [15-17]. (See 'Older adults'
below.)
● Causes of higher values (may occasionally mask underlying anemia)
• Smoking – Smoking causes an increase in hemoglobin, HCT, and RBC count due to increased levels of carbon monoxide, which
reduces oxygen delivery. Thus, individuals who smoke or have significant exposure to secondary smoke or other sources of
carbon monoxide may have HCT higher than normal [18]. A study of blood donors who smoke found a significant correlation
between the patients' blood carboxyhemoglobin and hemoglobin values [19]. (See "Carbon monoxide poisoning", section on
'Pathophysiology'.)
• Hemoconcentration – Individuals with dehydration or hypovolemia related to vomiting or diarrhea will have a relative increase in
hemoglobin and HCT due to hemoconcentration. Anemia will become apparent after volume replacement. This is particularly a
problem in patients with severe burns, in whom substantial RBC loss may be masked by exudative loss of plasma volume until
fluid resuscitation has occurred [20].
• High altitude – Persons living at high altitude have higher values than those living at sea level due to relative hypoxia [21]. (See
"High altitude, air travel, and heart disease", section on 'Long-term altitude exposure'.)
RBC indices — The red blood cell (RBC) indices describe RBC size, hemoglobin content, and uniformity of the RBC population. These
values can be very helpful in determining the cause of anemia. The mean corpuscular volume (MCV) and red cell distribution width (RDW)
are generally the most useful.
● MCV – Mean corpuscular volume (MCV) is the average volume (size) of the RBCs. It can be measured, as it is in automated cell
counters, or calculated (MCV in femtoliters [fL] = 10 x HCT [in percent] ÷ RBC [in millions/microL]). RBCs with MCV in the normal range
are roughly the same diameter as the nucleus of a normal lymphocyte on the peripheral blood smear. Anemia can be classified
based on whether the MCV is low, normal, or elevated. (See 'Evaluation based on MCV' below.)
● MCH – Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a RBC. It is calculated (MCH in picograms [pg]/cell
= hemoglobin [in g/dL] x 10 ÷ RBC [in millions/microL]). A low MCH is typically reflected in an enlarged area of central pallor in RBCs
on the peripheral blood smear (greater than one-third of the RBC diameter), which defines "hypochromia" on the blood smear. This
may be seen in iron deficiency and thalassemia.
● MCHC – Mean corpuscular hemoglobin concentration (MCHC) is the average hemoglobin concentration per RBC. It is calculated as
(MCHC in grams [g]/dL = hemoglobin [in g/dL] x 100 ÷ HCT [in percent]). Very low MCHC values are typical of iron deficiency anemia,
and very high MCHC values typically reflect spherocytosis or RBC agglutination. Examination of the peripheral blood smear is helpful
in distinguishing these findings. (See "Evaluation of the peripheral blood smear", section on 'Red blood cells'.)
● RDW – Red cell distribution width (RDW) is a measure of the variation in RBC size, which is reflected in the degree of anisocytosis on
the peripheral blood smear. RDW is calculated as the coefficient of variation (CV) of the red cell volume distribution (RDW = [standard
deviation/MCV] x 100).
A high RDW implies a large variation in RBC sizes, and a low RDW implies a more homogeneous population of RBCs. A high RDW can
be seen in a number of anemias, including iron deficiency, vitamin B12 or folate deficiency, myelodysplastic syndrome (MDS), and
hemoglobinopathies, as well as in patients with anemia who have received transfusions. Review of the peripheral blood smear often
is helpful in identifying the cause. (See "Evaluation of the peripheral blood smear".)
Details of how these indices are determined and potential causes of spurious results are presented separately. (See "Automated
hematology instrumentation".)
Reticulocyte production — The reticulocyte is a stage in RBC development directly before the mature RBC. Reticulocytes are continually
produced to replace RBCs that are cleared from the circulation (approximately 1 percent of RBCs are cleared per day). The reticulocyte
count reflects the rate of RBC production.
● Measurement – Reticulocytes can be reported as a percentage of total RBCs or as an absolute count (
table 2). Reticulocytes can
be appreciated on a standard blood smear stained with Wright-Giemsa as RBCs with a blue tint (polychromatophilia) that are larger
than mature RBCs, with irregular borders and a lack of central pallor (
picture 3).
• Manual count (percentage) – Reticulocytes can be enumerated manually after supravital staining of a blood sample with dyes
such as new methylene blue (
picture 4). The manual reticulocyte count is reported as a percentage of RBCs, with a normal
range of 0.5 to 2 percent in the absence of anemia.
• Automated count (million cells/microL) – Automated blood counters measure the absolute reticulocyte count directly after
staining with a fluorescent dye such as thiazole orange, which binds to the RNA of reticulocytes; the reticulocyte percentage from
those devices is a calculated value [22]. (See "Automated hematology instrumentation", section on 'Automated counting of
reticulocytes'.)
● Interpretation – The appropriate count depends on the hemoglobin level. The "normal" reticulocyte count refers to the count in a
non-anemic individual at steady state.
• Steady state – At steady state, approximately 1 to 2 percent of circulating RBCs are reticulocytes, corresponding to an absolute
reticulocyte count of approximately 25,000 to 100,000/microL (0.25 to 1 x 1011/L).
• Anemia – In anemia, the reticulocyte count rises. A normal bone marrow can increase the rate of RBC production approximately
fivefold in adults (seven- to eightfold in children). Thus, under optimal conditions, reticulocyte percentages of at least 4 to 5
percent (often considerably higher) and absolute reticulocyte counts as high as 350,000/microL (3.5 x 1011/L) are possible.
An increased reticulocyte count represents a normal bone marrow response to anemia. Incorporation of the reticulocyte count into
the anemia evaluation can be especially helpful in diagnosing certain disorders including hemolytic anemias and multifactorial
anemias. (See 'Reticulocyte count' below.)
● Correction factors for the manual count – The usefulness of reticulocyte counting can be improved in some settings by adjusting
for the degree of anemia and its effects on reticulocyte production; examples include the corrected reticulocyte count and/or the
reticulocyte production index. Alternatively, the absolute reticulocyte count can be used.
The reticulocyte stage of RBC development lasts for approximately four days. In the steady state, reticulocytes generally spend three
days in the bone marrow and one day in the circulation. In severe anemia, reticulocytes can leave the bone marrow earlier and can
circulate for two to three days, as illustrated in the figure (
figure 2). This is the basis for the calculation of the reticulocyte
production index [23]. (See "Regulation of erythropoiesis".)
If a laboratory does not report an absolute reticulocyte count or one of the corrected reticulocyte count parameters, calculators and
other tools are available online (calculator 1).
Correlation with symptoms — The function of RBCs is to deliver oxygen to tissues, and with the exception of symptoms like pica in iron
deficiency, the cardinal signs and symptoms of anemia result from impaired oxygen delivery.
Oxygen delivery, in turn, reflects a complex interplay of factors including the degree of anemia.
● Blood oxygen content and release – The oxygen content of blood reflects the quantity of RBC hemoglobin present. The amount of
hemoglobin is assessed by the hemoglobin concentration and indirectly by the HCT and RBC counts. Each gram of RBC hemoglobin
can bind 1.34 to 1.39 mL of oxygen [24].
While blood oxygen content is a function of hemoglobin, oxygen delivery to the tissues can also be affected by changes in the
affinity of hemoglobin for oxygen, expressed as the partial pressure of oxygen at which hemoglobin is 50 percent saturated (p50), as
well as blood volume and tissue perfusion. (See "Oxygen delivery and consumption" and "Hemoglobin variants that alter
hemoglobin-oxygen affinity", section on 'Hemoglobin variants that can affect oxygen affinity'.)
Oxygen delivery is increased by:
• Decreases in pH
• Increases in RBC 2,3 bisphosphoglycerate (2,3 BPG) concentration
• Increased body temperature
● Blood volume and tissue perfusion – Studies in animal models demonstrate that at any given HCT, systemic oxygen transport is
lower with lower blood volume [25]. This is primarily a consequence of decreased tissue perfusion.
Other conditions besides hypovolemia that can impair tissue perfusion include:
• Hypotension
• Peripheral vasoconstriction
• Decreased cardiac output
• Bradycardia
• Coronary artery obstruction
Any or all of these can worsen symptoms at a given degree of anemia.
● Rate of decline in red cell mass – Symptoms of anemia also reflect the rate with which RBC mass declines, which determines the
extent of compensatory changes. Following acute blood loss, an individual will initially have normal values for hemoglobin and HCT,
but these values will decline over the ensuing 36 to 48 hours as most of the total blood volume deficit will be replaced by the
movement of fluid from the extravascular into the intravascular space or with fluid resuscitation. Only then will the hemoglobin and
HCT reflect blood loss. Thus, until the total blood volume deficit is fully repleted, the hemoglobin and HCT will underestimate the
degree of blood loss [26]. The rapid onset of symptoms in these cases primarily reflects initial hypovolemia and hypotension and
their effects on tissue oxygenation.
Conversely, when anemia develops gradually over time (as with iron deficiency, vitamin B12 deficiency, or a myelodysplastic
syndrome [MDS]), compensatory increases in blood volume and tissue adaptation to hypoxia may prevent symptoms from
developing until the hemoglobin is very low.
In general, clinical scenarios associated with a rapid decline in red cell mass that do not permit compensatory mechanisms to
mitigate reduced tissue perfusion (large volume acute blood loss, acute hemolysis) will be more symptomatic for any given level of
hemoglobin or HCT than low-level chronic blood loss, hemolysis, or anemias due to underproduction of RBCs.
WAYS TO APPROACH THE DIAGNOSIS
Categories to consider — All approaches to the diagnosis of anemia divide patients into categories; they are then informed by the
probability of particular diagnoses in each category. An example is provided in the flowchart (
algorithm 1).
There are several conceptual frameworks in which to categorize anemia. Most clinicians with experience in evaluating anemia use a
combination of these conceptual frameworks tailored to the specific patient and the urgency with which diagnostic confirmation is
required. Typically, this starts with the clinical features (patient sex, age, and underlying conditions), with review of the complete blood
count (CBC) and red blood cell (RBC) indices, and reticulocyte count with other testing (especially useful if the mean corpuscular volume
[MCV] is in the normal range).
Some of the more common ways to categorize anemia are based on:
● Obvious clinical features such as acute blood loss or known cause for malabsorption of nutrients needed for RBC production. (See
'Evaluation based on clinical presentation' below.)
● Medications and underlying conditions known to be associated with anemia. Selected medicines that can cause anemia and their
mechanisms are summarized in the table (
table 3).
● "Flags" on the initial CBC and chemistry panel, including other cytopenias, an abnormal differential, abnormalities of RBC shape, or
evidence of kidney or liver dysfunction. (See 'Evaluation based on CBC/retic count' below.)
● Whether the RBCs are small (microcytic) or large (macrocytic). (See 'Evaluation based on MCV' below.)
● Whether the bone marrow is functioning appropriately (based on whether the reticulocyte count appropriately increased). (See
'Reticulocyte count' below.)
An experienced clinician will consider all of these frameworks simultaneously.
The clinical scenarios and certain findings on the CBC are most likely to point to serious, "can't-miss" diagnoses that require immediate
interventions. (See 'Pancytopenia' below.)
Information to gather
General clinical information — A history and physical examination may identify features that increase the likelihood of specific
diagnoses.
● Known underlying medical conditions and medications (
table 3) that cause anemia
● Family history of a specific type of anemia
● Causes of acquired anemia
• Dietary practices (eg, vegan diet lacks vitamin B12)
• Travel (eg, acquired parasitic infections)
• Infections
• Bleeding (heavy menses, melena)
● Chronicity of the anemia
● Symptoms or conditions that would suggest hemolysis
• Dark urine
• Jaundice
• History of gallstones
• Anemia with certain food or drug exposures (fava beans, oxidant drugs)
● Symptoms or findings that suggest kidney or liver disease or hypersplenism
● Rapidity with which symptoms developed (if present) (see 'Correlation with symptoms' above)
Laboratory test results — Laboratory parameters may be especially useful for constructing a list of likely diagnoses before the clinical
history can be elicited (eg, if the patient is not present or not able to provide relevant history) and when the clinical context does not point
to an obvious cause.
It is assumed that the individual has already had a CBC with RBC indices and white blood cell (WBC) differential.
With some caveats, the following testing is appropriate in the initial evaluation of unexplained anemia:
● Reticulocyte count – Reflects the ability of the bone marrow to produce RBCs and can be used to categorize possible causes of
anemia. (See 'Reticulocyte count' below.)
● Chemistry panel – Should include assessments of kidney and liver function, with creatinine, alanine aminotransferase (ALT), and
aspartate aminotransferase (AST).
● Hemolysis labs – Lactate dehydrogenase (LDH), bilirubin, and haptoglobin (
table 4), if the clinical history suggests hemolytic
anemia and/or the reticulocyte count is increased. (See 'Hemolysis' below.)
● Blood smear – A review of the peripheral blood smear is always desirable in the initial evaluation of anemia. However, it is not always
possible to obtain this immediately, and some workflows will direct the blood smear to an off-site reviewer who is unfamiliar with the
patient. These practices may make blood smear review during the initial evaluation an unrealistic expectation in many primary care
practices. In contrast, review of the blood smear is a routine component of the anemia evaluation by a hematologist.
In some settings, review of a blood smear by an experienced professional is critical to the evaluation and treatment; these settings
are indicated in the following sections. Interpretation of specific findings is discussed separately. (See "Evaluation of the peripheral
blood smear".)
More extensive initial testing may be needed in an individual who is critically ill. Conversely, certain tests may be omitted in an individual
with an obvious clinical presentation that suggests a specific diagnosis. As an example, a young woman with new onset microcytic anemia
can be evaluated for iron deficiency by iron studies, without the need for reticulocyte count, LDH, liver function tests, or review of the
peripheral blood smear. (See 'Evaluation based on clinical presentation' below.)
Ideally, laboratory results are incorporated with clinical information as soon as possible to help narrow and/or expand the diagnostic
possibilities, as illustrated in the flowchart (
algorithm 1). Further information can be gathered simultaneously or sequentially,
depending on the clinical scenario.
EVALUATION BASED ON CLINICAL PRESENTATION
Certain patterns (features of the clinical history or obvious abnormalities in the initial laboratory results) can be very helpful in suggesting
specific diagnoses if present.
Acute blood loss — Diagnosis of the underlying etiology of anemia is generally not a challenge in an individual with obvious
gastrointestinal bleeding or trauma.
Typically, the major challenge is identifying and managing the specific site of bleeding. If an obvious anatomic site of bleeding cannot be
identified, further evaluations for occult bleeding are appropriate. (See "Evaluation of occult gastrointestinal bleeding".)
Other assessments such as coagulation studies or assessment for a bleeding disorder may also be appropriate. (See "Approach to the
adult with a suspected bleeding disorder".)
The immediate goal of management is to maintain or restore tissue perfusion and oxygen delivery by supporting intravascular volume
and red blood cell (RBC) mass. This may require transfusions, including use of a massive transfusion protocol in some cases. (See
"Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Thresholds for specific patient populations'
and "Massive blood transfusion".)
After the patient is stabilized, iron stores should be assessed and iron replaced if low. Serum ferritin, if low, is a reliable indicator of iron
stores. Serum iron concentration is not a reliable indicator of iron stores because it can be increased acutely by recent transfusion (due to
iron release from damaged RBCs in the transfused product). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in
adults", section on 'Sequence of testing'.)
Congenital anemia or a family history of anemia — A history of lifelong anemia or a family history of anemia can be helpful in reaching
a diagnosis of a heritable/genetic syndrome.
● Family history – If there is a family history of anemia, it is important to identify the specific relatives who were anemic, since not all
positive family histories imply a familial syndrome. As an example, females with iron deficiency anemia due to menses and/or
pregnancies will often report a family history of anemia, when in fact the affected family members are all females with iron deficiency
anemia.
● Patient history – Individuals with lifelong anemia due to chronic hemolytic disorders may describe episodes of jaundice during
acute illnesses or episodes of anemia that is exacerbated during acute illnesses or with exposures to medications. Pigment
gallstones may also be seen in chronic hemolytic anemias.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common cause of episodic hemolysis associated with febrile illnesses
and certain medications (
table 5). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency",
section on 'Diagnostic evaluation'.)
● Laboratory findings – Many of the heritable anemias cause hemolysis. Laboratory findings obtained around the time of the event
may show anemia, high reticulocyte count, high lactate dehydrogenase (LDH) and indirect bilirubin, and low haptoglobin (
The most common types of heritable hemolytic anemias and specific causes of each type are summarized in the figure (
table 4).
figure 3).
The direct antiglobulin test (DAT) distinguishes immune causes (DAT-positive) from non-immune causes (DAT-negative). Heritable
syndromes are typically DAT-negative. DAT-positivity can sometimes occur following transfusion (due to an immunologic transfusion
reaction).
● Blood smear – Evaluation of the peripheral blood smear is especially useful in individuals with lifelong anemia because many of the
heritable syndromes have characteristic and easily visible abnormalities of RBC shape and appearance. (See "Evaluation of the
peripheral blood smear", section on 'Red cell abnormalities'.)
The blood smear findings can in turn direct the subsequent laboratory tests needed to confirm or exclude a specific diagnosis.
As examples:
• Bite or blister cells (
picture 5) – G6PD deficiency, evaluated by measuring the G6PD level.
• Microcytosis, target cells, teardrop cells (
picture 6) – Thalassemia, evaluated by hemoglobin analysis or molecular (DNA)
testing.
• Spherocytes (
picture 7), elliptocytes (
picture 8), or stomatocytes (
picture 9) – Hereditary spherocytosis (HS),
elliptocytosis (HE), or stomatocytosis (HSt).
Details of testing are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD)
deficiency" and "Methods for hemoglobin analysis and hemoglobinopathy testing" and "Hereditary spherocytosis" and "Hereditary
elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
Premenopausal women — Iron deficiency is common in premenopausal women, due to menses and/or pregnancies. RBCs are microcytic
in some individuals but may be normocytic in people with early or mild iron deficiency [27]. Other conditions contributing to anemia can
also be present.
● If the clinical history and examination are otherwise negative, we obtain iron studies (serum iron, serum transferrin or total iron
binding capacity (TIBC), serum ferritin, and calculated transferrin saturation [TSAT]). A low ferritin is highly specific for iron deficiency.
Obtaining the studies after an overnight fast may be useful as it avoids interference by dietary iron or iron-containing vitamins, which
can increase the serum iron and calculated TSAT. (See "Iron requirements and iron deficiency in adolescents", section on 'Evaluation
and presumptive diagnosis' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on
'Diagnostic evaluation'.)
● Findings that suggest another cause of anemia should also be pursued. This may include anemia during childhood, symptoms
related to hemolysis, and other findings on the complete blood count (CBC) and blood smear.
Older adults — The prevalence of anemia increases substantially in patients over the age of 60 [28,29]. As noted above, we evaluate the
underlying cause rather than attributing anemia to aging. (See 'Anemia definitions' above.)
● Major causes – Major causes of anemia in older adults include [30]:
• Nutritional deficiencies in approximately one third.
• Kidney disease or anemia of chronic disease/inflammation (ACD/AI) in approximately one third.
• Unexplained in the remaining third. Clonal disorders such as myelodysplastic syndrome may account for a significant proportion
of unexplained anemias in older adults.
● Routine testing – All individuals over the age of 60 should have testing for the following:
• Kidney function – Estimation of glomerular filtration rate (GFR). eGFR <45 mL/min/1.73 m2 in the absence of another diagnosis
implicates chronic kidney disease (CKD) as a cause.
• Iron stores – Iron studies (serum iron, serum transferrin or TIBC, serum ferritin, and TSAT).
• Vitamin B12 – Vitamin B12 level, with methylmalonic acid level if vitamin B12 deficiency is suspected and vitamin B12 level is
equivocal.
• Folate – Folate level if at risk for malnutrition.
● Additional testing – Further testing may be appropriate in certain settings:
• Monoclonal gammopathy – Testing is indicated if the mean corpuscular volume (MCV) is increased and/or if there is reduced
eGFR or hypercalcemia. Serum free light chains and serum protein electrophoresis (SPEP) with immunofixation are obtained.
• Androgen deficiency – Testing with serum testosterone level is indicated in older men with an isolated normocytic anemia in
whom the testing above did not provide a diagnosis [31].
• MDS and clonal cytopenias – Testing for a clonal bone marrow disorder is indicated if the MCV is slightly elevated and/or if there
are other cytopenias or morphologic abnormalities on the blood smear. Molecular testing can be performed on peripheral blood
using a gene panel for myeloid disorders (myelodysplastic syndrome [MDS] panel) or clonal hematopoiesis (CH) panel. Bone
marrow can be examined for signs of dysplasia for possible diagnosis of MDS.
Unexplained anemia of aging is a poorly defined syndrome often seen in older individuals. The mechanism is unclear and appears to be
cytokine-mediated [32]. This is a diagnosis of exclusion in older individuals with normocytic anemia and an unrevealing workup. The
diagnosis should be reassessed periodically to avoid missing a correctable disorder.
Malabsorption/malnutrition — A number of specific causes of anemia diagnoses occur at increased frequency in individuals with
malnutrition and/or malabsorption. These may include deficiencies of iron, vitamin B12, folate, and copper, which may occur in isolation or
simultaneously. In individuals with severely reduced intake due to anorexia nervosa or starvation, the bone marrow is often affected.
● Gastric surgery – Gastric surgery, particularly bariatric surgery, is associated with malabsorption of vitamins and trace elements.
This is particularly the case following Roux-en-Y procedures [33]. Gastric acid, proteins, and sugars protect iron from alkaline
secretions of the duodenum. Rates of deficiencies with different procedures and details of routine supplementation are discussed
separately. (See "Bariatric surgery: Postoperative nutritional management".)
● Zinc supplements – Zinc ingestion, as a dietary supplement or in zinc-containing denture adhesives, can cause copper deficiency by
inhibiting copper absorption. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Copper deficiency'.)
● Starvation or anorexia nervosa – Anemia is seen in approximately one-third of individuals with severe malnutrition or anorexia
nervosa, either alone or in combination with neutropenia or leukopenia [34]. The bone marrow may show gelatinous necrosis.
Anemia will improve with restored food intake. (See "Anorexia nervosa in adults and adolescents: Medical complications and their
management", section on 'Hematologic'.)
Iron deficiency causes microcytosis, while vitamin B12, folate, and copper deficiency cause macrocytosis. If both iron deficiency and one of
the other deficiencies are present, the MCV may be in the normal range, often with an increased red cell distribution width (RDW).
Vitamin B12 and copper deficiency can cause other cytopenias; neutropenia commonly accompanies the anemia in copper deficiency.
Vitamin B12 and copper deficiency both can produce posterior column neurologic abnormalities.
The evaluation in all cases should include serum iron, transferrin or TIBC, ferritin, vitamin B12, and folate levels. Copper level should be
measured in malnourished individuals with anemia accompanied by neutropenia and/or neuropathy, as well as those with anemia in the
setting of gastric/bariatric surgery or a history of zinc ingestion. Individuals with any of these deficiencies should be evaluated for the
underlying cause.
Underlying systemic illness — Chronic anemia in patients with systemic illnesses may reflect anemia of chronic disease/inflammation
(ACD/AI), particularly in disorders associated with inflammatory processes such as rheumatoid arthritis or systemic lupus erythematosus
(SLE).
The reduction in hemoglobin is often mild to moderate. The red cells are typically normocytic, although there may occasionally be a
moderate degree of microcytosis due to iron-restricted erythropoiesis. Iron studies show decreased serum iron and TSAT and normal or
elevated ferritin concentrations. Serum erythropoietin is typically increased above the level seen in patients who are not anemic but to a
lesser degree than would be observed in uncomplicated iron deficiency (
figure 4). Serum hepcidin is not routinely available but would
be expected to be elevated.
Underlying conditions commonly associated with ACD/AI include:
●
●
●
●
●
Cancer
Chronic kidney disease (may be associated with concomitant erythropoietin deficiency)
Rheumatologic conditions
Hypothyroidism
Infections
There is debate about whether diabetes mellitus per se causes ACD/AI, or whether ACD/AI can only be caused by complications of
diabetes. Studies attempting to distinguish between the two are lacking, and many individuals with diabetes have other comorbidities
such as infection that could contribute to ACD/AI [35]. Anemia in an individual with diabetes should not be attributed to diabetes without a
thorough evaluation for other causes.
The evaluation focuses on eliminating other reversible contributing factors (eg, concomitant nutrient deficiencies), and management
focuses on treating the underlying condition. (See "Anemia of chronic disease/anemia of inflammation".)
EVALUATION BASED ON CBC/RETIC COUNT
The complete blood count (CBC) provides other information on white blood cell (WBC) and platelet counts and in some cases a reticulocyte
count, WBC differential, or information about abnormal cells.
This information should be assessed and may help to direct subsequent testing, especially if there are indications of potentially serious,
can't miss diagnoses such as those associated with pancytopenia (see 'Pancytopenia' below), or if there are schistocytes (indicative of
microangiopathic hemolysis) on the blood smear. (See 'Hemolysis' below.)
Pancytopenia — Pancytopenia is the combination of anemia, thrombocytopenia, and neutropenia (or leukopenia).
Findings from peripheral blood smear examination are critical in the assessment of pancytopenia. Other testing is directed by the findings,
as discussed separately. (See "Approach to the adult with pancytopenia".)
Findings of particular concern that warrant hematologist involvement and bone marrow examination include:
● Severe pancytopenia.
● Blasts or immature myeloid/lymphoid forms, which suggest acute leukemia.
● Abnormal lymphocytes (hairy cells, large granular lymphocytes, prolymphocytes).
● Leukoerythroblastosis (
picture 10) with or without teardrop cells (dacrocytes; (
picture 11)).
● Pancytopenia with hemolysis or thrombosis.
● Pancytopenia or bicytopenia (anemia with leukopenia or anemia with thrombocytopenia) in an older individual with normal vitamin
B12, folate, and copper levels.
Potential diagnoses are numerous (
anticonvulsants (
table 6). They include drug-induced pancytopenia (cytotoxic drugs, anti-infective drugs,
table 7)), certain infections (viral [hepatitis, cytomegalovirus, Epstein Barr virus] and severe non-viral [clostridial sepsis,
malaria, leishmaniasis, leptospirosis, babesiosis]), bone marrow failure (aplastic anemia), myelodysplasia, myelofibrosis, clonal disorders
such as paroxysmal nocturnal hemoglobinuria (PNH), and hematologic malignancies. (See "Approach to the adult with pancytopenia" and
"Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
These disorders can also present with isolated anemia or bicytopenia. In most cases, reticulocyte parameters are decreased (see
'Reticulocyte count' below). PNH is associated with bone marrow failure and hemolytic anemia, and reticulocyte values may be normal or
increased [36]. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
While a bone marrow disorder is always a consideration in individuals with pancytopenia, in some individuals, pancytopenia may be due to
other causes:
● Hypersplenism – Cirrhosis can cause pancytopenia due to sequestration of cells in the spleen (hypersplenism). Macrocytosis and
target cells are often seen on the peripheral blood smear. The mean corpuscular volume (MCV) will typically be elevated to a
moderate degree, usually no higher than 105 fL. Splenic imaging is appropriate if splenomegaly has not been previously
documented. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
● Nutrient deficiency – Deficiency of vitamin B12, copper, and/or folate may also cause pancytopenia and should be evaluated,
especially if the peripheral blood smear shows macroovalocytes (
picture 12), hypersegmented neutrophils (
picture 13), and/or if
the MCV is >110 fL. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
● Autoimmune – Autoimmune cytopenias typically affect a single cell line but can affect more than one cell line simultaneously,
especially if there is an underlying rheumatologic disorder such as systemic lupus erythematosus (SLE) or a lymphoid disorder such
as chronic lymphocytic leukemia (CLL). (See "Hematologic manifestations of systemic lupus erythematosus" and "Overview of the
complications of chronic lymphocytic leukemia".)
● HLH – Hemophagocytic lymphohistiocytosis (HLH) may be primary (typically in children) or secondary to an infection, malignancy, or
rheumatologic condition. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
● TMAs – Thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) typically cause thrombocytopenia
and microangiopathic hemolytic anemia, with a very low platelet count and schistocytes on the blood smear. Some types of druginduced TMAs such as due to quinine can cause pancytopenia. Disseminated intravascular coagulation (DIC) can cause pancytopenia
due to TMA plus bone marrow suppression, with coagulation abnormalities often prominent. (See "Diagnostic approach to suspected
TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)", section on
'Quinine' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
Reticulocyte count — Anemia can also be classified on the basis of reticulocyte production. This approach is most informative when the
reticulocyte count is either very decreased or very elevated. Attention must be paid to the particular reticulocyte parameter reported
(absolute count versus percentage) and is most helpful using a reticulocyte parameter that is corrected for the degree of anemia (
table 2). (See 'Reticulocyte production' above.)
Reticulocytosis requires a normally functioning bone marrow replete with iron, folate, cobalamin (vitamin B12), and copper, and a normally
functioning kidney that can sense a decrease in oxygen delivery and produce a compensatory increase in erythropoietin (EPO). Thus, a
decreased reticulocyte count suggests underproduction of red blood cells (RBCs; bone marrow suppression), and an increased reticulocyte
count usually suggests hemolysis or blood loss. If both bone marrow suppression and hemolysis or blood loss are present, the reticulocyte
count will be inappropriately low.
● Causes
• Decreased – Anemia with a decreased (or inappropriately low) reticulocyte count may be due to:
-
Deficiency of iron, vitamin B12, folate, or copper
Medications that suppress the bone marrow
Primary bone marrow disorders including myelodysplastic syndrome (MDS), myelofibrosis, or leukemia
Very recent bleeding (within five to seven days, before bone marrow compensation has occurred)
• Increased – Anemia with an increased reticulocyte count may be due to:
- Hemolysis
- Repletion of deficient iron, vitamin B12, folate, or copper (early phase of recovery)
- Recovery from bleeding
Regardless of other causes of anemia, an insufficient increase in the reticulocyte count suggests that the function of the bone
marrow and/or the kidney are impaired.
● Evaluation – If the reticulocyte count is increased and the cause of anemia is not readily apparent, additional laboratory testing for
hemolysis is appropriate (
table 4). (See 'Hemolysis' below.)
● Response to treatment – An increase in reticulocyte count following treatment can also be very helpful in determining if the cause
of anemia was determined accurately and completely. As examples:
• If anemia was attributed to a deficiency (iron, vitamin B12, folate), brisk reticulocytosis is expected to occur within one to two
weeks of repletion.
• If the reticulocyte count does not increase with correction of a deficiency, this suggests an additional cause of anemia is
interfering with bone marrow function. As an example, vitamin B12 or folate deficiency may occur concurrently with iron
deficiency, causing a normocytic anemia (see 'Normocytic (normal MCV)' below). This combination of findings is often seen in
malabsorption syndromes such as for celiac disease, autoimmune gastritis, or bariatric surgery. (See 'Malabsorption/malnutrition'
above.)
Hemolysis — Hemolytic anemia should be considered when there is a rapid fall in hemoglobin concentration with an increased
reticulocyte count in the absence of blood loss (
the table (
table 2). Other abnormal laboratory findings indicative of hemolysis are summarized in
table 4).
Schistocytes on the blood smear indicate likely hemolysis due to mechanical RBC destruction. Schistocytes plus thrombocytopenia indicate
possible thrombotic microangiopathy (TMA), which may be life-threatening. (See "Diagnostic approach to suspected TTP, HUS, or other
thrombotic microangiopathy (TMA)".)
Chronic hemolysis may present with a stable hemoglobin, a high reticulocyte count, and a normal lactate dehydrogenase (LDH) and
bilirubin. The combination of an increased LDH and reduced haptoglobin is 90 percent specific for acute 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 [37,38].
Intramedullary hemolysis (within the bone marrow) due to ineffective erythropoiesis, as may be seen in thalassemia or vitamin B12
deficiency, may produce elevations of bilirubin and LDH without reticulocytosis.
Causes of hemolysis are numerous and can be categorized in several ways, as summarized in the table (
table 8) and discussed in more
detail separately. (See "Diagnosis of hemolytic anemia in adults".)
These include:
● Hereditary, non-immune:
• Hemoglobinopathies (sickle cell disease, thalassemias, unstable hemoglobins)
• Hereditary red cell enzyme deficiencies (glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase [PK], glucose phosphate
isomerase, 5’ nucleotidase)
• Hereditary RBC membrane defects (hereditary spherocytosis [HS], elliptocytosis [HE], stomatocytosis [HSt])
● Acquired, non-immune
• Membrane defects (liver disease, acquired acanthocytosis)
• Infections (malaria, babesiosis, clostridial sepsis, Bartonellosis, trypanosomiasis, visceral leishmaniasis)
• Drug-induced (oxidant stress)
• Severe burns
• Thrombotic microangiopathies (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced
TMA)
• Mechanical (intravascular devices, artificial heart valve, giant hemangioma, footstrike hemolysis)
• Hypersplenism (may have a component of phagocytosis but is not antibody mediated)
• Vasculitis
• Severe hypertension
• Heavy metals (Wilson disease, copper toxicity, arsine toxicity)
• Envenomation (snake, brown recluse spider, hobo spider)
• Hypophosphatemia
● Acquired, immune-mediated
• Autoimmune (warm autoimmune hemolytic anemia [AIHA], cold agglutinin disease, paroxysmal cold hemoglobinuria)
• Hemolytic transfusion reactions
• Drug-induced
Once hemolysis is confirmed, the specific cause must be identified to ensure appropriate management. Details of the evaluation are
discussed in a separate topic review. (See "Diagnosis of hemolytic anemia in adults", section on 'Diagnostic approach'.)
EVALUATION BASED ON MCV
Many individuals with anemia will be otherwise well, and the clinical history and other initial findings on the complete blood count (CBC)
may not be helpful for suggesting specific diagnoses leading to anemia. A diagnostic approach based on the mean corpuscular volume
(MCV) is most useful in these cases, as illustrated in the flowchart (
algorithm 1).
Evaluation of anemia using the MCV is especially useful for microcytic and macrocytic anemia. (See 'Microcytosis (low MCV)' below and
'Normocytic (normal MCV)' below.)
Microcytosis (low MCV) — A decreased MCV (usually <80 fL) reflects a defect in cellular hemoglobin synthesis. These anemias are
summarized in the table (
table 9) and discussed in detail separately and briefly below. (See "Microcytosis/Microcytic anemia".)
● Causes
• Iron deficiency – Restricted iron availability (iron deficiency and some cases of anemia of chronic disease/anemia of inflammation
[ACD/AI], which can cause functional iron deficiency). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in
adults" and "Anemia of chronic disease/anemia of inflammation".)
• Decreased globin chains – Qualitative abnormalities in globin proteins such as thalassemia, hemoglobin (Hb) C, and Hb E (but
not Hb S). (See "Pathophysiology of thalassemia" and "Diagnosis of thalassemia (adults and children)" and "Overview of
compound sickle cell syndromes".)
• Decreased heme – Abnormalities of the heme porphyrin ring, including congenital sideroblastic anemias and lead poisoning.
(See "Causes and pathophysiology of the sideroblastic anemias" and "Lead exposure and poisoning in adults".)
● Very low MCV – Iron deficiency and thalassemia are the most likely causes of a very low MCV (<80 fL). The ratio of the MCV to the red
blood cell (RBC) count (Mentzer index) is useful in predicting the likelihood of thalassemia trait versus iron deficiency. If the ratio of
MCV (in fL) to RBC count (in millions of cells/microL) is less than 13, thalassemia is more likely than iron deficiency [39].
In practice, all individuals with a low MCV should have iron studies to evaluate iron status (and should have deficiency corrected if
present), because the results of hemoglobin analysis can be altered by concomitant iron deficiency. (See "Methods for hemoglobin
analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia'.)
● Evaluation
• All patients – All patients with microcytic anemia should have serum iron, total iron binding capacity (TIBC)/transferrin, and
serum ferritin concentrations measured, with calculated transferrin saturation (TSAT). Iron studies will identify iron deficiency (the
most likely diagnosis for microcytic anemia) and ACD/AI in most cases. Mild microcytosis with iron studies showing low iron, low
TIBC, and high-normal to high ferritin in the appropriate clinical context (eg, chronic inflammatory condition with normal MCV
prior to its development) is consistent with ACD/AI. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in
adults", section on 'Iron studies (list of available tests)'.)
• Individuals with normal iron studies – Hemoglobin quantitation should be ordered in individuals with microcytic anemia who
do not have iron deficiency or ACD/AI to identify beta thalassemia or other hemoglobinopathies. Globin gene studies may be
needed to diagnose alpha thalassemia; the family history may be helpful in determining likelihood of these disorders. Minimal to
mild anemia and microcytosis may indicate non-transfusion-dependent thalassemia (thalassemia trait). Basophilic stippling may
also be seen with beta thalassemia [40]. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)
• Individuals with normal hemoglobin – Basophilic stippling (
picture 14) suggests possible lead poisoning, and whole blood
lead levels should be measured. The diagnosis of sideroblastic anemia requires a bone marrow examination. (See "Bone marrow
aspiration and biopsy: Indications and technique", section on 'Indications' and "Evaluation of bone marrow aspirate smears".)
Macrocytosis (high MCV) — An increased MCV (>100 fL) is typically attributed to asynchronous maturation of nuclear chromatin, although
other causes may also be present. These anemias are summarized in the table (
table 10) and discussed in detail separately and briefly
below. (See "Macrocytosis/Macrocytic anemia".)
● Causes
• Megaloblastic anemia – Asynchronous nuclear maturation (megaloblastosis), in which the rate of cell division is reduced relative
to cytoplasmic expansion. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)
Megaloblastic maturation can be due to:
-
Vitamin B12 deficiency
Folate deficiency
Copper deficiency
Myelodysplastic syndrome (MDS)
Aplastic anemia
Diamond Blackfan anemia
Drugs that interfere with DNA synthesis
• Membrane changes – In some cases, conditions that increase RBC membrane (such as liver disease or excess alcohol [even
without liver disease]) and other underlying disorders such as hypothyroidism can cause increases in MCV. Stomatocytosis
(hereditary or acquired) can also cause macrocytic anemia. (See "Macrocytosis/Macrocytic anemia", section on 'Causes of
macrocytosis/macrocytic anemia'.)
• Reticulocytosis – Reticulocytes are larger than mature RBCs (
picture 3), and a high level of reticulocytosis will increase the
MCV. This will be associated with an increased red cell distribution width (RDW) and can often be suspected from examination of
the peripheral blood smear. (See 'Reticulocyte production' above.)
Reticulocytes may be increased in:
-
Hemolytic anemias (acute or chronic)
Recovery from bleeding
Repletion of iron or other deficient nutrient
Recovery from bone marrow suppression such as binge drinking alcohol
• Spurious – Increased concentrations of immunoglobulin or acute phase proteins such as occurs with inflammation or a polyclonal
or monoclonal gammopathy may cause small rouleaux (
picture 15) that are counted by electronic counters as single large cells.
This is a laboratory artifact that can be assessed by viewing the peripheral blood smear.
● Evaluation
• All individuals – Serum vitamin B12 level should be measured in all patients with unevaluated macrocytosis. All individuals who
are nutritionally compromised or who have had gastric surgery should also have serum folate measured. In patients without
known nutritional/gastric issues who have MCV >110 fL and a normal vitamin B12 level, serum methylmalonic acid (MMA) and
serum folate should be measured. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on
'Diagnostic evaluation'.)
• Individuals with normal vitamin B12 and folate
- Thyroid stimulating hormone (TSH) should be checked. (See "Macrocytosis/Macrocytic anemia", section on 'Hypothyroidism'.)
- Alcohol use should be assessed. The MCV typically is not >105 fL in alcohol-induced macrocytosis. (See "Hematologic
complications of alcohol use", section on 'Anemia'.)
- Serum copper level should be checked, especially if neutropenia and/or neuropathy are present or if the history reveals zinc
ingestion or other risk factors. (See "Copper deficiency myeloneuropathy", section on 'Causes of acquired copper deficiency'.)
- The peripheral blood smear (or report) should be reviewed. If the blood smear shows target cells, liver synthetic tests should
be measured. The MCV in liver disease typically is not >105 fL. Other morphologic abnormalities such as stomatocytosis
should be evaluated, if present. If the copper level is normal and the blood smear shows evidence of dysplasia such as
bilobed or immature neutrophils or binucleate RBCs, or other cytopenias, refer to a hematologist for bone marrow and/or
molecular (DNA) studies on bone marrow or peripheral blood. (See "Clinical manifestations and diagnosis of myelodysplastic
syndromes (MDS)".)
Normocytic (normal MCV) — A normal MCV (80 to 100 fL) is the most common finding in anemic men and postmenopausal women.
Normocytic anemias can be more challenging to evaluate than anemias with an MCV that is obviously low or high. Causes are more
numerous and may be multifactorial, an underlying condition may not be apparent, and other findings may be nonspecific.
Often normocytic anemia is associated with a slightly elevated RDW, and the reticulocyte count is not substantially increased (and may be
decreased). An increased RDW may indicate a population of microcytic or macrocytic RBCs that is too small to shift the MCV out of the
normal range, or combined microcytic and macrocytic processes, such as iron deficiency plus vitamin B12 or folate deficiency [41].
● Causes
• Nutrient deficiency – Any of the causes of acquired microcytic or macrocytic anemia, especially early stages of deficiency of iron,
vitamin B12, folate, or copper. (See 'Microcytosis (low MCV)' above and 'Macrocytosis (high MCV)' above.)
• Multiple causes – Combined microcytic plus macrocytic anemia [41]. The most characteristic situation is simultaneous deficiency
of vitamin B12 and iron in an individual with celiac disease or autoimmune gastritis. (See "Epidemiology, pathogenesis, and
clinical manifestations of celiac disease in adults" and "Metaplastic (chronic) atrophic gastritis".)
Hemolytic anemia without marked reticulocytosis (due to concomitant bone marrow suppression from another cause). (See
"Diagnosis of hemolytic anemia in adults", section on 'Hemolysis without reticulocytosis'.)
• ACD/AI – Anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Anemia of chronic disease/anemia of inflammation".)
• CKD – Anemia of chronic kidney disease (CKD). (See "Overview of the management of chronic kidney disease in adults", section on
'Anemia'.)
• HF – Anemia of heart failure (HF), including cardio-renal syndrome [42]. (See "Evaluation and management of anemia and iron
deficiency in adults with heart failure" and "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)
• Endocrine – Anemia with endocrine deficiency, including hypothyroidism (most cases), androgen deficiency, or adrenal
insufficiency (in adrenal insufficiency, anemia may be masked by volume contraction). (See 'Caveats for normal ranges' above and
"Clinical manifestations of adrenal insufficiency in adults", section on 'Hematologic findings'.)
• Cancer – Cancer-associated anemia, including monoclonal gammopathies. (See "Causes of anemia in patients with cancer".)
• Clonal hematopoietic stem cell disorders – Anemia due to a clonal disorder of erythropoiesis (myelodysplastic syndrome,
aplastic anemia, or clonal cytopenias of uncertain significance [CCUS]) [43]. The strict definition of clonal hematopoiesis of
indeterminate potential (CHIP) includes normal hemoglobin and other blood counts. (See "Clinical manifestations and diagnosis
of myelodysplastic syndromes (MDS)" and "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)
• Early blood loss – Blood loss that has not yet caused iron deficiency. (See "Evaluation of occult gastrointestinal bleeding".)
• PRCA – Pure red cell aplasia. (See "Acquired pure red cell aplasia in adults".)
• Partially treated anemia – Anemia in process of correction or following transfusion. A "dimorphic RBC population" (presence of
two distinct populations of RBCs of different sizes) may be suspected when an increased RDW is present; it can be confirmed by
examination of the peripheral blood smear, although the distinct populations may not always be recognized. This finding is
traditionally taught as a clue to sideroblastic anemia [44]. However, it is more commonly seen during early treatment of iron
deficiency or megaloblastic anemia, or following transfusion of a patient with microcytic or macrocytic anemia.
● Evaluation
• Reticulocyte count and chemistry panel – All individuals with normocytic anemia of unknown cause should have a reticulocyte
count and chemistry panel (or review of results of this testing) during the initial evaluation, and abnormalities of this testing
should be pursued (
algorithm 1). (See 'Laboratory test results' above.)
• Iron studies and hemolysis labs – If the reticulocyte count and chemistry panel are unrevealing, determine serum iron
concentration, serum TIBC/transferrin, and serum ferritin concentration measured and transferrin saturation (TSAT) calculated, in
order to diagnose iron deficiency or ACD/AI. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)
If iron stores are normal, evaluate for hemolysis. (See 'Hemolysis' above.)
• Additional tests – If hemolysis is absent and there are no other obvious diagnoses, consider conditions listed above including
cancer, endocrine disorders, blood loss, and nutrient deficiencies.
- Normocytic anemia with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 sq m and no other identified cause is
most probably the anemia of chronic kidney disease. (See "Overview of the management of chronic kidney disease in adults",
section on 'Anemia'.)
- Evaluation for disorders common in older adults is generally reasonable, including testing for monoclonal gammopathies,
clonal cytopenias, androgen deficiency (in men), and bone marrow evaluation for myelodysplasia and pure red cell aplasia.
(See 'Older adults' above.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Anemia in adults".)
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 education: Complete blood count (CBC) (The Basics)" and "Patient education: Anemia caused by low iron
(The Basics)" and "Patient education: Anemia of inflammation (anemia of chronic disease) (The Basics)" and "Patient education:
Autoimmune hemolytic anemia (The Basics)" and "Patient education: Pernicious anemia (The Basics)" and "Patient education: Vitamin
B12 deficiency and folate deficiency (The Basics)".)
● Beyond the Basics topics (See "Patient education: Anemia caused by low iron in adults (Beyond the Basics)" and "Patient education:
Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics)".)
SUMMARY AND RECOMMENDATIONS
● Definitions – Criteria for diagnosing anemia and caveats for defining normal ranges are summarized in the table (
discussed above. (See 'Anemia definitions' above and 'Caveats for normal ranges' above.)
table 1) and
● Conceptual framework – Anemia can be categorized in several ways (pattern recognition for typical clinical presentations and
laboratory findings; classified according to red blood cell [RBC] size; or divided by whether the bone marrow is able or unable to
increase RBC production). Most experienced clinicians will consider these frameworks simultaneously. (See 'Categories to consider'
above.)
● Initial assessment – A history and physical examination may identify features that suggest specific diagnoses or medications that
might be implicated (
table 3). In addition to a complete blood count (CBC) with RBC indices and white blood cell (WBC) differential,
most patients with anemia should have a reticulocyte count and chemistry panel with creatinine and hepatic transaminases. Tests for
hemolysis and review of the peripheral blood smear are often appropriate. (See 'Information to gather' above.)
● Common clinical scenarios – Common presentations that can help narrow the diagnosis include acute bleeding, hereditary
anemias, iron deficiency in premenopausal women, bone marrow and nutritional disorders in older adults, combined nutrient
defects due to malabsorption, and inflammatory conditions that produce anemia of chronic disease/chronic inflammation (ACD/AI).
(See 'Evaluation based on clinical presentation' above.)
● Initial laboratory abnormalities – Pancytopenia raises concern for an underlying bone marrow disorder (
table 6), which may be
life-threatening in some cases. A high reticulocyte count suggests hemolysis or blood loss. Clinical and laboratory findings of
hemolysis (
immune (
table 4) warrant testing to determine whether RBC destruction is hereditary versus acquired and immune versus nontable 8). (See 'Evaluation based on CBC/retic count' above.)
● RBC size – For most individuals who lack an obvious clinical pattern that can be used to narrow the diagnosis, the evaluation can
focus on RBC size, as determined by the mean corpuscular volume (MCV). MCV is also useful for expanding or narrowing diagnostic
possibilities in individuals with various clinical presentations. Causes of anemia categorized by MCV are listed in the table (
); an approach summarizing the evaluation is provided in the flowchart (
table 11
algorithm 1).
• Low MCV – Common causes of microcytic anemia (MCV <80 fL) include iron deficiency, thalassemia, and some cases of ACD/AI (
table 9). (See 'Microcytosis (low MCV)' above and "Microcytosis/Microcytic anemia".)
• High MCV – Common causes of macrocytic anemia (MCV >100 fL) include megaloblastic anemias (vitamin B12, folate, or copper
deficiency; certain drugs; and myelodysplastic syndrome [MDS]), liver disease, alcohol, hypothyroidism, and hemolysis with a high
reticulocyte count (
table 10). (See 'Macrocytosis (high MCV)' above and "Macrocytosis/Macrocytic anemia".)
• Normal MCV – Normocytic anemia (MCV between 80 and 100 fL) can be challenging to evaluate. Causes include early or
combined nutrient deficiencies, multifactorial causes, a number of chronic medical conditions, clonal bone marrow disorders, and
other causes of bone marrow dysfunction. Testing for iron deficiency, hemolysis, endocrine disorders, and other disorders may be
appropriate, guided by the patient's age and other medical conditions. (See 'Normocytic (normal MCV)' above.)
ACKNOWLEDGMENT
We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge
Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and
longstanding involvement with the UpToDate program.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Causey MW, Miller S, Foster A, et al. Validation of noninvasive hemoglobin measurements using the Masimo Radical-7 SpHb Station.
Am J Surg 2011; 201:592.
2. Shamir MY, Avramovich A, Smaka T. The current status of continuous noninvasive measurement of total, carboxy, and methemoglobin
concentration. Anesth Analg 2012; 114:972.
3. Kim SH, Lilot M, Murphy LS, et al. Accuracy of continuous noninvasive hemoglobin monitoring: a systematic review and meta-analysis.
Anesth Analg 2014; 119:332.
4. World Health Organization. Nutritional anaemias: Report of a WHO scientific group. Geneva, Switzerland: World Health Organization;
1968.
5. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;
107:1747.
6. 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.
7. Reed WW, Diehl LF. Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks. Arch Intern Med 1991;
151:501.
8. 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.
9. Robins EB, Blum S. Hematologic reference values for African American children and adolescents. Am J Hematol 2007; 82:611.
10. 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.
11. Hollowell JG, van Assendelft OW, Gunter EW, et al. Hematological and iron-related analytes--reference data for persons aged 1 year
and over: United States, 1988-94. Vital Health Stat 11 2005; :1.
12. Michalak SS, Rupa-Matysek J, Gil L. Comorbidities, repeated hospitalizations, and age ≥ 80 years as indicators of anemia development
in the older population. Ann Hematol 2018; 97:1337.
13. Mindell J, Moody A, Ali A, Hirani V. Using longitudinal data from the Health Survey for England to resolve discrepancies in thresholds
for haemoglobin in older adults. Br J Haematol 2013; 160:368.
14. Means RT. Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood
Parameters. Nutrients 2020; 12.
15. 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.
16. 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.
17. Patel KV. Epidemiology of anemia in older adults. Semin Hematol 2008; 45:210.
18. Nordenberg D, Yip R, Binkin NJ. The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA 1990; 264:1556.
19. Stewart RD, Baretta ED, Platte LR, et al. Carboxyhemoglobin levels in American blood donors. JAMA 1974; 229:1187.
20. Sen S, Hsei L, Tran N, et al. Early clinical complete blood count changes in severe burn injuries. Burns 2019; 45:97.
21. Ruíz-Argüelles GJ. Altitude above sea level as a variable for definition of anemia. Blood 2006; 108:2131; author reply 2131.
22. 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.
23. Hillman RS. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest
1969; 48:443.
24. Otto JM, Montgomery HE, Richards T. Haemoglobin concentration and mass as determinants of exercise performance and of surgical
outcome. Extrem Physiol Med 2013; 2:33.
25. MURRAY JF, GOLD P, JOHNSON BL Jr. The circulatory effects of hematocrit variations in normovolemic and hypervolemic dogs. J Clin
Invest 1963; 42:1150.
26. 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.
27. Hillman RS. Red cell manual, FA Davis Co, 1974. p.16.
28. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J
Med 2006; 119:327.
29. Phillips R, Wood H, Weaving G, Chevassut T. Changes in full blood count parameters with age and sex: results of a survey of almost
900 000 patient samples from primary care. Br J Haematol 2021; 192:e102.
30. 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.
31. Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial.
JAMA Intern Med 2017; 177:480.
32. Ferrucci L, Semba RD, Guralnik JM, et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 2010; 115:3810.
33. Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric surgery. Curr Opin Clin Nutr Metab Care 2004; 7:569.
34. Hütter G, Ganepola S, Hofmann WK. The hematology of anorexia nervosa. Int J Eat Disord 2009; 42:293.
35. Almoznino-Sarafian D, Shteinshnaider M, Tzur I, et al. Anemia in diabetic patients at an internal medicine ward: clinical correlates and
prognostic significance. Eur J Intern Med 2010; 21:91.
36. Mercuri A, Farruggia P, Timeus F, et al. A retrospective study of paroxysmal nocturnal hemoglobinuria in pediatric and adolescent
patients. Blood Cells Mol Dis 2017; 64:45.
37. Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA 1980; 243:1909.
38. Galen RS. Application of the predictive value model in the analysis of test effectiveness. Clin Lab Med 1982; 2:685.
39. Mentzer WC Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet 1973; 1:882.
40. Calero F, Villegas A, Porres A, et al. Hematologic data in 825 cases of beta-thalassemia trait in Spain. Nouv Rev Fr Hematol 1990;
32:265.
41. Spivak JL. Masked megaloblastic anemia. Arch Intern Med 1982; 142:2111.
42. Kazory A, Ross EA. Anemia: the point of convergence or divergence for kidney disease and heart failure? J Am Coll Cardiol 2009;
53:639.
43. Steensma DP. Clinical Implications of Clonal Hematopoiesis. Mayo Clin Proc 2018; 93:1122.
44. Tuckfield A, Ratnaike S, Hussein S, Metz J. A novel form of hereditary sideroblastic anaemia with macrocytosis. Br J Haematol 1997;
97:279.
Topic 7133 Version 66.0
GRAPHICS
Microhematocrit determination
The capillary tube is plugged at one end and centrifuged (left). The
proportion of blood volume occupied by red cells can be readily determined
by eye in a microhematocrit reader (right).
Courtesy of Nathaniel Duke.
Graphic 61513 Version 3.0
Manual (spun) hematocrit
This photo shows two anticoagulated blood-filled Wintrobe
hematocrit tubes following high-speed centrifugation. The tube on
the left is from an individual with a hematocrit of 38 percent (blue
arrow). The tube on the right is from a 19-year-old female with
essential thrombocytosis, a normal white blood cell count, and a
platelet count of 5,000,000/microL. 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), and the white
blood cell count is not markedly elevated, the platelet count can be
estimated by the thickness of this layer, with each mm being
equivalent to one million platelets/microL. 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.
Graphic 68024 Version 6.0
Normal CBC parameters in adults
Parameter
Males
Females
13.6 to 16.9
11.9 to 14.8
Hematocrit (%)
40 to 50
35 to 43
RBC count (×106 /microL)
4.2 to 5.7
3.8 to 5.0
Hemoglobin (g/dL)
MCV (fL)
82.5 to 98
MCHC
32.5 to 35.2
RDW (%)
11.4 to 13.5
Reticulocyte count (×103 /microL or ×109 /L)
16 to 130
16 to 98
Platelet count (×103 /microL)
152 to 324
153 to 361
WBC count (×103 /microL)
3.8 to 10.4
These parameters were determined for approximately 1500 to 2000 individuals ages 20 to 80 (varies slightly by category). Reference ranges may
differ depending on the instrument used. Refer to the laboratory-specific reference values provided with the individual's results.
CBC: complete blood count; RBC: red blood cell; MCV: mean corpuscular volume; fL: femtoliter; MCHC: mean corpuscular hemoglobin
concentration; RDW: red cell distribution width; WBC: white blood cell.
Data from:
1. Adeli K, Raizman JE, Chen Y, et al. Complex Biological Profile of Hematologic Markers across Pediatric, Adult, and Geriatric Ages: Establishment of Robust Pediatric and Adult
Reference Intervals on the Basis of the Canadian Health Measures Survey. Clinical Chemistry 2015; 61:1075.
2. Van den Bossche J, Devreese K, Malfait R, et al. Reference Intervals for a Complete Blood Count Determined on Different Automated Haematology Analysers: Abx Pentra 120
Retic, Coulter Gen-S, Sysmex SE 9500, Abbott Cell Dyn 4000 and Bayer Advia 120. Clin Chem Lab Med 2002; 40:69.
Graphic 127504 Version 6.0
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%), resulting in a 40% rise in blood volume and a
dilutional fall in the hematocrit.
Graphic 62723 Version 4.0
Reticulocyte parameters for assessing anemia
Absolute reticulocyte count (millions of cells/microL)
= Reticulocytes (%) × RBC count (millions of cells/microL)
Corrected reticulocyte count (%)
= Reticulocytes (%) × (observed patient HCT [percent] ÷ 45 [percent])
or
= Reticulocytes (%) × (observed patient hemoglobin [g/dL] ÷ 15 [g/dL])
Reticulocyte production index (no units)
= Corrected reticulocyte count (%) ÷ maturation correction factor* (days)
Reticulocyte parameters may be reported as an absolute count (cells per volume) or a relative measure (percent of total RBCs).[1] The reticulocyte
percentage may be corrected for the individual's hemoglobin or HCT and may be adjusted in severe anemia for the reticulocyte maturation time.
Refer to UpToDate topics on anemia for additional details.
RBC: red blood cell; HCT: hematocrit.
* Maturation correction (in days): HCT >35%: 1; HCT 26 to 35%: 1.5; HCT 16 to 25%: 2; HCT <15%: 2.5.
Reference:
1. Hillman RS. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest 1969; 48:443.
Graphic 129992 Version 1.0
Polychromatophilia due to increased reticulocytes
Peripheral blood smear taken from a patient with increased
reticulocytes. Unlike mature red cells (arrows), which have central
pallor and are the same size as the nucleus of a small lymphocyte
(arrowhead), reticulocytes (dashed 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.
Graphic 67042 Version 5.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Reticulocytes after supravital staining
Supravital stain of a peripheral blood smear shows blue-stained
residual reticulin (ribosomal RNA) in reticulocytes.
Courtesy of Stanley L Schrier, MD.
Graphic 74294 Version 3.0
Prolongation of reticulocyte maturation time in
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: Normal erythropoiesis. In: Hematology in Clinical Practice, Hillman
RS, Ault KA (Eds), McGraw-Hill, New York. p.29.
Graphic 61552 Version 3.0
Anemia evaluation in outpatients (nonpregnant adults)
This algorithm addresses anemia in healthy outpatients, which is often an incidental finding or may be identified when a CBC
is performed to evaluate mild symptoms such as fatigue. It is not appropriate for individuals who are acutely ill with fever,
bleeding, neurologic symptoms, or any severe cytopenia (hemoglobin <7 to 8 g/dL; platelet count <50,000/microL, absolute
neutrophil count [ANC] <1000/microL). Consider the history, CBC, MCV, and reticulocyte count (if available) simultaneously.
Refer to UpToDate for details of testing for specific causes of anemia.
CBC: complete blood count; MCV: mean corpuscular volume; ACD/AI: anemia of chronic disease/anemia of inflammation;
TSAT: transferrin saturation; MDS: myelodysplastic syndrome; RBC: red blood cell.
* Iron studies include serum iron, transferrin, ferritin, and transferrin saturation (TSAT).
¶ Ferritin <30 ng/mL or TSAT <19% are generally used as evidence of iron deficiency. Ferritin is an acute phase reactant and
may be higher in individuals with chronic inflammatory conditions.
Δ Other causes of anemia include monoclonal gammopathies, androgen deficiency (male), MDS, clonal cytopenias, copper
deficiency, and others. Multiple causes may be present. The risks of clonal disorders and hematologic malignancies generally
increases with age or exposure to bone marrow toxins including certain chemotherapy drugs. Aplastic anemia and DiamondBlackfan anemia are less age dependent.
◊ The reticulocyte count is helpful in narrowing the diagnosis of unexplained anemia. A high reticulocyte count typically
indicates hemolysis; recovery from bleeding; removal of a bone marrow insult (drug or infection); or repletion of iron, folic
acid, or vitamin B12. Genetic causes of hemolytic anemia may be associated with a positive family history and often have
characteristic RBC morphologies on the blood smear that can be useful in guiding the evaluation.
Graphic 130710 Version 3.0
Mechanisms of drug-associated anemia
Type of anemia
Iron deficiency
Mechanism(s)
Gastrointestinal mucosal irritation
Examples of implicated medications
Aspirin
NSAIDs
Glucocorticoids
Vitamin B12 deficiency
Impaired absorption due to
Proton pump inhibitors
increased gastric pH
H2 receptor blockers
Antacids
Folate deficiency
Altered calcium homeostasis
Metformin
Inactivation
Nitrous oxide
Interference with folate
Methotrexate
metabolism
Certain antibiotics (trimethoprim, pyrimethamine)
Antiseizure medications (phenytoin, valproate, carbamazepine)
Hemolysis
Immune-mediated
Antibiotics
Anti-cancer drugs
Lorazepam
Others (refer to separate UpToDate table for extensive list)
Oxidative stress
Antibiotics (primaquine, dapsone)
Phenazopyridine
Others (refer to separate UpToDate table)
Methemoglobinemia
Benzocaine (topical)
Lidocaine
Nitrites
Thrombotic microangiopathy
Quinine
Chemotherapy agents (gemcitabine, others)
Immunosuppressive therapies
Others (refer to separate UpToDate table)
Impaired bone marrow
Impaired DNA synthesis
function
Hydroxyurea
Chemotherapy agents
Sideroblastic anemia
Isoniazid
Chloramphenicol
Linezolid
Chemotherapy agents
Zinc
Myelodysplastic syndrome
Alkylating agents (melphalan, cyclophosphamide, carboplatin, cisplatin,
others)
Topoisomerase II inhibitors (vincristine, vinblastine)
Others
Numerous medicines can cause anemia by a variety of mechanisms; this table is only intended to illustrate selected examples. Iron deficiency and
vitamin deficiencies should be corrected by repletion of iron or vitamins as appropriate. Additional evaluations for a source of gastrointestinal
blood loss are generally indicated. Refer to UpToDate topics on specific causes of anemia for details of the mechanisms, likelihood of anemia,
evaluation, and management.
NSAIDs: nonsteroidal antiinflammatory drugs.
Graphic 131773 Version 2.0
Laboratory findings in hemolysis and hemolytic anemia
Finding
Anemia*
Change in hemolytic anemia
Decreased hemoglobin
Decreased hematocrit
Bone marrow response/recovery
Increased reticulocyte count
Underestimation of HbA1C
Release of RBC contents
Increased LDH
Increased indirect bilirubin
Decreased haptoglobin
Hemoglobinemia in intravascular hemolysis¶
Hemoglobinuria in intravascular hemolysis¶
RBC morphology changesΔ
Spherocytes or microspherocytes in immune hemolysis
Schistocytes in microangiopathic hemolysis
Blister or bite cells in oxidant injury
Sickle cells in sickle cell disease
Target cells and teardrop cells in thalassemia
Intravascular hemolysis often starts acutely and can be a medical emergency associated with DIC, AKI, and hypotension. Extravascular hemolysis
can be chronic. Severe hemolysis can have intravascular and extravascular features. Values for HbA1C may be lower due to increased RBC turnover.
Refer to UpToDate for details of the evaluation, interpretation of laboratory findings, use of the Coombs (antiglobulin) test, and management.
HbA1C: glycosylated (glycated) hemoglobin; RBC: red blood cell; LDH: lactate dehydrogenase; DIC: disseminated intravascular coagulation; AKI:
acute kidney injury.
* The presence and severity of anemia depends on the degree of hemolysis and capacity of the bone marrow to compensate by increasing
erythropoiesis.
¶ Intravascular hemolysis can be a medical emergency with free hemoglobin in the blood and associated with complications including DIC and
acute renal failure. Findings associated with intravascular hemolysis may include schistocytes on the blood smear, hemoglobinemia (with red
serum), hemoglobinuria (with dark or red urine), and hemosiderinuria in the urine sediment.
Δ Refer to UpToDate for additional details of these and other RBC morphologies and their implications.
Graphic 126234 Version 3.0
Partial list of medicines and other substances thought to be unsafe or safe in individuals with G6PD deficiency
Medicines and other substances likely to be UNSAFE in moderate to severe G6PD deficiency*
Medications
Chlorpropamide
Dabrafenib
Dapsone (diaminodiphenyl sulfone)
Fluoroquinolones (ciprofloxacin, moxifloxacin, norfloxacin, ofloxacin)¶
Methylene blue (methylthioninium chloride)Δ
Nalidixic acid◊
Nitrofurantoin, nifuratel, and nitrofurazone (nitrofural)◊
Phenazopyridine (pyridium)
Primaquine and tafenoquine
Rasburicase and pegloticase
Sulfonylureas (eg, glipizide, glyburide [glibenclamide])
Chemical exposures and foods
Fava beans
Henna compounds (black and red Egyptian)
Naphthalene (mothballs, lavatory deodorant)
Phenylhydrazine
"RUSH" (isobutyl nitrite, amyl nitrite)
Medicines that are PROBABLY SAFE given in usual therapeutic doses in G6PD deficiency*; NOTE: some of these were
previously considered unsafe; safety in Class I variants is generally not known
Acetaminophen (Tylenol, Paracetamol)
Aminophenazone, dipyrone, and metamizole (NSAIDs)◊
Antazoline (antihistamine)
Antipyrine (phenazone)
Ascorbic acid (vitamin C)
Aspirin (acetylsalicylic acid)
Benzhexol (Artane)
Chloramphenicol
Chloroquine and hydroxychloroquine
Colchicine
Clotrimazole
Diphenhydramine (Benadryl)
Isoniazid
Levodopa (L-Dopa) and levodopa-carbidopa
Para-aminosalicylic acid
Para-aminobenzoic acid (PABA)
Phenylbutazone
Phenytoin
Probenecid (Benemid)
Procainamide (Pronestyl)
Pyrimethamine (Daraprim)
Quinine
Streptomycin
Sulfa-containing drugs§ (sulfacetamide, sulfadiazine, sulfamethoxazole [Gantanol], trimethoprim-sulfamethoxazole, sulfamethoxypyridazine
[Kynex], sulfanilamide, sulfisoxazole [Gantrisin])
Tiaprofenic acid
Trimethoprim
Tripelennamine (Pyribenzamine)
Vitamin K
This is a general list and may not apply to all G6PD-deficient individuals. Use clinical judgment, and refer to UpToDate discussions, patient history,
and other resources for additional information.
G6PD: glucose-6-phosphate deficiency; NSAIDs: nonsteroidal antiinflammatory drugs.
* Applies to Class I, II, and III G6PD variants. However, note that there is marked variability in reports. This list is based on evidence supporting a
clear association with drug-induced hemolysis. Individual characteristics (ie, degree of G6PD deficiency, dose, presence of infection) will determine
actual safety or injury. Medicines known to be unsafe in G6PD deficiency that are no longer in clinical use are excluded from this list. In cases where
the patient truly requires the medication and G6PD status is unknown, it may be appropriate to administer and monitor closely.
¶ Levofloxacin is not listed because some cases of hemolytic anemia with levofloxacin have been associated with a positive Coombs test.
Δ Methylene blue is a component of some combination urinary tract products.
◊ Not available in the United States.
§ Sulfamethoxazole is widely used. Some cases of hemolysis in individuals with G6PD deficiency have been reported. Use with caution.
References:
1. ​Beutler E. Glucose-6-phosphate dehydrogenase deficiency: A historical perspective. Blood 2008; 111:16.
2. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371:64.
3. G6PD deficiency favism association website: http://www.g6pd.org/en/G6PDDeficiency/SafeUnsafe/DaEvitare_ISS-it.
4. Luzzatto L, Ally M, Notaro R. Glucose-6-Phosphate Dehydrogenase Deficiency. Blood 2020.
5. Luzzatto L, Seneca E. G6PD deficiency: A classic example of pharmacogenetics with on-going clinical implications. Br J Haematol 2014; 164:469.
6. Youngster I, Arcavi L, Schechmaster R. Medications and glucose6-phosphate dehydrogenase deficiency. Drug Saf 2010; 33:713.
Graphic 74254 Version 25.0
Conceptual framework for inherited hemolytic anemias
Hemoglobinopathies and membrane disorders tend to have characteristic abnormalities of RBC morphology on the peripheral blood smear.
Membrane disorders may have nonspecific findings or bite cells on the blood smear. Refer to UpToDate for other distinguishing features among these
conditions and the approach to diagnostic testing.
RBC: red blood cell; LDH: lactate dehydrogenase; Hb: hemoglobin; G6PD: glucose-6-phosphate dehydrogenase; PK: pyruvate kinase; SAO: Southeast
Asian ovalocytosis; HPP: hereditary pyropoikilocytosis.
* Hemoglobinopathies can often coexist (eg, sickle-beta thalassemia; Hb E-beta thalassemia; Hb SC disease). Not all forms of thalassemia cause
hemolysis; hemolysis is seen with hemoglobin H disease and transfusion-dependent beta thalassemia, but not with milder forms of thalassemia such
as one or two alpha globin gene deletions or heterozygous beta thalassemia.
Graphic 117376 Version 4.0
Bite and blister cells
Examples of a bite cell (thick arrow) and blister cells (arrows) in a patient with G6PD deficiency.
Courtesy of Bertil Glader, MD, PhD, and Bessie Visco, CLS, MLS (ASCP).
Graphic 117737 Version 1.0
Peripheral blood smear in beta thalassemia
intermedia
Peripheral smear from a patient with beta thalassemia intermedia
postsplenectomy. This field shows target cells, hypochromic cells,
microcytic cells, red cell fragments, red cells with bizarre shapes, and
a single nucleated red cell (arrow).
Courtesy of Stanley Schrier, MD.
Graphic 76666 Version 4.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Spherocytes
Peripheral blood smear shows multiple spherocytes, which are
small, dark, dense hyperchromic red cells without central pallor
(arrows). These findings are compatible with hereditary
spherocytosis or autoimmune hemolytic anemia.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 70611 Version 5.0
Elliptical red cells in hereditary elliptocytosis
Peripheral blood smear from a patient with hereditary elliptocytosis
shows multiple elliptocytes.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 63129 Version 4.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Stomatocytosis
Peripheral blood smear showing multiple stomatocytes
characterized by a mouth-shaped area of central pallor.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 75535 Version 2.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Serum erythropoietin levels in anemia
This graph indicates the exponential relationship between serum
erythropoietin levels (EPO, milliUnits/mL, logarithmic scale) and
venous hematocrit (percent, linear scale) in normal and anemic
subjects without renal or chronic diseases. EPO was assayed by
either bioassay or radioimmunoassay.
Adapted from:
1. Erslev AJ, Caro J. Physiologic and molecular biology of erythropoietin. Med
Oncol Tumor Pharmacother 1986; 3:159.
2. Erslev AJ, Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic patients.
J Lab Clin Med 1987; 109:429.
Graphic 53916 Version 4.0
Leukoerythroblastic peripheral blood 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, primary myelofibrosis) or reactive to conditions such
as metastatic cancer.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 68110 Version 3.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Teardrop-shaped red blood cells (dacrocytes)
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).
Graphic 55274 Version 4.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Causes of pancytopenia (organized by mechanism*)
Acquired
Bone marrow infiltration/replacement
Malignant
Acute leukemias
Chronic leukemias/myeloproliferative neoplasms (MPN)
Myelodysplastic syndromes (MDS)
Multiple myeloma
Metastatic cancer
Non-malignant
Myelofibrosis
Infectious (eg, fungal, tuberculous)
Storage diseases
Bone marrow failure
Immune destruction/suppression
Aplastic anemia/paroxysmal nocturnal hemoglobinuria
Medications¶
Cytotoxic drugs
Idiosyncratic reactions to medications
Large granular lymphocyte leukemia
Autoimmune disorders (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], sarcoidosis)
Hemophagocytic lymphohistiocytosis (HLH)
Nutritional
Megaloblastic (vitamin B12, folate)
Excessive alcohol
Other (eg, copper deficiency, zinc toxicity)
Malnutrition/anorexia nervosa with gelatinous degeneration
Marrow suppression
Viral infection (eg, HIV, hepatitis, Epstein-Barr virus [EBV])
Ineffective hematopoiesis (eg, MDS, nutritional)
Destruction/sequestration/redistribution
Consumption
Disseminated intravascular coagulation (eg, associated with sepsis, acute promyelocytic leukemia)
Splenomegaly
Portal hypertension/cirrhosis
Infections (eg, EBV)
Autoimmune disorders (eg, SLE, RA/Felty syndrome)
Malignancies (eg, lymphomas, MPN)
Myelofibrosis with myeloid metaplasia
Storage diseases (eg, Gaucher)
Congenital
Wiskott Aldrich syndrome
Fanconi anemia
Dyskeratosis congenital/telomere biology disorders
Shwachman-Diamond syndrome
GATA2 deficiency
Hemophagocytic lymphohistiocytosis (HLH)
* Note that some disorders are included in more than one category, as they may cause cytopenias by multiple mechanisms (eg, lymphomas may be
associated with bone marrow failure due to marrow replacement, increased sequestration due to splenomegaly, and immune destruction).
¶ Refer to accompanying table of drugs associated with cytopenias.
Graphic 112134 Version 4.0
Major causes of acquired aplastic anemia
Idiopathic
Cytotoxic drugs and radiation
Cancer treatment (anticipated effect)
Drug reaction
Anti-seizure agents: carbamazepine, phenytoin, others
Antibiotics: sulfonamides, chloramphenicol
Nonsteroidal anti-inflammatory drugs (NSAIDs): phenylbutazone, indomethacin
Anti-thyroid medications: methimazole, propylthiouracil
Gold
Arsenicals
Toxic chemicals
Benzene
Solvents
Glue vapors
Viral infections
Epstein-Barr virus
Seronegative (non-A through -G) hepatitis
Human immunodeficiency virus (HIV)
Other herpes viruses
Immune disorders
Eosinophilic fasciitis
Systemic lupus erythematosus
Graft-versus-host disease
Miscellaneous
Paroxysmal nocturnal hemoglobinuria
Thymoma
Pregnancy
Anorexia nervosa
Graphic 70072 Version 7.0
Peripheral blood smear showing megaloblastic
changes
Peripheral blood smear showing a hypersegmented neutrophil
(seven lobes) and macroovalocytes, a pattern that can be seen with
vitamin B12 (cobalamin) or folate deficiency.
Courtesy of Stanley L Schrier, MD.
Graphic 58820 Version 5.0
Hypersegmented neutrophil in megaloblastic
anemia
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
fewer.
Courtesy of Stephen A. Landaw, MD, PhD.
Graphic 70609 Version 4.0
Common causes of hemolysis and hemolytic anemia in adults
Non-immune causes
Hereditary
Enzyme deficiencies (eg, deficiencies of G6PD, pyruvate kinase, glucose-phosphate isomerase, 5' nucleotidase)
Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable hemoglobins)
Membrane defects (eg, hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis)
Acquired
Liver disease
Hypersplenism
Infections (eg, Bartonella, Babesia, malaria, clostridial sepsis)
Oxidant agents (eg, dapsone, nitrites, aniline dyes)
Toxins (eg, lead, copper, snake and spider bites)
Infusion of a hypotonic solution
Microangiopathic hemolytic anemia (eg, TTP, HUS, aortic stenosis, prosthetic valve leak)
Immune causes
Warm autoimmune hemolytic anemia
Drug-induced immune hemolysis
Transfusion reactions (eg, ABO incompatibility, alloantibodies)
Paroxysmal cold hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Cold agglutinin disease
Intravenous infusion of IVIG or anti-RhD immune globulin
Non-immune causes generally have a negative Coombs test (also called direct antiglobulin test [DAT]); immune causes are typically DAT-positive.
Refer to UpToDate for an approach to the evaluation. Any form of hemolytic anemia can lead to an underestimation of the hemoglobin A1C
(HbA1C).
G6PD: glucose-6-phosphate dehydrogenase; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic uremic syndrome; IVIG: intravenous
immune globulin.
Graphic 72394 Version 17.0
Causes of microcytic anemia (MCV <80 fL)
Common
Hereditary
Rare
Alpha thalassemia
Other thalassemic variants (Hb E, Hb Lepore)
Beta thalassemia
X-linked and other sideroblastic anemias
Hereditary hypotransferrinemia
Hereditary aceruloplasminemia
Erythropoietic protoporphyria
Iron-refractory iron deficiency anemia
Pathogenic variants in SLC11A2
Acquired
Iron deficiency
Lead poisoning
ACD/AI*
Zinc deficiency
Copper deficiency¶
AlcoholΔ
Certain drugs
Refer to UpToDate for details of the evaluation and other rare causes of microcytic anemia.
MCV: mean corpuscular volume; Hb: hemoglobin; ACD/AI: anemia of chronic disease/anemia of inflammation.
* ACD/AI often causes normocytic rather than microcytic anemia.
¶ Copper deficiency may be due to zinc toxicity.
Δ Excess alcohol use can cause multifactorial anemia from iron deficiency, folate deficiency, hemolysis, and/or direct bone marrow suppression. The
MCV may be low, normal, or high.
Graphic 138464 Version 1.0
Basophilic stippling of red cells in lead poisoning
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).
Graphic 71989 Version 4.0
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several
platelets (arrowheads) and a normal lymphocyte (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 (dashed
arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 59683 Version 5.0
Causes and mechanisms of macrocytosis
Abnormalities of DNA metabolism
Vitamin B12 (cobalamin) deficiency
Folate deficiency
Drugs
Antiretroviral therapies for HIV infection (eg, zidovudine)
Azathioprine or 6-mercaptopurine
Capecitabine
Cladribine
Cytosine arabinoside
Hydroxyurea
Imatinib, sunitinib
Methotrexate
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
Some sideroblastic anemias
Large granular lymphocyte (LGL) leukemia
Lipid abnormalities
Liver disease
Hypothyroidism
Mechanism unknown
Alcohol abuse
Multiple myeloma and other plasma cell disorders
Graphic 66772 Version 3.0
Rouleaux formation in multiple myeloma
Peripheral blood smear from a patient with multiple myeloma shows
red blood cell rouleaux (arrows), giving the appearance of stacked
coins.
Courtesy of Carola von Kapff, SH (ASCP).
Graphic 74369 Version 3.0
Causes of anemia in adults
Reticulocyte count
RBC size/
MCV
Low or normal*
Increased
Microcytic
Iron deficiency (late)
Thalassemia
MCV <80 fL
Anemia of chronic disease/inflammation
Hemolysis¶
Normocytic
Bleeding (acute)
Bleeding (with bone marrow recovery)
MCV 80 to 100 fL
Iron deficiency (early)
Hemolysis¶
Anemia of chronic disease/inflammation
Bone marrow recovery (eg, after infection, vitamin B12
Bone marrow suppression (cancer, aplastic anemia,
or folate replacement, and/or iron replacement)
Sideroblastic anemias
infection)
Chronic renal insufficiency
Hypothyroidism
Hypopituitarism
Excess alcohol
Copper deficiency/zinc poisoning
Macrocytic
Vitamin B12 or folate deficiency
Hemolysis¶
MCV >100 fL
Excess alcohol
Bone marrow recovery (eg, after infection, vitamin B12
Myelodysplastic syndrome
or folate replacement, and/or iron replacement)
Liver disease
Hypothyroidism
HIV infection
Medications that interfere with nuclear maturation
(hydroxyurea, methotrexate, some chemotherapy
agents)
Review of the RBC morphology is critical to the assessment of many anemias. Refer to UpToDate for features of specific causes of anemia and
discussions of the approach to the patient evaluation.
RBC: red blood cell; MCV: mean corpuscular volume; fL: femtoliters.
* A reticulocyte count in the normal range (especially the lower end of the normal range) may be inappropriately low in an individual with
significant anemia and may suggest a component of impaired bone marrow function.
¶ Hemolysis typically is associated with a normal or high MCV. Microcytosis is generally restricted to types of hemolysis with RBC fragmentation.
Hemolysis is typically associated with some degree of macrocytosis because reticulocytes are larger than mature RBCs.
Graphic 122070 Version 4.0
Contributor Disclosures
Robert T Means, Jr, MD, MACP Consultant/Advisory Boards: Pharmacosmos Therapeutics Inc.[Iron deficiency in pregnancy]. All of the relevant financial
relationships listed have been mitigated. Robert A Brodsky, MD Grant/Research/Clinical Trial Support: Alexion [PNH]. Consultant/Advisory Boards:
Alexion [PNH, aHUS]. All of the relevant financial relationships listed have been mitigated. William C Mentzer, MD Equity Ownership/Stock Options:
Johnson & Johnson [Anemia]. All of the relevant financial relationships listed have been mitigated. Jennifer S Tirnauer, MD No relevant financial
relationship(s) with ineligible companies to disclose. Lisa Kunins, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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