Evaluation of Anemia

Evaluation of anemia
Straight to the point of care
Last updated: Mar 24, 2021

Table of Contents
Overview 3
Summary 3
Theory 6
Etiology 6
Emergencies 15
Urgent considerations 15
Diagnosis 18
Approach 18
Differentials overview 28
Differentials 31
References 59
Images 66
Disclaimer 74
Evaluation of anemia Overview
Summary
Anemia is a hemoglobin (Hb) level two standard deviations below the mean for the age and sex of the
patient. Reference ranges vary between laboratories. The World Health Organization defines anemia as:[1]
OVERVIEW
Hb <11 g/dL in children under 5 years and in pregnant women
Hb <11.5 g/dL in children ages 5 to 11 years
Hb < 12 g/dL in children ages 12 to 14 years and in women (ages over 15 years)
Hb <13 g/dL in men (ages over 15 years)
The American Society of Hematology defines anemia as <13.5 g/dL in men and <12 g/dL in women.
Anemia is the most common hematologic disorder seen in general medical practice. Risk factors include
extremes of age, female sex, lactation, and pregnancy. The most common cause internationally is iron
deficiency.[2]
Anemia can cause significant morbidity if left untreated, and is often the presenting sign of a more serious
underlying condition.[3] The rate at which anemia develops is often as important as the severity, as a rapid
decline can overwhelm the compensatory mechanisms of the body.
Pathophysiology
Erythropoiesis takes place within the bone marrow and is controlled by the stromal network, cytokines, and
the hormone erythropoietin. A series of differentiation steps results in the generation of reticulocytes (red
blood cells [RBCs] with an intact ribosomal network).
Reticulocytes remain in the bone marrow for 3 days before being released into the circulation. After one
further day in the circulation, reticulocytes lose their ribosomal network and become mature RBCs, which
circulate for 110-120 days before being removed from the circulation by macrophages.
At steady state, the rate of RBC production equals the rate of RBC loss. Anemia develops when the rate of
RBC production decreases and/or the rate of RBC loss increases.
Morphological classification of anemia

The most clinically useful classification system is based on the mean corpuscular volume (MCV).[4]
• Microcytic (MCV <80 femtoliters [fL]).
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 24, 2021.
BMJ Best Practice topics are regularly updated and the most recent version
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OVERVIEW Evaluation of anemia Overview
Microcytic anemia
From the collection of Dr Robert Zaiden; used with permission
• Normocytic (MCV 80-100 femtoliters [fL]); further subclassified according to the reticulocyte count as:
• Hyperproliferative (reticulocyte count >2%): the proportion of circulating reticulocytes increases

as part of a compensatory response to increased destruction or loss of RBCs. The cause is
usually acute blood loss or hemolysis.
• Hypoproliferative (reticulocyte count <2%): these are primarily disorders of decreased RBC
production, and the proportion of circulating reticulocytes remains unchanged.
• Macrocytic (MCV >100 femtoliters [fL]); further subclassified as:
• Megaloblastic: a deficiency of DNA production or maturation resulting in the appearance of large

immature RBCs (megaloblasts) and hypersegmented neutrophils in the circulation.
• Nonmegaloblastic: encompasses all other causes of macrocytic anemia in which DNA synthesis
is normal. Megaloblasts and hypersegmented neutrophils are absent.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 24, 2021.
Evaluation of anemia Overview
OVERVIEW
Megaloblastic macrocytic anemia
Classification of anemia: MCV, mean corpuscular volume; fL, femtoliters

Created by the BMJ Knowledge Centre
5
Evaluation of anemia Theory
Etiology
Anemia occurs when the production of red blood cells (RBCs) is decreased, the destruction of RBCs is
accelerated, or there is a loss of RBCs due to bleeding. In many cases, a combination of these mechanisms
THEORY
is present.
Risk factors include extremes of age, female sex, lactation, and pregnancy.
Nutrient deficiency, acquired bone marrow disease, drugs, toxins, chronic systemic diseases and genetic
diseases may all lead to reduced RBC production. The resulting anemia can be microcytic, hypoproliferative
normocytic or macrocytic, depending on the cause.
Microvascular diseases, infections and drugs and genetic disorders may cause hemolytic anemia.
Hemolytic anemias are a group of anemias resulting from increased destruction of RBCs with a resultant
increase in circulating indirect bilirubin.[4] [5] The resulting anemia can be microcytic or hyperproliferative
normocytic, depending on the cause.
Acute hemorrhage causes a normocytic anemia and reticulocytosis occurs within 6 hours of the onset of
bleeding. By contrast, chronic slow bleeding causes microcytic anemia due to ongoing iron loss leading to
deficiency.
Nutrient deficiency or depletion

Iron deficiency anemia[6] [7]
• The most common cause of anemia worldwide.

• The formation of the heme moiety in hemoglobin, myoglobin, and cytochrome requires iron;
inadequate intake or absorption of iron, or excessive iron loss, leads to a microcytic anemia.
• At least 10% of women in the US between the ages of 12 and 49 years are iron deficient. 22% of
Mexican-American women and 19% of non-Hispanic black women in the US are iron deficient.[8]
• Inadequate iron intake: meat provides the main source of heme iron, and iron deficiency is common in
geographic regions where meat is sparse and there is poor dietary iron intake.
• Iron malabsorption occurs due to achlorhydria, gastric surgery, chronic pancreatitis, gallstones,
destruction of small bowel absorptive area in chronic diseases such as celiac disease, intestinal wall
edema in heart failure, or following extensive resection of the proximal small bowel.
• Excessive iron loss: gradual prolonged bleeding due to any cause produces iron depletion, because
two-thirds of the total body iron is contained in circulating hemoglobin (Hb). Menstruation and occult
gastrointestinal bleeding are the most common causes. Hemoglobinuria (iron loss in the urine) is rare.
The usual cause is paroxysmal nocturnal hemoglobinuria, but hemoglobinuria can occur following
rapid intravascular hemolysis of any cause.
Vitamin B12 deficiency[9]
• Vitamin B12 is an essential cofactor in DNA synthesis, which is obtained only from the diet or by
supplementation.
• Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs.
• Deficiency produces neurologic disorders and megaloblastic anemia.
• Decreased dietary intake may occur in chronic malnutrition, alcohol abuse, and strict vegan diets.
• Diminished breakdown of dietary vitamin B12 may be due to pernicious anemia, previous gastric or
intestinal surgery, or atrophic gastritis.
• Malabsorption occurs in gastric malabsorption, Crohn disease, celiac disease and bacterial
overgrowth.
THEORY
Folate deficiency[9]
• Folate is an essential cofactor in DNA synthesis, which is obtained only from the diet or by
supplementation.
• Dietary sources include green leafy vegetables, citrus fruits, and animal products.
• Deficiency produces a range of signs, including a glossitis; angular stomatitis; patchy
hyperpigmentation of the skin and mucous membranes; a persistent mild pyrexia (in the absence of
infection); and megaloblastic anemia.
• Common causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, dietary
restriction of protein intake), impaired absorption (achlorhydria, celiac disease, tropical sprue, zinc
deficiency, bacterial overgrowth), and increased folate requirement (infancy, pregnancy, lactation,
malignancy).
• Patients with vitamin B12 deficiency can have excessive renal folate excretion. Similarly, chronic
alcohol abuse can lead to excessive biliary folate excretion.
• Rarely, hypothyroidism and congenital enzyme deficiencies may impair folate metabolism.
Generalized malnutrition
• Often causes iron deficiency.

• Patients often have associated vitamin B12 and/or folate deficiency, in which case the resulting anemia
is normocytic.
• Associated copper deficiency is rare, but should be considered in patients on prolonged total
parenteral nutrition.
Acquired bone marrow disease

Myelodysplastic syndrome[10]
• A heterogeneous group of clonal stem cell disorders. Uncontrolled proliferation and clonal expansion
of neoplastic multipotential hematopoietic stem cells compromise the production of normal cells,
producing a range of cytopenias.
• Usually due to acquired chromosomal abnormalities, but can be caused by chemotherapy or radiation
therapy.
• The anemia is a nonmegaloblastic macrocytic anemia, but the peripheral blood smear may show
hypersegmented neutrophils similar to those seen in megaloblastic macrocytic anemias. A normal
random distribution of red cell width in the setting of macrocytic anemia in an older adult should raise
this suspicion.
Leukemias
• Acute lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia are
caused by the uncontrolled proliferation and clonal expansion of abnormal progenitor cells. These
diseases affect progenitor cells at different stages of the differentiation process, but all cause anemia
by compromising the production of normal RBCs.
Infiltration of the bone marrow by secondary malignancy
7
• Metastasis of solid tumors to the bone marrow can cause anemia by infiltration of the marrow space.
Any tumor can metastasize to the bone marrow, but the most commonly seen are neuroblastoma in
children, and breast, prostate, and lung cancer in adults. Metastasis to the bone marrow is a poor
prognostic sign.
THEORY
Aplastic anemia[11]
• A disorder of stem cell failure, leading to pancytopenia in the absence of splenomegaly.
• Can be due to an inherited bone marrow failure syndrome or acquired (induced by a variety of
disorders, e.g., autoimmune or toxic) where immune mechanisms with local activation of interferon
gamma may be a common etiologic pathway.
• Affected patients typically present with recurrent infections due to neutropenia, bleeding episodes due
to thrombocytopenia, and, less often, fatigue due to anemia.
• Toxic causes include benzene, dipyrone, chloramphenicol, penicillamine, and gold.
• Definitive diagnosis is established following bone marrow aspiration and biopsy.
Pure red cell aplasia
• Caused by congenital or acquired impairment of erythroid progenitor cells.

• Acquired forms can be self-limited or chronic.
• Self-limited acquired disease can be caused by infections or medications. The most common
infectious cause is parvovirus B19. Other infectious causes include infectious mononucleosis, viral
hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.
• Certain medications exert a toxic effect on erythroid progenitor cells that is reversible once the
medication is discontinued. Examples include phenytoin, carbamazepine, sodium valproate,
azathioprine, chloramphenicol, sulfonamides, isoniazid, and procainamide.
• Chronic acquired disease is caused by autoimmune diseases (e.g., systemic lupus erythematosus,
rheumatoid arthritis, dermatomyositis, polyarteritis nodosa, scleroderma), persistent infection
(persistent parvovirus B19 infection in immunosuppressed patients, chronic active hepatitis), and
thymomas.
• Congenital forms are produced by in-utero damage of erythroid progenitor cells. The cause is
unknown.
Toxin exposure
Drugs
• Drugs may cause anemia through multiple mechanisms, including: immune-mediated or direct RBC
hemolysis; interference with DNA synthesis; impaired absorption, metabolism, or action of important
DNA synthesis cofactors; or a toxic effect on progenitor cells in the bone marrow.
• Hemolytic anemia: common culprits include penicillin, methyldopa, levodopa, quinidines,
cephalosporins, and some non-steroidal anti-inflammatory drugs (NSAIDs).
• Drugs that directly interfere with DNA synthesis include purine analogs (6-mercaptopurine,
6-thioguanine, acyclovir), pyrimidine analogs (5-fluorouracil, 5-azacytidine, zidovudine), and
ribonucleotide reductase inhibitors (hydroxyurea, cytarabine arabinoside).
• Drugs that affect DNA synthesis cofactors include: methotrexate and trimethoprim (impair folic
acid function); phenytoin, phenobarbital and primidone (interfere with folate absorption); and p-
aminosalicylic acid, metformin, colchicine, and neomycin (interfere with B12 metabolism).
• Drugs and chemicals that produce a toxic effect on a range of progenitor cells include benzene,
THEORY
chloramphenicol, penicillamine, and gold.
• Drugs that produce a toxic effect on erythroid progenitor cells, producing pure red cell aplasia,
include antiepileptic medications (phenytoin, carbamazepine, valproate sodium), azathioprine,
chloramphenicol (which can also cause aplastic anemia), sulfonamides, isoniazid, and procainamide.
• Drugs that inhibit erythroid stimulation and suppress erythropoietin production include ACE inhibitors
and angiotensin-II receptor blockers.[12]
Radiation exposure
• Radiation exposure can produce a pancytopenia.
Lead toxicity
• Occurs after occupational or home exposure to lead. Anemia can occur because lead competes with
zinc, an important cofactor in heme synthesis. Some patients also have a concurrent iron deficiency
anemia.
Alcohol abuse
• Long-term alcohol intake directly suppresses the bone marrow, independent of any concurrent liver
disease or vitamin deficiency. The effect resolves only after months of abstinence, and may persist
even after normalization of vitamin B12 and folate levels.
Chronic systemic disease

Anemia of chronic disease[7] [13]
• Usually causes a mild hypoproliferative normocytic anemia. Coexisting iron deficiency produces a
microcytic anemia.
• It is caused by chronic inflammation. Proinflammatory cytokines, especially interleukin-6 (IL-6),
trigger a cascade of events, mediated via upregulation of hepcidin, that decrease RBC production
(by lowering serum iron and erythropoietin levels) and increase RBC destruction (by stimulating
erythrophagocytosis and oxygen free radical formation).[14]
• Common underlying processes include infection, neoplasms, autoimmune reactions, and injury to
tissue from trauma or major surgery.
• These underlying processes may coexist.
Chronic kidney disease[15]
• Produces a normocytic or microcytic anemia. The etiology is complex and multifactorial.

Decreased erythropoietin production, accumulation of erythropoiesis inhibitors and secondary
hyperparathyroidism all contribute.
• Chronic blood loss, inflammation, and nutritional deficiency cause an iron deficiency anemia. Patients
often need to reduce their protein intake, which leads to decreased meat in the diet and poor iron
intake. Poor iron absorption may also occur. Erythropoietin therapy and chronic inflammation can
cause functional iron deficiency, produced by an inability to mobilize iron stores effectively.
Chronic liver disease
9
• A mild to moderate nonmegaloblastic macrocytic anemia is produced by a combination of intravascular

dilution due to volume overload, increased RBC destruction, and impaired bone marrow compensatory
responses.
Hypothyroidism
THEORY
• Causes a mild hypoproliferative normocytic anemia due to the loss of the stimulatory effect of thyroid
hormones on erythropoiesis.
Heart failure
• Up to one third of patients with heart failure have anemia. Anemia of chronic disease, iron deficiency,
hemodilution and adverse effects of medication may all contribute.[16]
Inflammatory bowel disease
• Anemia associated with inflammatory bowel disease is often due to a combination of iron deficiency
and anemia of chronic disease.[17]
Hypogonadism
• Testosterone increases production of hematopoietic growth factors, and iron bioavailability, and
primary hypogonadism may cause anemia in older men.
Immune reactions
Autoimmune hemolytic anemia[18] [19]
• RBCs are attacked by autoantibodies and targeted for extravascular destruction. This usually occurs
either as part of other autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid
arthritis, or scleroderma) or in relation to a lymphoproliferative disorder (usually non-Hodgkin
lymphoma or chronic lymphocytic leukemia).
• Autoimmune diseases can also cause pure red cell aplasia.
Alloimmune hemolytic anemia
• Can be caused by transfusion reactions, usually due to ABO incompatibility.
Infections
Hemolytic anemia
• A range of infections can produce a hemolytic anemia, including cytomegalovirus, infectious

mononucleosis, and toxoplasmosis. Leishmaniasis produces combined RBC hemolysis, bone marrow
suppression, and blood loss.
• Causes of pure red cell aplasia include parvovirus B19, infectious mononucleosis, viral hepatitis,
malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.[20]
Genetic disorders
Thalassemias[21] [22]
• A group of autosomal-recessive genetic conditions that result in decreased or absent production of
THEORY
the alpha-globin (alpha-thalassemia) or beta-globin (beta-thalassemia) chains in the Hb molecule.
The decreased or absent globin production results in impairment of erythropoiesis. Increased RBC
destruction occurs, producing hemolytic anemia.
• Disease severity depends on the underlying mutations and ranges from asymptomatic to severe,
transfusion-dependent anemia with skeletal changes.
Sickle cell anemia[21]
• A hemolytic anemia caused by an autosomal-recessive single gene defect in the beta chain of Hb
(HbA), which results in sickle cell Hb. RBCs containing sickle cell Hb become rigid and are distorted
into a crescent shape.
• Patients are prone to episodes of vaso-occlusion due to the rigid, deformed RBCs, and a
prothrombotic state created by the accompanying leukocytosis, which increases cytokine release.
• Persistent pain in the abdomen, chest, or skeleton and dactylitis are the key presenting symptoms.
Hereditary spherocytosis
• A hemolytic anemia caused by an autosomal-dominant inherited abnormality of RBCs that produces

defects in the skeletal proteins of the red cell membrane. As a result, RBCs lose their biconcave
structure and become spherical (spherocytes). Spherocytes are fragile, and are selectively removed
and destroyed by the spleen. Increased RBC destruction leads to anemia with hyperbilirubinemia and
splenomegaly.
• Disease severity ranges from asymptomatic to a transfusion-dependent anemia with jaundice,
depending on the severity of the underlying membrane defect.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency[23]
• An inherited (X-linked) hemolytic anemia due to an enzyme deficiency that is common among
populations originating from parts of the world where malaria is or was common, such as sub-Saharan
Africa, Asia, the Mediterranean region, and the Middle East.
• G6PD catalyzes a reaction that is linked to the generation of reduced glutathione. RBCs rely solely on
reduced glutathione as an antioxidant defense, so deficiency of G6PD increases RBC destruction.
• The severity of the disease varies, depending on the severity of the underlying mutation. Most patients
are asymptomatic. Symptomatic disease produces episodes of acute hemolysis, with pallor and
jaundice, following exposure to oxidant stress.
• Triggers include fava beans (favism), sulfa drugs, aspirin, nitrofurantoin, naphthalene, and febrile
illness. The resulting hemolysis is usually self-limited. Life-threatening symptoms are more common
with the Mediterranean variant.
Congenital bone marrow failure syndromes
• Fanconi anemia is the most common. It is usually autosomal recessive, but can also be X-linked.
Mutations in 13 genes have been identified. The genes code for proteins that form a nuclear complex
involved in the DNA damage response. However, the precise mechanisms by which the mutations
produce bone marrow failure are not known.
11
• Dyskeratosis congenita is characterized by the triad of abnormal nails, reticulated skin rash, and
leukoplakia. X-linked, autosomal-dominant, and autosomal-recessive inheritance patterns have been
observed. The genetic defects all decrease telomerase function. Telomeres maintain chromosomal
stability, and the bone marrow is heavily dependent on telomere preservation to support its high rate of
THEORY
cell proliferation. Loss of telomerase produces bone marrow failure.

• Shwachman-Diamond syndrome is a rare autosomal-recessive disease that produces exocrine
pancreatic dysfunction, anemia, neutropenia (which can be intermittent), and skeletal abnormalities.
About 90% of patients harbor mutations in a gene known as the SBDS gene, but the relationship of
the mutations to bone marrow failure is not understood.
Microvascular disease
Microangiopathic hemolytic anemias are often considered as a group. They produce a hyperproliferative
normocytic anemia.
The underlying disease process produces endothelial damage and activates the coagulation cascade,
leading to fibrin deposition on the damaged endothelial surfaces. In small vessels, the endothelial fibrin
causes mechanical fragmentation and shearing of RBCs, leading to hemolysis. The irregular-shaped RBC
fragments produced by this process are called schistocytes and can be seen on a peripheral blood smear.
Hemolytic uremic syndrome[24]
• Damage to the endothelium of the glomerular bed produces hemolytic anemia, thrombocytopenia and
nephropathy.
• Causes include verotoxins, produced by Escherichia coli ; neuraminidase, produced by streptococcal
species; inherited defects in proteins that control complement; and drugs (cyclosporine and some
chemotherapy agents).
Disseminated intravascular coagulation (DIC)[25]
• An acquired syndrome produced by activation of coagulation pathways, resulting in the formation of

intravascular thrombi and the depletion of platelets and coagulation factors.
• DIC can be triggered by major trauma; burns; organ failure (pancreatitis, acute liver failure); sepsis or
severe infection; severe obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae,
retained dead fetus syndrome); malignancies (acute myelocytic leukemia or metastatic mucin-
secreting adenocarcinoma); major vascular disorders (hemangiomas, large aortic aneurysms); and
severe toxic or immunologic reactions.
Thrombotic thrombocytopenic purpura[26] [27]
• A clinical syndrome of microangiopathic hemolytic anemia and thrombocytopenic purpura.

• Believed to be due to the production of abnormally large von Willebrand factor (vWF) multimers. The
abnormal vWF triggers aggregation of circulating platelets at sites of high intravascular shear stress,
which in turn results in thrombi in the microvasculature system.
• Thrombocytopenia is produced by excessive consumption of platelets; purpura and other signs of
bleeding appear in a small proportion of patients. Thrombus formation in the microvasculature also
produces severe central nervous system symptoms and renal disease.
Hemangiomas[28]
• Vascular tumors that occur as a result of abnormal angiogenesis and overproliferation of blood
vessels. These range from obvious superficial lesions to internal organ hemangiomas.
• A local consumptive coagulopathy (Kasabach-Merritt syndrome) can occur as a complication, leading
to thrombus formation and thrombocytopenia. Shearing and fragmentation of RBCs against the clots in
THEORY
the small vessels of the hemangiomas can lead to a hemolytic anemia.
• Kasabach-Merritt syndrome can also produce DIC in severe cases.
Malignant hypertension
• A hypertensive emergency with systolic BP >210 mmHg and diastolic BP >130 mmHg, associated with
rapid deterioration of vital organ function. Common causes include untreated essential hypertension,
renal disease, eclampsia, use of sympathomimetic drugs, and use of monoamine oxidase inhibitors.
The disease is more common in older people, males, and those of black ethnicity.
• Causes endothelial injury and endothelial fibrin deposition. Mechanical RBC shearing and
fragmentation, resulting from high pressures and fibrin in the small vessels, produces hemolytic
anemia.
Prosthetic valves and surfaces[29]
• The shear stresses and turbulence created by the foreign surface cause shearing and fragmentation
of RBCs. Improved prosthetics have reduced the incidence of this complication, and the anemia, if it
occurs, is usually mild.
Blood loss
Acute hemorrhage
• Any acute hemorrhage can cause a normocytic anemia. A reticulocytosis is seen within 6 hours of
the onset of bleeding. By contrast, chronic slow bleeding leads to ongoing iron loss and produces a
microcytic anemia due to iron deficiency.
• The most common causes are trauma (including gunshot wounds, major fractures, or crush injuries),
acute gastrointestinal bleeding, rupture of a vascular aneurysm (especially abdominal aortic
aneurysm), and recent surgery.
• Patients are at increased risk of hemorrhage if they are taking anticoagulant therapy, have an
underlying defect in hemostasis, or have a consumptive or dilutional coagulopathy following repeated
blood transfusions.
Gradual, prolonged bleeding
• Bleeding due to any cause produces iron depletion, because two-thirds of the total body iron is
contained in circulating Hb.
• Excessive menstrual losses are a common cause in females.
• The gastrointestinal tract is a common site of bleeding. Common causes include hemorrhoids,
salicylate ingestion, peptic ulcer disease, hiatal hernia, diverticular disease, neoplastic disease, and
ulcerative colitis.
• Hookworm ( Necator americanus ) infection is rare in developed countries but is a significant cause of
iron-deficiency anemia in low and middle-income countries.[30]
• Rare causes include cows' milk allergy in infants, Meckel diverticulum, schistosomiasis, trichuriasis,
and hereditary hemorrhagic telangiectasia.
13
Rare sources of blood loss from other sites include pulmonary bleeding (seen in idiopathic pulmonary
hemosiderosis and Goodpasture syndrome), blood donation, and self-harm. In addition, any underlying
disorder that impairs hemostasis increases the risk of bleeding and iron deficiency anemia.
THEORY
Other causes
Pregnancy
• Anemia in pregnancy is common, with a prevalence of 2.1% in the US.[31] Prevalence is highest in

non-Hispanic black women and teenagers.[31] Worldwide, 38% of pregnant women are anemic.[32]
• Pregnancy increases physiologic demand on iron, which is needed for fetal brain and placental
development. In addition, the plasma volume expands out of proportion to the RBC mass causing
hemodilution.
• Iron deficiency in pregnancy is associated with an increased risk of maternal and perinatal morbidity
and mortality.[33]
• Anemia may be due to a dilutional effect, as the plasma volume expands out of proportion to the RBC
mass.
• Despite being an important problem in pregnancy with effective treatment available, there is a lack of
high-quality evidence on the benefits of a national screening program for anemia in pregnancy in terms
of reduced maternal and infant morbidity.[34]
Thermal burns
• Patients with burns affecting more than 10% of the body's surface area can develop hemolytic anemia
due to intravascular hemolysis of RBCs (at the site of the burn and systemically), loss of red cell mass
due to thrombus formation, and damage to RBCs from systemically released proteases and oxygen
free radicals.[35]
Hospital-acquired anemia
• New-onset anemia in hospitalized patients with previously normal hemoglobin. Hospital-acquired

anemia (HAA) is typically related to increased phlebotomy and iatrogenic blood loss from invasive
procedures or hemodilution. Acute inflammatory response to illness decreases compensatory
erythropoiesis. HAA is associated with increased morbidity and length of hospital stay.[36]
Evaluation of anemia Emergencies
Urgent considerations
(See Differentials for more details)
Anemia is life threatening if there is more than 40% loss of total body volume. These patients should
receive packed red blood cell (RBC) transfusions for stabilization as soon as possible, especially if there are
underlying cardiac or pulmonary comorbidities. A reticulocyte count, ferritin, and peripheral smear should be
obtained before transfusion, if possible, as this makes subsequent workup more accurate.
Dilutional, or consumptive, coagulopathy from tissue injury may result from the decrease of platelets and
coagulation factors (factor V, factor VIII, and fibrinogen) in massive transfusions and must be corrected by
the addition of these factors.
Clinical guidelines from the AABB (formerly known as the American Association of Blood Banks) suggest
a restrictive transfusion threshold of 7 g/dL in hospitalized hemodynamically stable patients, and 8 g/dL in
those undergoing orthopedic or cardiac surgeries, or with pre-existing cardiovascular disease, unless there is
an underlying acute coronary syndrome, severe thrombocytopenia, or chronic transfusion dependence.[37]
EMERGENCIES
Transfusion thresholds in ischemic coronary artery disease and resuscitation of septic shock remain
controversial.
Acute hemorrhage
Causes of acute hemorrhage include trauma, acute gastrointestinal bleeding, rupture of a vascular aneurysm
(especially abdominal aortic aneurysm), and recent surgery. Patients may report associated symptoms such
as hematemesis or hematochezia in acute gastrointestinal bleeding, or back or abdominal pain in the case of
a ruptured abdominal aortic aneurysm. Patients may feel lightheaded, clammy and nauseous.
Key signs include hypotension, pallor, cold clammy skin, thready pulse, tachycardia, dyspnea, and altered
mental status. Flat neck veins when supine indicate at least 30% to 40% total blood volume loss. All orifices
should be examined for bleeding. The mechanism and site of any trauma should also be determined.
Rapid evaluation, identification, and control of bleeding are essential before any further workup. Dilution
does not occur acutely, so hemoglobin (Hb) and hematocrit levels do not provide an accurate reflection of the
degree of blood loss and anemia.[38] Obtain intravenous access with two large-bore peripheral intravenous
catheters. Perfusion to critical organs must be maintained through early goal-directed therapy, including
volume resuscitation with crystalloid fluid and blood products, blood pressure support, and tissue perfusion.
Crossmatched blood (or O negative, if crossmatch is unavailable) should be given as soon as possible.
In addition, bleeding following major trauma requires coagulation support and monitoring, and the
appropriate use of local hemostatic measures, tourniquets, calcium, desmopressin, and consideration for
tranexamic acid.[39] [40]
Definitive management of acute hemorrhage depends on the underlying cause, but usually requires surgery.
A meta-analysis concluded that the use of hydroxyethyl starch (HES) solutions to decrease volume overload
in large volume resuscitations was associated with increased risk of acute kidney injury and death.[41] HES
solutions for infusion have been significantly restricted across the European Union and are contraindicated
in critically ill patients and those with sepsis or renal impairment. These measures were introduced to
protect patients from the increased risk of kidney injury and death associated with HES.[42] The restrictions
followed a January 2018 review by the European Medicines Agency’s Pharmacovigilance Risk Assessment
15
Committee, which recommended that HES should be suspended from the market because, despite initial
warnings, it was still being used in these at-risk patient populations.[43]
Microangiopathic hemolytic anemias

Hemolytic uremic syndrome, disseminated intravascular coagulation (DIC), and thrombotic thrombocytopenic
purpura (TTP) produce life-threatening rapid hemolysis.[24] [25] [27]
Treatment of DIC is aimed at the underlying cause. Corticosteroids and immunosuppression should be
commenced if hemolytic uremic syndrome or TTP are suspected. Intravenous immunoglobulins or urgent
plasmapheresis may be necessary for rapid clearance of autoantibodies. Antibody screening should be done
prior to blood transfusion. Antibody-free blood products should be used to prevent additional alloimmune
hemolysis.
Patients with malignant hypertension may have microangiopathic hemolytic anemia. The most common
EMERGENCIES
symptoms include headaches (often occipital), visual disturbances, chest pain, dyspnea, and neurologic
deficits. Systolic BP >210 mmHg and diastolic BP >130 mmHg indicate malignant hypertension; associated
signs may include new murmurs, third heart sound on auscultation of the heart, jugular venous distension,
rales or lower-extremity edema, oliguria or polyuria, focal neurologic signs, and hypertensive retinopathy.
The initial goal of therapy in hypertensive emergencies is to reduce mean arterial blood pressure by no more
than 25% (within minutes to 1 hour), then, if stable, to 160/100 to 110 mmHg within the next 2 to 6 hours.
Labetalol is the agent of choice.
Sickle cell vaso-occlusive crisis

This is a common complication of sickle cell anemia, which presents with severe pain precipitated by cold,
dehydration, infection, or ischemia (often due to strenuous exercise). The crisis may give rise to skeletal pain
due to bone infarction or avascular necrosis, especially of the hip or shoulder. Other presentations include
acute abdominal pain and acute chest syndrome, which is clinically indistinguishable from pneumonia.
Treatment involves adequate analgesia, hydration with oral or intravenous fluids, oxygen, and treatment of
the underlying cause.
Combined vitamin B12 and folate deficiency

If a patient has folate deficiency, it is essential to check for and correct any coexisting vitamin B12 deficiency
before giving folate. Folate is believed to exacerbate inhibition of vitamin B12-containing enzymes, thereby
worsening vitamin B12-associated neuropathy and subacute combined degeneration of the spinal cord.[44]
Leukemias or aplastic anemia

Usually present with a normocytic anemia and coexisting neutropenia and thrombocytopenia. Signs of
leukemia include generalized painless lymphadenopathy, ecchymoses, petechiae, hepatosplenomegaly and
abdominal or testicular masses. Circulating blasts may be reported on peripheral smear.
If these conditions are suspected, an immediate hematology consultation is required for bone marrow biopsy
and flow cytometry studies. If the anemia requires transfusion, only leukoreduced, irradiated blood products
should be used, as these patients may be transplant candidates.[11] [45]
Decreased physiologic reserve

It is important to identify patients with decreased physiologic reserve, such as those with coexisting
cardiovascular or pulmonary disease, as these patients are less able to tolerate anemia and have more
severe symptoms.
EMERGENCIES
17
Evaluation of anemia Diagnosis
Approach
The urgency with which anemia is evaluated depends on the severity at presentation and whether the patient
has active or acute bleeding.
Initial assessment
Patients with active or acute bleeding
Evaluation should include identification of any source of active or acute bleeding.
• The initial goal in a patient with acute bleeding is rapid hemodynamic stabilization. Up to 30% of total
blood volume may be lost before clinical manifestations are appreciated at rest.
• Patients with an acute severe hemorrhage present with symptoms and signs of hypovolemia and the
underlying cause.[4]
• Key signs of hypovolemia include hypotension, pallor, cold clammy skin, thready pulse, tachycardia,
dyspnea and altered mental status. Flat neck veins when supine indicate at least 30% to 40% total
body volume loss. All orifices should be examined for bleeding.
• History of prior episodes of gastrointestinal bleeding, gastritis, inflammatory bowel disease, non-
steroidal anti-inflammatory drug (NSAID) or corticosteroid use, alcohol use, or cirrhosis should prompt
suspicion of gastrointestinal bleeding. NSAIDs and corticosteroids are associated with peptic ulcer
disease. Alcohol use and cirrhosis are associated with coagulation disorders and esophageal varices.
A lower gastrointestinal bleed presents with fresh red rectal bleeding (hematochezia). Melena and/or
hematemesis with or without abdominal pain indicate an upper gastrointestinal bleed.
• Sudden tearing pain should prompt suspicion of a ruptured vascular aneurysm; the pain may be
spontaneous, or precipitated by trauma or by cocaine or amphetamine use. Loss of consciousness
may occur if a major vessel is involved. A history of hypertension or collagen disorders may also be
present. A wide pulse pressure suggests a ruptured aneurysm. A pulsatile abdominal mass may
indicate an abdominal aortic aneurysm. Flank or abdominal ecchymosis suggests intra-abdominal
bleeding.
DIAGNOSIS
• The mechanism and site of any trauma should be determined.

• If there is a history of recent surgery, ongoing blood loss at the surgical site must be considered.
A detailed history of the pre-, intra-, and postoperative course should be obtained, including any
complications noted during the operation. Any antibiotics administered should be noted, as some can
produce a decrease in platelet levels.
• A history of bleeding disorders or excessive bruising may indicate an underlying coagulation disorder.
• Jaundice, especially accompanied by fatigue and pallor, with episodic dark urine suggests a hemolytic
process, especially with recent infection, new medications, or history of malignancy.
Tests are guided by the history and exam and the suspected etiology of active bleeding. These may include
the following procedures.
• Complete blood count (CBC), which shows a normocytic anemia with a high reticulocyte count (>2%)
and a normal or decreased hematocrit (Hct). Dilution does not occur initially, so hemoglobin (Hb) and
Hct do not accurately reflect the true severity of the anemia.
• Prothrombin time/activated partial prothrombin time, which is usually normal, but tested to identify
patients with decreased coagulation due to anticoagulants, underlying defects in hemostasis, or
consumptive coagulopathy. In patients with upper gastrointestinal bleeding, elevated BUN may be
seen, even in the absence of renal impairment, due to digestion of blood, which is a source of urea.
• Abdominal ultrasound scan: allows rapid identification of intra-abdominal bleeding and indicated if
abdominal trauma or a ruptured abdominal aortic aneurysm are suspected.
• Joint x-rays, indicated in patients with trauma to identify fractures. Long-bone fractures can be a
significant source of bleeding.
• Computed tomography scanning of the body region affected by trauma or aneurysm rupture, which will
identify internal injuries or the extent and nature of the aneurysm, and identify sources of bleeding.
• Upper gastrointestinalI endoscopy, required to identify sources of upper gastrointestinal bleeding.[46]
[47]
• Colonoscopy, required to identify sources of lower gastrointestinal bleeding.
• Capsule endoscopy may have diagnostic, but not therapeutic, utility in situations where there is
concern for gastrointestinal bleeding in inaccessible areas such as the small bowel.[48]
• Exploratory laparotomy, which may be required in patients with abdominal bleeding to identify the
source, especially if there is a history of abdominal trauma or previous abdominal surgery.
Patients without active or acute bleeding
Many anemic patients with no acute or active bleeding are asymptomatic, and the anemia is only noted
on a CBC taken as part of the assessment of an unrelated condition. The duration of anemia must be
investigated, if possible.
Generally, healthy individuals tolerate extreme anemia well, with cardiovascular status being the major
limiting factor.
Symptoms of anemia may include fatigue, weakness, decreased exercise tolerance, shortness of breath with
exercise, palpitations, dizziness, irritability and impaired concentration.[7]
There is a strong relationship between pica (a medical disorder in which children develop an appetite for non-
nutritive substances) and iron deficiency.
Pallor is the most common sign in patients with anemia.[7] Jaundice is an additional sign seen in patients
with hemolytic anemias.
DIAGNOSIS
The first step in diagnosis is to identify the type of anemia that is present, using the results of the CBC.
Due to their relative reproducibility, mean corpuscular volume (MCV) and red cell width are the most useful
components in the initial classification of most anemias.
The anemia may be:
• Microcytic (MCV <80 femtoliters [fL]): serum iron studies should be performed.[2]
• Normocytic (MCV 80-100 femtoliters [fL]): the reticulocyte count should be examined to determine if
the anemia is hypoproliferative (<2%) or hyperproliferative (>2%).
• Macrocytic (MCV >100 femtoliters [fL]): the peripheral smear should be examined for megaloblasts
and hypersegmented neutrophils. If these cells are present, the anemia is megaloblastic. If they are
absent, the anemia is nonmegaloblastic.
19
Algorithm for the assessment of anemia

Microcytic anemia: abnormal serum iron studies

A low serum iron, an elevated total iron-binding capacity, and a low ferritin indicate iron deficiency anemia.
Serum ferritin is the most sensitive and specific test for iron deficiency.[2]
Iron deficiency produces an associated reactive thrombocytosis that provides an additional clue.
Iron deficiency is not a diagnosis and requires further investigation to elucidate the cause.
DIAGNOSIS
Associated symptoms may indicate a source of chronic bleeding e.g., heavy menstrual bleeding, coffee-
ground vomiting, hematemesis, melena, rectal pain or rectal bleeding. Hemoptysis may indicate Goodpasture
syndrome or idiopathic pulmonary hemosiderosis. A history of dark-colored urine may indicate paroxysmal
nocturnal hemoglobinuria.
Enquire about the patient's diet. Diets low in meat may produce iron deficiency. Generalized malnutrition
often produces combined vitamin B12 and/or folate deficiency, in which case the resulting anemia is
normocytic. Children may have pica.
Alcohol use and cirrhosis are associated with coagulation disorders and esophageal varices.
Rarely, a history of excessive blood donation or self-harm may be elicited. Patients who are avid runners
may have runner's anemia from repetitive mechanical trauma (also known as march hematuria). A history
of gastric surgery, celiac disease, or extensive small bowel resection suggests malabsorption as the cause.
Pregnancy is a common cause of iron deficiency.[11]
Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, and thinning hair. Peripheral blood
smear may show pencil cells.[49]
Koilonychia
Reproduced with permission from Bickle Ian. Clinical exam skills: Hand signs BMJ 2004; 329 :0411402
DIAGNOSIS
Angular cheilosis
Science Photo Library
Investigations are guided by the history and examination, and include the following:
• Fecal occult blood testing, which should be done in all patients and is positive if gastrointestinal
bleeding is present.
• Upper gastrointestinal endoscopy, which should be performed if there is a history of upper
gastrointestinal bleeding or a positive fecal occult blood test. It may identify sources of an upper
21
gastrointestinal bleed (peptic ulcer disease, gastritis, esophageal varices), hiatus hernia, Meckel
diverticulum, or increased gastric pH in achlorhydria.
• Following negative endoscopy in the setting of persistent iron deficiency anemia, testing for
Helicobacter pylori may be considered.[50]
• Immunoglobulin A-tissue transglutaminase (IgA-tTG) test should be performed in all patients and is
positive in celiac disease.
• Colonoscopy, which should be performed if there is a history of lower gastrointestinal bleeding or
a positive fecal occult blood test. An occult blood test may reveal malignancy, diverticular disease,
ulcerative colitis, or rare causes such as hereditary hemorrhagic telangiectasia. US and UK guidelines
report risk thresholds for testing among low- to average-risk symptomatic populations.[51] [52] [53] UK
guidelines recommend quantitative fecal immunochemical tests (FITs) for patients who do not have
rectal bleeding and are:[52]
• ages 50 years and over with unexplained abdominal pain or weight loss, or
• ages 60 years and under with changes in bowel habit or iron-deficiency anemia, or
• ages 60 years and over and have anemia even without iron deficiency.
Patients who have a positive quantitative FIT should be referred for an urgent appointment (within
2 weeks) through the suspected cancer referral pathway.[52] Refer to guidelines for information
regarding the referral and/or testing of patients <50 years with signs or symptoms of colorectal cancer,
including rectal bleeding, iron deficiency anemia, weight loss, or change in bowel habit.[54] [52] [53]
One retrospective review of the medical records of a sample of patients with colorectal cancer found
that anemia was one of the commonest signs in those considered to have had a missed diagnostic
opportunity (a clinical encounter where, even in the presence of presumptive symptoms of colorectal
cancer, the diagnostic process was not started).[55] In the UK, the National Institute for Health and
Care Excellence recommends that adults ages over 60 who have iron-deficiency anemia should be
referred urgently for investigation for colorectal cancer.[56]
• Flow cytometry should be considered if there is a history of passing red urine, or red blood cell (RBC)
results consistent with a hemolytic anemia. It detects decreased expression of RBC surface proteins
DIAGNOSIS
(CD55 and CD59) and is diagnostic of paroxysmal nocturnal hemoglobinuria.

• Transvaginal ultrasound, which may reveal causes of menorrhagia including hyperplasia, dysplasia,
fibroids, polyps or malignancy.
• Stool microscopy, which may identify hookworm, whipworm, or Schistosoma eggs. This should be
performed if clinical features suggest the diagnosis or there is a history of travel to endemic areas.
A low serum iron, a low total iron-binding capacity, and a low/normal ferritin suggest coexistence of anemia of
chronic disease with iron deficiency.
• A history of an underlying inflammatory process (infection, neoplasms, autoimmune reactions, and

injury to tissue from trauma or major surgery) is usually present. Serum C-reactive protein may be
raised.[17]
• A serum erythropoietin level should be considered; the result is usually normal or mildly elevated.
Ferritin is an acute phase protein and serum levels can rise in inflammatory conditions, liver disease
and malignancy, even though iron stores are low.[57] Hypothyroidism and vitamin C deficiency may
produce a falsely low ferritin level.[58]
Microcytic anemia: normal serum iron studies

The most important cause to exclude is thalassemia. A family history is usually present. The disease is more
common in individuals of Mediterranean, Middle Eastern, or Southeast Asian descent.[21] [22]
The examination findings may be normal, or reveal splenomegaly, jaundice, abdominal distension,
and icterus. Morphologic changes including skeletal abnormalities, a large head, chipmunk facies, and
misaligned teeth are seen in beta-thalassemia intermedia and major.
Distinct features on the CBC that suggest the diagnosis include a marked decrease in MCV (usually close
to 70 femtoliters [fL]) with a low mean corpuscular Hb, target cells on the peripheral smear, and an elevated
reticulocyte count (>2%).[49] A Mentzer index (MCV/RBC) <13 is suggestive of thalassemia, and an index
>14 suggests iron deficiency.[59] In a meta-analysis of various mathematical indices used to distinguish
between iron deficiency anemia and thalassemias, the microcytic to hypochromic RBC ratio (M/H) showed
the best performance, although the authors concluded that none were high enough to make definitive
diagnoses.[60]
Thalassemia is diagnosed using Hb electrophoresis. The presence of Hb H, Hb Bart, and concomitant

hemoglobinopathies (Hb E, Hb S, Hb C, Hb D) is diagnostic of alpha-thalassemia. A high HbF with minimal
or absent HbA and an elevated HbA2 is diagnostic of beta-thalassemia.
Normocytic anemia: hypoproliferative

Hematological malignancies and aplastic anemia are the most important diagnoses to exclude, and are
usually associated with multiple cytopenias.[11] An isolated anemia is usually due to pure red cell aplasia.
Chronic kidney disease or hypothyroidism can also cause an isolated anemia.[15]
History
• Symptoms of bleeding, easy bruising, night sweats, or weight loss suggest hematologic malignancy or
aplastic anemia. Enquire about symptoms and risk factors for infections which can cause self-limiting
pure red cell aplasia, such as parvovirus infection, infectious mononucleosis, viral hepatitis, malaria,
DIAGNOSIS
respiratory infections, gastroenteritis, and mumps.
• Medication: Phenytoin, carbamazepine, sodium valproate, azathioprine, sulfonamides, isoniazid
and procainamide cause pure red cell aplasia. Benzene, penicillamine, and gold can cause aplastic
anemia. Chloramphenicol can cause either aplastic anemia or pure red cell aplasia. Chemotherapy
causes pancytopenia.[61]
• Radiation therapy, especially to pelvic or sternal areas, can cause pancytopenia.
• A history of autoimmune disease or chronic hepatitis suggests persistent pure red cell aplasia.
• There may be a history or features of chronic kidney disease or hypothyroidism.
Exam
• Ecchymoses or petechiae due to thrombocytopenia suggest hematologic malignancy, myelodysplastic

syndrome, or aplastic anemia. Lymphadenopathy or fever suggest malignancy or infections.
Splenomegaly may be seen in hematologic malignancies.
Initial investigations
• Should be guided by the history and examination findings.
23
• CBC may show an associated cytopenia and characteristic changes specific to a hematological
malignancy. A pancytopenia suggests aplastic anemia, or may be due to chemotherapy or radiation
therapy. An isolated anemia suggests pure red cell aplasia or anemia due to chronic kidney disease.
• Bone marrow biopsy is required for the definitive diagnosis of acute leukemia (acute lymphocytic
leukemia, acute myelogenous leukemia), chronic myelogenous leukemia, aplastic anemia, or bone
marrow metastases.
• Antiparvovirus antibodies are positive in parvovirus infection, the most common infectious cause of
pure red cell aplasia.
Other tests to consider
• Hepatitis serology, to exclude acute or chronic active hepatitis

• Monospot test (heterophile antibodies) or Epstein-Barr virus-specific antibodies, to exclude infectious
mononucleosis. Viral capsid antigen-IgM (VCA-IgM) is detectable in most patients with symptom onset
• Thick and thin peripheral smear, to exclude malaria if history and clinical findings suggest the
diagnosis
• Thyroid function tests; thyroid-stimulating hormone is elevated and free thyroxine reduced in
hypothyroidism
• Antinuclear antibodies, which are positive in systemic lupus erythematosus or scleroderma
• Rheumatoid factor, which may be positive in rheumatoid arthritis
• Serum creatine kinase, which is elevated in dermatomyositis
• Erythropoietin levels, which may be inappropriately decreased in patients with chronic kidney disease.
Serum calcium and parathyroid hormone levels should be considered if associated secondary
hyperparathyroidism is suspected
• Chest x-ray, which may show infiltrates in atypical pneumonia or a smooth mass in thymoma.
Normocytic anemia: hyperproliferative

Potential diagnoses include hemorrhage and hemolytic anemias.
History
DIAGNOSIS
• Drugs that can cause hemolysis include penicillin, methyldopa, levodopa, quinidines, cephalosporins,
and some NSAIDs. Cyclosporine, tacrolimus, clopidogrel, oral contraceptive pills, and some
chemotherapy drugs may cause hemolytic uremic syndrome.
• There may be a history suggestive of microangiopathic disease. Known triggers of disseminated
intravascular coagulation (DIC) include ongoing severe infection, sepsis, malignancy, obstetric
emergency, trauma, burns, pancreatitis, liver failure, envenomation, drug overdose, or any cause of
endothelial damage.
• The presence of acute-onset neurologic symptoms, including headache, confusion, focal weakness,
seizures, or coma, should prompt suspicion of thrombotic thrombocytopenic purpura. Female patients
may have associated menorrhagia.
• Sudden-onset dizziness, headache, mental status changes, loss of sensation or motor strength, chest
pain or pressure, dyspnea, or edema in a patient with known hypertension should prompt suspicion of
malignant hypertension; a history of renal failure or eclampsia may also be present.
• An expanding vascular skin lesion in a young infant or child should prompt suspicion of a
hemangioma.
• A history of prosthetic valve replacement may indicate hemolysis induced by the prosthesis.
• Bloody diarrhea should prompt suspicion of Escherichia coli infection and hemolytic uremic
syndrome.
• Persistent pain in the skeleton, chest, or abdomen; priapism; lower-extremity skin ulcers; or an acute
pneumonia-like syndrome suggest sickle cell anemia.
• Patients with inherited hemolytic anemias such as sickle cell anemia, hereditary spherocytosis, or
glucose-6-phosphate dehydrogenase (G6PD) deficiency may have a positive family history.
• There may be a previous history of autoimmune disease (e.g., systemic lupus erythematosus,
rheumatoid arthritis, or scleroderma) or lymphoproliferative disorders (usually non-Hodgkin lymphoma
or chronic lymphocytic leukemia), which can lead to autoimmune hemolytic anemia. Note that
autoimmune diseases may also cause pure red cell aplasia, in which case the reticulocyte count would
be low, with normal lactate dehydrogenase, haptoglobin, and bilirubin levels.
• Recent blood transfusion may indicate hemolysis due to a transfusion reaction.
• Occupational or home exposure to lead should prompt suspicion of lead toxicity.
Examination
• Features of microangiopathic disease: there may be purpura or ecchymoses due to bleeding. Systolic
BP >210 mmHg and diastolic BP >130 mmHg indicate malignant hypertension; associated signs may
include new murmurs, third heart sound on auscultation of the heart, jugular venous distension, rales
or lower-extremity edema, oliguria or polyuria, focal neurologic signs, and hypertensive retinopathy.
Cutaneous reddish-brown or violaceous vascular lesions may indicate hemangioma.[28]
• Splenomegaly is seen in hereditary spherocytosis. Clinical features of underlying autoimmune
diseases may be present. Lymphadenopathy may indicate infectious mononucleosis, leukemia,
lymphoma, or autoimmune disease.
• The CBC and peripheral blood smear should be examined for clues to the underlying cause. A
thrombocytopenia with schistocytes strongly suggests a microangiopathic hemolytic anemia.
Spherocytes suggest autoimmune hemolytic anemia or hereditary spherocytosis. Hereditary
spherocytosis is also associated with increased mean corpuscular Hb. Sickling of RBCs is diagnostic
DIAGNOSIS
of sickle cell anemia.[21] Heinz bodies, eccentrocytes, or bite cells are seen in G6PD deficiency.
• If hemolytic anemia is suspected, serum lactate dehydrogenase, haptoglobin, and bilirubin should
be measured. Elevated lactate dehydrogenase and bilirubin levels with a decreased haptoglobin are
strongly suggestive of a hemolytic anemia. Clinical jaundice is seen once bilirubin levels rise above 2
to 4 mg/dL.
Tests to consider in suspected microangiopathic hemolytic anemias
• Serum creatinine, which may be elevated in patients with hemolytic uremic syndrome or malignant
hypertension.
• Urine dipstick, which may show hematuria and/or proteinuria in hemolytic uremic syndrome.
• Stool tests: culture, polymerase chain reaction for enterohemorrhagic E. coli genes, or enzyme-linked
immunosorbent assay for Shiga toxin in hemolytic uremic syndrome.[62]
• Prothrombin time and activated partial prothrombin time, which are prolonged in DIC but normal in
other microangiopathic hemolytic anemias.
• DIC panel shows elevated D-dimers and fibrin degradation products with low fibrinogen in patients with
DIC.
• X-rays and magnetic resonance imaging scanning of suspected regions reveal internal hemangiomas.
25
Tests to consider in other hemolytic anemias
• Direct antiglobulin (Coombs) test, which is positive in autoimmune hemolytic anemia.

• Tests to identify hereditary causes. Sickle cell anemia is diagnosed on CBC. Osmotic fragility test is
positive in hereditary spherocytosis; cells lyse on exposure to hypo-osmotic solution. G6PD assays
identify deficiencies of the enzyme.
• Tests to identify infection. Monospot test or Epstein-Barr virus IgM is positive in infectious
mononucleosis. Cytomegalovirus (CMV) IgM is positive in CMV infection. Double-sandwich
IgM enzyme-linked immunosorbent assay (ELISA) or IgG avidity test is positive for IgM in acute
toxoplasmosis. Splenic or bone marrow aspirate shows amastigotes of the parasite in leishmaniasis.
• Blood lead levels, which are elevated in lead toxicity.
Macrocytic anemia: megaloblastic

The main causes to consider are vitamin B12 or folate deficiency, or drugs that interfere with DNA synthesis.
Autoimmune thyroid disease may coexist with pernicious anemia and atrophic gastritis, which decrease B12
absorption. Therefore, screening for B12 deficiency when the etiology of hypothyroidism is thought to be
autoimmune is recommended.[63]
History
• Poor intake due to malnutrition, alcohol abuse, or strict vegan or low-protein diets can produce
deficiency of vitamin B12 and/or folate.
• A history of celiac disease, tropical sprue, Crohn disease, previous gastric or intestinal surgery, or
bacterial overgrowth may indicate malabsorption.
• A swollen, red, painful tongue; angular stomatitis; patchy hyperpigmentation of the skin and mucous
membranes; and a persistent mild pyrexia are symptoms of folate deficiency.
• Drug history: known causative medications include purine analogs, pyrimidine analogs, reductase
inhibitors, methotrexate, trimethoprim, anticonvulsants, oral contraceptives, cycloserine, p-
aminosalicylic acid, metformin, colchicine, neomycin, and biguanides. Hydroxyurea, in particular, is
DIAGNOSIS
known to cause oval macrocytosis with MCV>110 femtoliters (fL).

• Serum vitamin B12 levels are decreased and serum methylmalonic acid levels are elevated in vitamin
B12 deficiency.[64] The latter is more sensitive and should be used to definitively exclude vitamin B12
deficiency. An MCV of >115 fL is typically seen in nutritional deficiency.
• Serum folate levels are low in folate deficiency. If folate levels are low, serum vitamin B12 and
methylmalonic acid levels should be measured to exclude concurrent vitamin B12 deficiency before
folate levels are corrected. Normal serum homocysteine levels make folate deficiency unlikely. RBC
folate is a more accurate indicator of folate deficiency than serum folate level.
• Anti-intrinsic factor and parietal cell antibodies are positive in pernicious anemia.
Macrocytic anemia: nonmegaloblastic

Potential diagnoses
• Causes to consider include alcohol abuse, myelodysplastic syndrome, chronic liver disease, and
congenital bone marrow failure syndromes.
History
• High alcohol intake indicates alcohol-induced anemia, which usually persists for months after total
abstinence. A history of chronic liver disease indicates liver disease-induced anemia.
• History of prior exposure to petroleum distillates (especially benzene), chemotherapy, or radiation
therapy should prompt suspicion of myelodysplastic syndrome.
• A history of fever, chills, fatigue, weakness, recurrent infection, anorexia, night sweats, shortness of
breath, and easy bruising should prompt suspicion of myelodysplastic syndrome.
• Recurrent infections in an infant should prompt suspicion of congenital bone marrow failure
syndromes.
Exam
• May reveal stigmata of chronic alcoholism or chronic liver disease.

• Pallor, petechiae and purpura may be present in myelodysplastic syndrome.
• Dyskeratosis congenita is characterized by the triad of abnormal nails, reticulated skin rash, and
leukoplakia.
• Skeletal abnormalities and growth retardation are seen in Shwachman-Diamond syndrome.
Investigations
• CBC shows associated neutropenia and thrombocytopenia with macro-ovalocytes in myelodysplastic

syndrome.
• Bone marrow aspiration and biopsy shows myeloblasts with immature precursors in myelodysplastic
syndrome. Diagnostic features of congenital bone marrow failure syndromes are also identified.
• Cytogenetics reveal chromosomal translocations in myelodysplastic syndrome.
• Additional tests for congenital bone marrow syndromes: diepoxybutane or mitomycin-c fragility test is
positive in Fanconi anemia. Genetic testing reveals underlying mutations.
DIAGNOSIS
27
Differentials overview
Common
Trauma
Acute gastrointestinal bleeding
Rupture of a vascular aneurysm
Surgery
Menorrhagia
Iron deficiency
Vitamin B12 deficiency
Folate deficiency
Myelodysplastic syndrome
Acute lymphocytic leukemia
Acute myelogenous leukemia
Chronic myelogenous leukemia

DIAGNOSIS
Hairy cell leukemia
Acquired aplastic anemia
Infiltration by secondary malignancy
Drug toxicity
Anemia of chronic disease
Chronic kidney disease
Chronic liver disease
Pregnancy
Uncommon
Cytotoxic chemotherapy
Radiation therapy
Alcohol abuse
Lead toxicity
Hypothyroidism
Autoimmune hemolytic anemia
Transfusion reaction
Malaria
Viral hepatitis
Toxoplasmosis
Leishmaniasis
Parvovirus B19 infection
Infectious mononucleosis
DIAGNOSIS
Cytomegalovirus (CMV)
Sickle cell anemia
Thalassemias
Hereditary spherocytosis
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Bone marrow failure syndromes
Hemolytic uremic syndrome
Disseminated intravascular coagulation (DIC)
29
Uncommon
Thrombotic thrombocytopenic purpura
Hemangioma
Prosthetic valves and surfaces
Cutaneous burns
DIAGNOSIS
Differentials
Common
Trauma
History Exam 1st Test Other tests
history of trauma evidence of injury »CBC: normal or »diagnostic

(including gunshot (wounds, bruises, decreased hematocrit; laparotomy:
wounds, major deformities), decreased hemoglobin; identification of
fractures, crush hypotension, pallor, reactive leukocytosis bleeding source
injuries); history of prior tachycardia, thready and thrombocytosis due »CT scan of affected
bleeding episodes; or pulse, dyspnea/air to a stress response, body region:
use of anticoagulants hunger, altered mental thrombocytopenia identification of internal
or non-steroidal anti- status or confusion; flat from dilutional effect of injuries
inflammatory drug neck veins when supine multiple transfusions
(NSAID) indicate at least 30% to »prothrombin time/
40% total body volume activated partial
loss thromboplastin
time: usually normal;
prolonged with
anticoagulants,
underlying defects
in hemostasis,
or consumptive
coagulopathy
Consumptive
coagulopathy may
be due to repeated
blood transfusions
or to disseminated
DIAGNOSIS
intravascular
coagulation.
»joint or spine x-
rays: identification of
fractures
history of prior hypotension, pallor, »CBC: normal or

episodes of tachycardia, thready decreased hematocrit;
gastrointestinal pulse, dyspnea/air decreased hemoglobin;
bleeding, gastritis, hunger, altered mental reactive leukocytosis
peptic ulcer disease, status or confusion; and thrombocytosis due
hiatal hernia, neoplastic flat neck veins when to a stress response
disease, nonsteroidal supine indicate at »reticulocyte count:
anti-inflammatory least 30% to 40% total >2%
drug (NSAID) or blood volume loss;
31
Common

corticosteroid use, ascites, hepatomegaly/ average delay of 3-4
alcohol use, cirrhosis, splenomegaly, days before reticulocyte
anticoagulants, cirrhotic hard liver,
ulcerative colitis, caput medusae, response, after acute
diverticular disease; gynecomastia, melena, blood loss.
symptoms of rectal or bright red blood on
bleeding, melena, rectal examination »prothrombin time/
hematemesis, activated PTT :
abdominal pain usually normal;
prolonged in cirrhosis,
anticoagulant therapy,
or underlying defects in
hemostasis; elevated
BUN may be seen
»upper
gastrointestinal
endoscopy: bleeding
varices or ulcers if
source is from upper
gastrointestinal tract
»colonoscopy:
visualization of bleeding
lesion or mass

DIAGNOSIS
may be sudden tearing hypotension, pallor, »CBC: normal or »chest x-ray: may
pain, affecting the tachycardia, dyspnea/ decreased hematocrit; show widened
back, abdomen or air hunger, altered decreased hemoglobin; mediastinum in thoracic
chest depending on mental status or reactive leukocytosis aortic aneurysm
aneurysm location, may confusion; flat neck and thrombocytosis due
be accompanied by veins when supine to a stress response
loss of consciousness if indicate at least 30% »reticulocyte count:
major vessel involved; to 40% total blood >2%
history of hypertension, volume loss; wide pulse
average delay of 3-4
collagen disorders, pressure or absent
distal pulses; thready days before reticulocyte
pulse, may rapidly
Common

trauma, cocaine or progress to circulatory response, after acute
amphetamine use collapse and death blood loss.
»ultrasonography
of affected region:
shows extent and
nature of aneurysm
Intravascular
ultrasound is more Chest x-ray
accurate if patient is showing a widened
stable. mediastinum
From the collection
»CT scan of affected
region: shows extent of Professor James
and nature of aneurysm Brown; used
Spiral CT or MRI are with permission
better if patient is
stable.
DIAGNOSIS
CT scan of a
ruptured abdominal
aortic aneurysm
University of
Michigan, specifically
the cases of Dr
Gilbert R. Upchurch
reflecting the
Departments of
Vascular Surgery
and Radiology
33
Common
Surgery
recent surgery with hypotension, pallor, »CBC: normal or »reticulocyte count:

at least moderate tachycardia, thready decreased hematocrit; >2%
blood loss; history of pulse, continuous decreased hemoglobin; »ultrasound of
bleeding disorders or bleeding from surgical reactive leukocytosis affected region:
excessive bruising; use wound, petechiae, and thrombocytosis due shows source and
of antibiotics purpura; severe to a stress response extent of bleeding
bleeding produces
dyspnea/air hunger, »CT scan of affected
altered mental status region: shows source
or confusion; flat neck and extent of bleeding
veins when supine »diagnostic
indicate at least 30% to laparotomy: shows
40% total blood volume source and extent of
loss bleeding
◊ Menorrhagia
excessive menstrual pallor, adnexal masses »CBC: chronic »pregnancy test:

bleeding; fatigue, or fibroids microcytic anemia with negative
dyspnea on exertion, normal WBC; reactive »prothrombin time/
pica; history of fibroids thrombocytosis if iron activated partial
deficient thromboplastin
»serum ferritin: <15 time: usually normal;
micrograms/L if iron prolonged with
deficient anticoagulants,
DIAGNOSIS
underlying defects
in hemostasis,
or consumptive
coagulopathy
»thyroid-stimulating
hormone (TSH)/
free thyroxine
(T4): elevated TSH
with low free T4 in
hypothyroidism
»transvaginal
ultrasound: may see
hyperplasia, dysplasia,
fibroids, or polyps
Endometrial carcinoma
should be excluded in
patients >40 years.
Common
◊ Iron deficiency
history of poor dietary pallor, dyspnea, »CBC with »upper

iron intake, celiac poor exercise peripheral smear: gastrointestinal
disease, Crohn tolerance, koilonychia, microcytic anemia with endoscopy:
disease, ulcerative angular cheilosis, thrombocytosis identification of
colitis, small bowel glossitis, thinning hair, »serum iron studies: source of upper
resection, peptic systolic flow murmur; gastrointestinal
low serum iron,
ulcer disease, hemorrhoids, fresh bleeding; elevated
elevated total iron-
regular running, blood or melena on gastric pH in
binding capacity, low
chronic blood loss rectal examination; achlorhydria
ferritin, elevated soluble
(melena, hematuria, evidence of pregnancy; transferrin receptor »colonoscopy:
menorrhagia, adnexal masses or identification of source
hemoptysis, frequent fibroids »immunoglobulin
of lower gastrointestinal
blood donation, self- A-tissue
bleeding or chronic
harm), pica, salicylate transglutaminase
inflammation
ingestion, gastric (IgA-tTG) test: positive
bypass, hookworm in celiac disease »CT colonography:
infestation, pregnancy, Guaiac can react identification of source
or menorrhagia with food or medicine of lower gastrointestinal
bleeding
leading to a false-
Useful alternative for
positive result, but
patients who cannot
quantitative fecal
tolerate colonoscopy.
immunochemical tests
(FITs) use antibodies »flow cytometry:
specific to the globin identification of
paroxysmal nocturnal
part of human
hemoglobinuria
hemoglobin to detect
»transvaginal
DIAGNOSIS
small amounts of blood. ultrasound: may see
As globin degrades hyperplasia, dysplasia,
while traversing the fibroids, or polyps
gastrointestinal tract, Endometrial carcinoma
theoretically these should be excluded
tests are less likely in patients aged >40
to detect globin from years.
upper gastrointestinal
»stool microscopy:
bleeding.[65] US visualization of
and UK guidelines hookworm, whipworm,
report risk thresholds or Schistosoma eggs
for testing among »Helicobacter pylori
low- to average- test: positive result if H
pylori present
risk symptomatic
Following negative
populations.[51] [52]
endoscopy in the
[53] In 2021, the UK's
setting of persistent
National Institute
iron deficiency anemia,
for Health and Care
H pylori testing
35
Common
◊ Iron deficiency

Excellence added may be considered
certain quantitative when malignancies,
FITs to its guidance B12 deficiency,
on recognition and and idiopathic
referral for patients at thrombocytopenic
low risk of colorectal purpura have been
cancer without rectal excluded.[50]
bleeding.[52]
◊ Vitamin B12 deficiency
history of celiac impaired vibration »CBC with

or Crohn disease, sense and extremity peripheral smear:
autoimmune thyroid numbness, vitiligo, megaloblastic
disease, gastric glossitis, poor balance macrocytic anemia;
bypass, chronic or coordination, basophilic stippling may
antibiotic use (intestinal tachycardia, pallor, be seen
bacterial overgrowth hepatosplenomegaly »serum vitamin B12
syndrome), vegan levels: low
diet or alcohol abuse;
fatigue, palpitations, »serum
distal paresthesias, methylmalonic acid
depression, confusion, levels: elevated
tinnitus, dementia Confirms deficiency
DIAGNOSIS
if B12 levels are

borderline.
»anti-intrinsic factor
antibodies: positive in
pernicious anemia
»antiparietal cell
pernicious anemia
◊ Folate deficiency
history of celiac or mild persistent pyrexia, »CBC with »serum

Crohn disease, gastric tachycardia, pallor, peripheral smear: homocysteine levels:
bypass, hemodialysis, hepatosplenomegaly, megaloblastic elevated
pregnancy, alcohol glossitis, angular macrocytic anemia;
abuse, or use stomatitis, patchy basophilic stippling may
of antiseizure hyperpigmentation be seen
Common
◊ Folate deficiency

medications; fatigue, of skin and mucous »serum folate: low
palpitations, headaches membranes »serum vitamin B12
levels: normal; low in
combined vitamin B12
and folate deficiency
Neurologic symptoms
will worsen if folate
is corrected in the
presence of low vitamin
B12.
Myelodysplastic syndrome
history of prior pallor, petechiae, »CBC: macrocytic »bone marrow

exposure to purpura anemia with aspiration and
petroleum distillates leukopenia, macro- biopsy: myeloblasts
(especially benzene), ovalocytes; associated with immature
chemotherapy, or cytopenias include precursors
radiation therapy; neutropenia and Prussian blue iron
fever, chills, fatigue, thrombocytopenia staining of bone
weakness, recurrent »reticulocyte count: marrow aspirate
infection, anorexia, <2%
night sweats, shortness can show ringed
of breath, easy bruising sideroblasts - abnormal
DIAGNOSIS
erythroid precursor
cells which have
granules around the
nucleus.
»cytogenetics of
bone marrow biopsy:
multiple chromosomal
translocations possible,
especially 5q-, 7q-, or
trisomy 8 (+8)
»serum vitamin B12:
normal
»folate: normal
37
Common
Acute lymphocytic leukemia
malaise, fatigue, easy pallor, petechiae, »CBC with »bone marrow

bruising or bleeding, purpura, tachycardia, peripheral smear: aspirate and biopsy:
recurrent infections, hepatosplenomegaly, pancytopenia, ≥20% blasts
fever, arthralgias, lymphadenopathy, with ≥20% blasts; Immunohistochemistry,
infection, anorexia, painless scrotal normocytic cytochemistry, and
night sweats, shortness enlargement, bleeding anemia; may see
of breath, bony gums hypereosinophilia cytogenetics help to
tenderness, epistaxis, Up to 10% of patients further classify disease.
bleeding gums, gingival do not have peripherally
hyperplasia
circulating blasts.
»reticulocyte count:
<2%
history of prior pallor, petechia, »CBC with »bone marrow

chemotherapy or purpura, dyspnea, peripheral smear: aspirate and biopsy:
radiation therapy; tachycardia pancytopenia, ≥20% blasts
malaise, night sweats, with ≥20% blasts; Immunohistochemistry,
fatigue, easy bruising normocytic cytochemistry, and
or bleeding, recurrent anemia; may see
infections, fever, bony hypereosinophilia cytogenetics help to
tenderness, epistaxis, Cytoplasmic granules further classify disease.
bleeding gums, gingival
DIAGNOSIS
indicate myeloid lineage

hyperplasia
of blasts. May also see
Auer rods.
Common
Peripheral blood
film of a patient with
acute myelogenous
leukemia showing
myeloid blasts
with an Auer rod
From the collection
of Dr Kavita Raj
and Dr Priyanka
Mehta; used with
patient consent
<2%
Chronic myelogenous leukemia
DIAGNOSIS
usually in middle-aged tender splenomegaly, »CBC with »cytogenetics:

patients; fatigue, weight painful sternum, peripheral smear: t(19;22) Philadelphia
loss, night sweats, lymphadenopathy, normocytic anemia; chromosome - bcr-abl
early satiety, petechiae, splenomegaly myeloid maturing cells, translocation
purpura, recurrent elevated basophils, and »serum uric acid:
fevers, bone pain, eosinophils elevated
gouty arthritis »reticulocyte count: Due to elevated
<2% leukocyte count and
»bone marrow turnover.
aspirate and
biopsy: hypercellular
with granulocytic
hyperplasia
39
Common
Hairy cell leukemia
weakness, fatigue, massive splenomegaly »CBC with »bone marrow

weight loss, night peripheral smear: aspirate and biopsy:
sweats, early satiety, pancytopenia with core biopsy shows
petechiae, purpura, normocytic anemia hairy cells
recurrent fevers, Characteristic
abdominal discomfort mononuclear "hairy"
or fullness due to large
spleen cells, which stain
positive for tartrate-
resistant acid
phosphatase
Cytospin prepared
»reticulocyte count: from bone marrow
<2%
aspirate illustrates
the typical cell
cytology, with
oval- to bean-
shaped nuclei and
moderate amounts
of cytoplasm with
irregular cytoplasmic
borders (Wright
Giemsa 100x oil)
From the collection of
Lynn Moscinski, MD;
DIAGNOSIS
used with permission
history of hepatitis, pallor, petechiae, »CBC with »bone marrow

HIV, benzene purpura, dyspnea, peripheral smear: aspirate and biopsy:
exposure, use of known tachycardia pancytopenia with hypocellular with
causative medications, mild macrocytosis; decrease in all
radiation exposure, normocytic anemia elements, replaced
paroxysmal nocturnal mostly by fat cells; no
hemoglobinuria; infiltration by fibrosis or
<2%
malaise, fatigue, easy malignant cells
bruising or bleeding, Residual
recurrent infections, hematopoietic cells are
fever
morphologically normal
Common

»serum vitamin B12:
normal
»folate: normal
Infiltration by secondary malignancy
weight loss, malaise, pallor, petechiae, »CBC with »CT imaging:

fevers, fatigue, purpura, tachycardia, peripheral smear: identification of site of
dyspnea, easy abnormal exam pancytopenia, teardrop primary malignancy
bleeding or bruising; or presence of cells, poikilocytes;
history of solid organ mass (if solid organ normocytic anemia
malignancy (particularly malignancy), bruising, »reticulocyte count:
breast, prostate, lung, cachexia <2%
neuroblastoma)
»bone marrow
aspirate and biopsy:
infiltration of marrow
space by malignant
cells
Provide history
to pathologist so
appropriate stains
can be ordered if
metastatic malignancy
DIAGNOSIS
is suspected.
◊ Pure red cell aplasia
self-limited disease: clinical signs of »CBC: normocytic »thick and thin

history of use of underlying infection or anemia peripheral smear:
known causative autoimmune disease intracellular parasites
medications, clinical seen with Wright or
<2%
features of causative Giemsa staining in
infections (parvovirus »trial of malaria infection
B19, infectious discontinuation
»serum IgM + IgG
mononucleosis, viral of causative
anti-HAV: positive in
hepatitis, malaria, medication: anemia
hepatitis A infection
respiratory infections, resolves
gastroenteritis, primary »serum IgM + IgG
»antiparvovirus B19
atypical pneumonia, HBcAb: positive in
mumps); chronic hepatitis B infection
parvovirus infection
disease: history of
autoimmune disease
41
Common
◊ Pure red cell aplasia

(systemic lupus The most common »serum HBsAg:
erythematosus [SLE], infectious cause. positive in hepatitis B
rheumatoid arthritis, infection
dermatomyositis, »serum IgM + IgG
scleroderma, anti-HCV: positive in
polyarteritis nodosa), hepatitis C infection
persistent infection, or
thymoma »antinuclear
SLE or scleroderma
»ds-DNA, Smith
antigen: positive in
SLE
»rheumatoid factor:
positive in rheumatoid
arthritis
»serum creatine
kinase: elevated in
dermatomyositis
»chest x-ray: infiltrates
in atypical pneumonia;
smooth mass in
thymoma, typically
projecting into one of
the hemithoraces and
obscuring the aortic
arch, or silhouette sign
DIAGNOSIS
◊ Drug toxicity
known or suspected pallor, jaundice (with »CBC with »serum bilirubin:

ingestion of causative hemolytic anemia only), peripheral smear: elevated in hemolytic
drug prior to onset of dyspnea typically normocytic anemia
anemia, poor exercise anemia; inhibitors
tolerance of DNA synthesis,
folate, or vitamin B12
produce megaloblastic
macrocytic anemia
<2% if drugs suppress
bone marrow; >2%
if drugs produce
hemolysis
»trial of
discontinuation
of causative
Common
◊ Drug toxicity

medication: anemia
resolves
Anemia of chronic disease
history of known pallor, fatigue, dyspnea; »CBC: normocytic »serum

chronic inflammatory, specific signs of anemia erythropoietin level:
autoimmune, or underlying disease May be microcytic normal or elevated;
infectious states, if anemia of chronic often decreased in
sustained physiologic chronic kidney disease
stress, renal failure, disease is coexistent
Elevation, if present,
heart failure, vasculitis with iron deficiency
is usually inadequate
or collagen vascular anemia.
diseases, poor exercise to compensate for the
tolerance; anemia »serum iron studies: degree of anemia.
correlates with severity low/normal serum iron,
of inflammatory low total iron-binding
process capacity and normal/
elevated ferritin; ferritin
normal or elevated in
acute-phase reaction
When anemia of
chronic disease is
coexistent with iron
deficiency anemia,
DIAGNOSIS
these parameters may
be different.
◊ Chronic kidney disease
chronic kidney disease, pallor, fatigue, dyspnea; »CBC: normocytic or »serum calcium
poor exercise tolerance; signs of renal failure: microcytic anemia with level: decreased in
features of secondary jaundice, skin bruising, thrombocytosis associated secondary
hypoparathyroidism: lung rales, pericardial hyperparathyroidism
muscle cramps, bone rub, edema, poor <2% »serum intact
pain concentration or parathyroid
memory, myoclonus; »serum creatinine:
hormone level:
positive Chvostek elevated
increased in
sign or Trousseau »urinalysis: associated secondary
sign in associated hematuria and/or hyperparathyroidism
hyperparathyroidism proteinuria
»renal ultrasound:
small kidney size;
43
Common
◊ Chronic kidney disease

»serum iron studies: presence of obstruction
low serum iron and or hydronephrosis;
normal/elevated kidney stones
ferritin, high total iron- »kidney biopsy:
binding capacity in iron identification of
deficiency underlying kidney
»serum pathology
erythropoietin level:
normal or decreased
◊ Chronic liver disease
history of chronic liver pallor, fatigue, dyspnea, »CBC: »abdominal

disease, poor exercise jaundice, lower- nonmegaloblastic ultrasound, CT, or
tolerance; may be extremity swelling; macrocytic anemia; MRI scanning: liver
asymptomatic or with hand and nail features: thrombocytopenia may surface nodularity,
fatigue, weakness, leukonychia, palmar be present small liver, possible
weight loss, recurrent erythema, finger hypertrophy of left/
»prothrombin time:
infections, decreased clubbing, spider caudate lobe, evidence
decreased in hepatic
libido; altered mental angiomata; facial of ascites or collateral
synthetic dysfunction
status in hepatic features: telangiectasia, circulation
encephalopathy bruising, rhinophyma, »LFTs: abnormal;
»liver biopsy:
parotid gland pattern depends on
diagnosis of underlying
swelling, paper-dollar underlying cause
cause or subsequent
appearance of skin, cirrhosis
seborrheic dermatitis,
DIAGNOSIS
xanthelasma;
abdominal features:
caput medusae,
bruising, hepatomegaly,
splenomegaly,
abdominal distension;
in males, loss of
secondary sexual hair
and testicular atrophy,
gynecomastia
◊ Pregnancy
pregnancy, especially in abdominal distension »CBC: microcytic »serum iron studies:

third trimester consistent with anemia with low serum iron,
pregnancy, pallor thrombocytosis elevated total iron-
in iron deficiency; binding capacity, low
megaloblastic ferritin, elevated soluble
Common
◊ Pregnancy

macrocytic anemia in transferrin receptor in
folate deficiency iron deficiency
»serum folate: low in
folate deficiency
Uncommon
protein calorie loss of subcutaneous »CBC with »serum vitamin B12:

deprivation; fat, apathy and lethargy, peripheral smear: low
malabsorption depigmentation, microcytic anemia »serum folate: low
syndrome; neglect; enlarged abdomen, in iron deficiency;
history of an eating winged scapula, flaky megaloblastic »serum copper level:
disorder skin, bipedal edema macrocytic anemia in low
vitamin B12 and folate Copper deficiency
deficiency; normocytic needs to be considered
anemia with combined
in patients on
vitamin and mineral
deficiencies prolonged total
parenteral nutrition.
»serum iron studies:
low serum iron,
elevated total iron-
binding capacity, and
low ferritin in iron
DIAGNOSIS
deficiency
Cytotoxic chemotherapy
history of pallor, lethargy, »CBC: pancytopenia

myelosuppressive dyspnea with a normocytic
chemotherapy; fatigue; anemia
headaches; poor Counts usually reach
exercise tolerance nadir 7 to 10 days
after administration of
chemotherapy.
<2%
45
Uncommon
Radiation therapy
history of recent pallor, lethargy, »CBC: anemia »bone marrow

radiation exposure, dyspnea, skin erythema (pancytopenia) aspirate and biopsy:
especially to pelvic or on radiation sites marrow fibrosis or
sternal areas; fatigue, malignant infiltration
<2%
headaches, poor
exercise tolerance
◊ Alcohol abuse
history of chronic high overweight status, »CBC: macrocytic »diagnostic

alcohol intake increased prominence anemia interview: diagnosis of
of superficial cutaneous alcohol dependence
vasculature, peripheral »alcohol level
neuropathy, alterations (breath and blood):
in normal dentition elevated
and halitosis, possible
signs of liver disease:
hepatomegaly or small
liver, jaundice, ascites
Lead toxicity

DIAGNOSIS
history of occupational blue gingival line »CBC with

or recreational (Burton line), peripheral smear:
exposure to lead hypertension, gout normocytic anemia with
products or old paint; (saturnine gout); wrist basophilic stippling;
neuropsychiatric or foot drop microcytic anemia
disturbance, insomnia, if associated iron
abdominal pain, poor deficiency is present
appetite, pica »reticulocyte count:
>2%
»whole blood lead
level: elevated
◊ Hypothyroidism
weakness, lethargy, pallor; dyspnea; coarse, »CBC:

slow speech, feeling dry skin; eyelid edema; nonmegaloblastic
cold, forgetfulness, thick tongue; facial macrocytic anemia
constipation, weight edema; bradycardia
Uncommon
◊ Hypothyroidism

gain, poor exercise »serum thyroid-
tolerance stimulating
hormone: elevated
»serum thyroxine:
reduced
<2%
◊ Autoimmune hemolytic anemia
history of autoimmune pallor, lethargy, »CBC with »antinuclear

diseases (systemic dyspnea, tachycardia, peripheral smear: antibodies: positive in
lupus erythematosus jaundice, splenomegaly normocytic anemia, SLE or scleroderma
[SLE], rheumatoid (especially if with spherocytes »ds-DNA, Smith
arthritis, or extravascular »reticulocyte count: antigen: positive in
scleroderma), hemolysis) >2%; usually 4% SLE
lymphoproliferative
The elevated »rheumatoid factor:
disorders (non-Hodgkin
lymphoma or chronic reticulocyte count may positive in rheumatoid
lymphocytic leukemia), incorrectly increase arthritis
recent viral illness, MCV on automated
or mononucleosis;
counters.
may be asymptomatic;
symptoms include
weakness, fatigue,
DIAGNOSIS
headaches, poor
exercise tolerance, prior
gallstones, dark urine,
clay-colored stools
Peripheral blood
smear with
spherocytes,
reticulocytes, and
a nucleated red
blood cell (RBC)
From the collection
of John Densmore,
Department of
Medicine, University
of Virginia; used
with permission
»LDH: elevated
47
Uncommon
◊ Autoimmune hemolytic anemia

»haptoglobin: low
»direct antiglobulin
(Coombs) test:
usually positive;
negative in 5% to 10%
of cases
»serum bilirubin:
elevated
Transfusion reaction
multiple prior pallor, lethargy, »ABO typing: »direct antiglobulin

transfusions; fever, dyspnea, dark urine, discrepancy to blood (Coombs) test:
back pain, and jaundice used for transfusion IgG anti-A, anti-B, or
dyspnea, usually within Most commonly a anti-AB detected on
6 hours of transfusion clerical error. Stop circulating red cells
transfusion immediately »serum bilirubin:
elevated
and stabilize patient.
»inspection
of plasma in
centrifuged,
anticoagulated
venous blood
DIAGNOSIS
sample: clear
or pink-red within
first few hours of
hemoglobinemia
»inspection
of centrifuged
urine: clear red in
hemoglobinemia
Malaria
history of mosquito bite jaundice or pallor, »CBC: normocytic »serum bilirubin:

or habitation in malaria- splenomegaly, anemia ± elevated
prone region; fatigue, dyspnea, high flow thrombocytopenia and
dyspnea, fevers and cardiac murmur, leukopenia
prostration, decreased pulmonary edema, dark »reticulocyte count:
exercise tolerance, urine, fevers >2%; usually 4%
headaches, malaise;
symptoms usually
Uncommon
Malaria

cycle every 48 to 72 »thick and thin
hours, coinciding with peripheral smear:
red blood cell (RBC) intracellular parasites
destruction seen with Wright or
Giemsa staining
Banana-shaped
gametocytes or multiple
signet-ring forms in
RBCs are typical for
Plasmodium falciparum
, which requires
hospital admission.
Viral hepatitis
perinatal exposure, jaundice, »CBC: normocytic

direct body fluid hepatomegaly, right anemia
transmission, exposure upper quadrant »reticulocyte count:
to foodborne outbreak pain, acholic stools, <2%
(in hepatitis A); nausea, maculopapular or
vomiting, abdominal urticarial skin rash (in »serum
pain, fever, malaise, hepatitis B); usually aminotransferases:
fatigue and headache, normal in hepatitis C elevated
dark urine, acholic »serum IgM + IgG
DIAGNOSIS
(clay-colored) stools, anti-HAV: positive in
jaundice, pruritus (in hepatitis A infection
hepatitis B); hepatitis C
is usually asymptomatic »serum IgM + IgG
HBcAb: positive in
hepatitis B infection
»serum HBsAg:
positive in hepatitis B
infection
»serum IgM + IgG
anti-hepatitis C
virus: positive in
hepatitis C infection
Toxoplasmosis
usually seen jaundice, fever, »CBC: normocytic »polymerase

in pregnant or fatigue, lethargy, rash, anemia and chain reaction for
49
Uncommon
Toxoplasmosis

immunosuppressed hepatosplenomegaly; thrombocytopenia; may Toxoplasma gondii:
patients and newborns; newborns infected see leukocytosis and positive
history of exposure to in utero may have eosinophilia
domestic cats, sheep, chorioretinitis, »reticulocyte count:
or cattle, or to raw meat microcephaly, seizures, >2%; usually 4%
mental retardation
»IgM enzyme-linked
immunosorbent
assay (ELISA) or
IgG avidity test:
IgM detected in acute
infection; IgG detected
in chronic or previous
exposure
IgM may persist long
after infection; its
absence excludes
infection.
»Sabin-Feldman dye
test: IgG antibodies
positive
Leishmaniasis

DIAGNOSIS
history of exposure to pallor, jaundice, »CBC: normocytic »reticulocyte count:

sand fly bite, especially hepatosplenomegaly, anemia, >2%
in tropical or subtropical lymphadenopathy, thrombocytopenia, »polymerase chain
zones; AIDS, diarrhea, skin leukopenia, reaction: Leishmania
immunosuppression, ulcerations, erythroblastosis DNA
or malnutrition; nasopharyngeal »Leishmania Recommended to
fatigue and anorexia; ulcerations serology: positive for confirm diagnosis of
prolonged, persistent, Leishmania antibodies,
low-grade intermittent suspected cutaneous or
or antibody titre above
fevers; failure to thrive, locally validated visceral leishmaniasis,
distended abdomen threshold if available. More
Recommended to sensitive than
confirm diagnosis of microscopic
suspected visceral examination or
leishmaniasis.[66] parasite culture for the
diagnosis of suspected
Considered the
cutaneous and
test of choice in
visceral leishmaniasis
immunocompetent
cases.[66]
patients with suspected
Uncommon
Leishmaniasis

visceral leishmaniasis, Sensitivity estimates
but it is less sensitive range from 70% to
in immunosuppressed 100% when using
patients. tissue biopsies
for cutaneous
leishmaniasis diagnosis
and when using
peripheral blood for
visceral leishmaniasis
diagnosis.[67]
»splenic or
bone marrow
aspirate: presence
of amastigotes of the
parasite
Splenic aspirate is most
sensitive technique
(>95%), but carries a
1:1000 risk of major
bleeding; considerable
technical expertise is
required.[68]
Examination of bone
DIAGNOSIS
marrow aspirate or
lymph node fluid is
safer, but is of lower
sensitivity (70% to 90%
and 58%, respectively).
(Coombs) test:
positive
◊ Parvovirus B19 infection
acute infection: acute infection: »CBC: normocytic »antiparvovirus B19

characteristic skin "slapped cheek" anemia antibodies: positive
rash with or without appearance followed Used to exclude
arthralgia by a reticular parvovirus when typical
<2%
erythematous eruption
on extremities, and
51
Uncommon
◊ Parvovirus B19 infection

arthritis of hands, clinical features are
wrists, knees, or ankles absent.
◊ Infectious mononucleosis
fatigue, malaise, sore fever, »CBC with »LDH: elevated

throat, nausea, ocular lymphadenopathy, peripheral smear: »haptoglobin: low
pain, photophobia pharyngitis, rash, normocytic anemia,
tender splenomegaly, with spherocytes and »monospot test or
palate petechiae, atypical lymphocytes viral capsid antigen
periorbital edema, (VCA) IgM: positive
jaundice >2% and usually 4% in
hemolytic anemia, <2%
in pure red cell aplasia
◊ Cytomegalovirus (CMV)
infection is usually usually normal; »CBC: normocytic »LDH: elevated

asymptomatic; a jaundice occurs due anemia »haptoglobin: low
maculopapular rash to hemolytic anemia; »reticulocyte count:
following administration symptomatic infection »monospot test
>2%; usually 4%
of antibiotics may produces fever, or viral capside
DIAGNOSIS
occur; fatigue occurs lymphadenopathy, antigen (VCA) IgM:

due to anemia; pharyngitis, rash, negative
symptomatic infection tender splenomegaly, Rules out Epstein-Barr
is a sign of underlying palate petechiae, virus, which is clinically
immunosuppression periorbital edema
indistinguishable from
CMV.
»CMV IgM: positive
◊ Sickle cell anemia
known diagnosis of high fever, pallor, »CBC with

sickle cell disease in lethargy, dyspnea, peripheral smear:
patient and/or parents; jaundice during acute normocytic anemia with
prior painful vaso- crisis sickle cells
occlusive crises;
fatigue, poor exercise
tolerance; persistent
Uncommon
◊ Sickle cell anemia

pain in skeleton, chest, Pancytopenia occurs in
or abdomen; priapism, aplastic crisis (usually
gallstones, stroke,
lower-extremity skin self-limited).
ulcers, pneumonia-like
syndrome
Red cells in sickle

cell disease
From the personal
collection of Sophie
Lanzkron, MD; used
with permission
>2%
»hemoglobin (Hb)
isoelectric focusing:
elevated HbS/A ratio
(close to 100/0)
»LDH: elevated
»serum bilirubin:
DIAGNOSIS
elevated
◊ Thalassemias
family history of splenomegaly, »CBC with »serum ferritin:

blood disorders, jaundice, abdominal peripheral smear: elevated in iron
especially requiring distension, icterus; microcytic anemia overload
repeated transfusions; skeletal abnormalities, with MCV typically
Mediterranean, Middle large head, chipmunk closer to 70 fL, low
Eastern, or Southeast facies, and misaligned mean corpuscular
Asian descent; variable teeth seen in beta- hemoglobin (Hb); target
severity ranging from thalassemia intermedia cells seen
asymptomatic to severe and major »Hb electrophoresis:
transfusion-dependent elevated HbF; other
symptoms Hb patterns consistent
with respective
thalassemias
53
Uncommon
◊ Hereditary spherocytosis
family history of may be normal or »CBC with »direct antiglobulin

blood disorder, show pallor, jaundice, peripheral smear: (Coombs) test:
splenectomy, or lower leg skin ulcers, normocytic anemia, negative
pigmented gallstones; splenomegaly with increased Excludes immune-
may be asymptomatic mean corpuscular mediated hemolytic
if extramedullary hemoglobin and
hematopoiesis spherocytes anemias.
compensates »reticulocyte count:
>2%
»osmotic fragility
test: positive (cells lyse
on exposure to hypo-
osmotic solution)
◊ Glucose-6-phosphate dehydrogenase deficiency (G6PD)
usually in males of pallor, jaundice, mild »CBC with »G6PD enzyme

African, Mediterranean, dyspnea peripheral smear: assays: quantitative
Sardinian, or Sephardic normocytic anemia or qualitative
Jewish descent; self- with Heinz bodies, abnormalities
limited episodes eccentrocytes, or bite May be falsely negative
of acute hemolysis cells during the acute
when exposed to Heinz bodies are
oxidant stress; life- hemolytic event, owing
rapidly cleared by the
threatening symptoms to the destruction of
DIAGNOSIS
more common with spleen within 24 hours,

affected cells.
Mediterranean variant resulting in "bite cells."
»serum bilirubin:
»reticulocyte count: elevated indirect
>2% bilirubin
»serum haptoglobin: »direct antiglobulin
decreased (Coombs) test:
»LDH: elevated negative
Distinguishes
glucose-6-phosphate
dehydrogenase
deficiency from immune
hemolytic anemias.
Uncommon
Bone marrow failure syndromes
recurrent infection ill-appearing, with »CBC with »bone marrow

shortly after birth, weight loss, pallor, peripheral smear: aspiration and
fever, easy bleeding lethargy, dyspnea, pancytopenia with biopsy: varies
or bruising, organ petechiae, purpura, normocytic or depending on
abnormalities, short and/or thrush macrocytic anemia underlying cause
stature Causes include »diepox ybutane or
Fanconi anemia, mitomycin-c fragility
dyskeratosis congenita, test: positive in Fanconi
anemia
and Shwachman-
Diamond syndrome. »genetic testing:
characteristic genetic
»reticulocyte count: mutations detected
<2%
acute renal failure pallor, lethargy, »CBC with »prothrombin time/

usually following dyspnea, petechiae, peripheral smear: activated PTT: normal
an enteric bacterial purpura, bloody normocytic anemia, Excludes disseminated
infection ( Escherichia diarrhea; usually self- thrombocytopenia, intravascular
coli 0157:H7) with limited in children schistocytes
bloody diarrhea, coagulation.
»erythrocyte count:
or Streptococcus >2% »serum haptoglobin:
pneumoniae ;
DIAGNOSIS
decreased
cyclosporine,
tacrolimus, clopidogrel, »LDH: elevated
oral contraceptive »serum creatinine:
pills, and some may be elevated
chemotherapy drugs
may cause hemolytic »serum bilirubin:
uremic syndrome elevated
(Coombs) test:
negative
Excludes immune-
mediated hemolytic
anemias.
»stool culture
and polymerase
chain reaction
tests: positive for
enterohemorrhagic E.
coli genes
55
Uncommon

»enzyme-linked
immunosorbent
assay: positive for
Shiga toxin
»urinalysis: may
show hematuria and/or
proteinuria
Disseminated intravascular coagulation (DIC)
ongoing severe diffuse bleeding, »CBC with

infection, sepsis especially from peripheral smear:
(typically gram- puncture sites or minor normocytic anemia,
negative), malignancy, trauma; unprovoked thrombocytopenia,
obstetric emergency, clots; clinical signs of schistocytes
trauma, burns, underlying cause »prothrombin time:
envenomations, drug prolonged
overdose, any cause of
endothelial damage »activated partial
thromboplastin time:
varies depending on
factor VII levels
»DIC panel: elevated
D-dimer and fibrin
degradation products
DIAGNOSIS
with low fibrinogen

Fibrinogen may be
normal or elevated
as an acute-phase
reactant.
nonspecific prodrome pallor, lethargy, »CBC with

followed by headache, dyspnea, purpura, peripheral smear:
confusion, focal ecchymoses normocytic anemia with
weakness, seizures, schistocytes
coma; menorrhagia »reticulocyte count:
may be seen due to >2%
bleeding
(Coombs) test:
negative
Uncommon

Excludes immune-
mediated hemolytic
anemias.
◊ Hemangioma
typically young child or depends on location »CBC with »x-ray of suspected

infant with expanding of lesion(s), which are peripheral smear: region: soft-tissue
vascular skin lesion; typically reddish-brown normocytic anemia, shadows, phleboliths
may also be hepatic or or violaceous; other thrombocytopenia »MRI of suspected
in other visceral site symptoms consistent Platelet sequestration region: increased
with anemia in enlarging signal on both T1- and
hemangiomas T2-weighted images
with areas of signal
(Kasabach-Merritt
void
syndrome) can
cause life-threatening
bleeding.
>2%
DIAGNOSIS
history of essential systolic BP >210 mmHg »CBC with »chest x-ray:

hypertension, renal and diastolic BP >130 peripheral smear: evidence of pulmonary
disease, or eclampsia; mmHg, lethargy, new normocytic anemia with edema indicating left
older age, male murmurs, third heart schistocytes ventricular failure
gender, black ethnicity; sound on auscultation »reticulocyte count: »head CT or MRI:
dizziness, headache, of heart, jugular venous >2% evidence of infarct or
mental status changes, distension, rales or hemorrhage
loss of sensation or lower-extremity edema, »ECG: evidence of
motor strength, chest oliguria or polyuria, ischemia or infarct
pain or pressure, focal neurologic such as ST- or T-wave
dyspnea, edema signs, hypertensive changes
retinopathy »serum creatinine:
elevated with renal
failure
57
Uncommon
◊ Prosthetic valves and surfaces
history of aortic or pallor, lethargy, »CBC with

mitral metallic valve dyspnea, petechiae, peripheral smear:
replacement, with purpura, jaundice normocytic anemia with
anticoagulation; schistocytes
weakness, fatigue, »reticulocyte count:
headaches; poor >2%
exercise tolerance, prior
gallstones, dark urine »direct antiglobulin
(Coombs) test:
negative
Excludes immune-
mediated hemolytic
anemias.
Cutaneous burns
burn injury to at least epidermal or dermal »CBC with »reticulocyte count:

10% of total body loss consistent with peripheral smear: >2%
surface area; multiple burn injury normocytic anemia
surgical procedures with thrombocytopenia;
schistocytes from
peripheral destruction
seen on blood smear
DIAGNOSIS
Evaluation of anemia References
Key articles
• Goldman L, Schafer AI, eds. Chapter 149: Approach to the anemias. In: Goldman-Cecil Medicine, 2-
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65
Evaluation of anemia Images
Images
IMAGES
Figure 1: Microcytic anemia

Figure 2: Megaloblastic macrocytic anemia

IMAGES
Figure 3: Classification of anemia: MCV, mean corpuscular volume; fL, femtoliters
Figure 4: Algorithm for the assessment of anemia

67
Figure 5: Koilonychia
Reproduced with permission from Bickle Ian. Clinical exam skills: Hand signs BMJ 2004; 329 :0411402
IMAGES
Figure 6: Angular cheilosis

Science Photo Library
IMAGES
Figure 7: CT scan of a ruptured abdominal aortic aneurysm
University of Michigan, specifically the cases of Dr Gilbert R. Upchurch reflecting the Departments of
Vascular Surgery and Radiology
69
IMAGES Evaluation of anemia Images
Figure 8: Chest x-ray showing a widened mediastinum

From the collection of Professor James Brown; used with permission
IMAGES
Figure 9: Peripheral blood film of a patient with acute myelogenous leukemia showing myeloid blasts with an
Auer rod
From the collection of Dr Kavita Raj and Dr Priyanka Mehta; used with patient consent
71
IMAGES Evaluation of anemia Images
Figure 10: Cytospin prepared from bone marrow aspirate illustrates the typical cell cytology, with oval- to
bean-shaped nuclei and moderate amounts of cytoplasm with irregular cytoplasmic borders (Wright Giemsa
100x oil)
From the collection of Lynn Moscinski, MD; used with permission
Figure 11: Peripheral blood smear with spherocytes, reticulocytes, and a nucleated red blood cell (RBC)
From the collection of John Densmore, Department of Medicine, University of Virginia; used with permission
Figure 12: Red cells in sickle cell disease

From the personal collection of Sophie Lanzkron, MD; used with permission
IMAGES
73
Evaluation of anemia Disclaimer
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75
Contributors:
// Authors:
Robert Zaiden, MD
Hematologist Oncologist
Baptist MD Anderson Cancer Center, Jacksonville, FL
DISCLOSURES: RZ declares that he has no competing interests.
// Acknowledgements:
Dr Robert Zaiden would like to gratefully acknowledge Dr Fauzia Rana, a previous contributor to this topic.
DISCLOSURES: FR declares that she has no competing interests.
// Peer Reviewers:
Christoph Pechlaner, MD
Associate Professor of Medicine
Innsbruck Medical University, Innsbruck, Austria
DISCLOSURES: CP declares that he has no competing interests.
John Densmore, MD, PhD

Associate Professor of Clinical Medicine
Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA
DISCLOSURES: JD declares that he has no competing interests.
Carlos Aravena, MD
Internal Medicine Instructor
Member of Evidence Based Medicine Unit, Catholic University of Chile, Santiago, Chile
DISCLOSURES: CA declares that he has no competing interests.

Evaluation of Anemia

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Evaluation of Anemia

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Evaluation of anemia

Straight to the point of care

Last updated: Mar 24, 2021

Hb <11.5 g/dL in children ages 5 to 11 years

Hb <13 g/dL in men (ages over 15 years)

Morphological classification of anemia

• Microcytic (MCV <80 femtoliters [fL]).

• Hyperproliferative (reticulocyte count >2%): the proportion of circulating reticulocytes increases

• Megaloblastic: a deficiency of DNA production or maturation resulting in the appearance of large

Classification of anemia: MCV, mean corpuscular volume; fL, femtoliters

Nutrient deficiency or depletion

• The most common cause of anemia worldwide.

• Often causes iron deficiency.

Acquired bone marrow disease

• A disorder of stem cell failure, leading to pancytopenia in the absence of splenomegaly.

• Toxic causes include benzene, dipyrone, chloramphenicol, penicillamine, and gold.

• Definitive diagnosis is established following bone marrow aspiration and biopsy.

Pure red cell aplasia

• Caused by congenital or acquired impairment of erythroid progenitor cells.

• Radiation exposure can produce a pancytopenia.

Chronic systemic disease

Chronic kidney disease[15]

• Produces a normocytic or microcytic anemia. The etiology is complex and multifactorial.

• A mild to moderate nonmegaloblastic macrocytic anemia is produced by a combination of intravascular

Alloimmune hemolytic anemia

• Can be caused by transfusion reactions, usually due to ABO incompatibility.

• A range of infections can produce a hemolytic anemia, including cytomegalovirus, infectious

• A group of autosomal-recessive genetic conditions that result in decreased or absent production of

• A hemolytic anemia caused by an autosomal-dominant inherited abnormality of RBCs that produces

cell proliferation. Loss of telomerase produces bone marrow failure.

Hemolytic uremic syndrome[24]

• An acquired syndrome produced by activation of coagulation pathways, resulting in the formation of

• A clinical syndrome of microangiopathic hemolytic anemia and thrombocytopenic purpura.

• Anemia in pregnancy is common, with a prevalence of 2.1% in the US.[31] Prevalence is highest in

• New-onset anemia in hospitalized patients with previously normal hemoglobin. Hospital-acquired

Microangiopathic hemolytic anemias

Sickle cell vaso-occlusive crisis

Combined vitamin B12 and folate deficiency

Leukemias or aplastic anemia

Decreased physiologic reserve

Evaluation should include identification of any source of active or acute bleeding.

• The mechanism and site of any trauma should be determined.

The anemia may be:

Algorithm for the assessment of anemia

Microcytic anemia: abnormal serum iron studies

(CD55 and CD59) and is diagnostic of paroxysmal nocturnal hemoglobinuria.

• A history of an underlying inflammatory process (infection, neoplasms, autoimmune reactions, and

Microcytic anemia: normal serum iron studies

Thalassemia is diagnosed using Hb electrophoresis. The presence of Hb H, Hb Bart, and concomitant

Normocytic anemia: hypoproliferative

• Ecchymoses or petechiae due to thrombocytopenia suggest hematologic malignancy, myelodysplastic

• Should be guided by the history and examination findings.

• Hepatitis serology, to exclude acute or chronic active hepatitis

Normocytic anemia: hyperproliferative

• Direct antiglobulin (Coombs) test, which is positive in autoimmune hemolytic anemia.

Macrocytic anemia: megaloblastic

known to cause oval macrocytosis with MCV>110 femtoliters (fL).

Macrocytic anemia: nonmegaloblastic

• May reveal stigmata of chronic alcoholism or chronic liver disease.

• CBC shows associated neutropenia and thrombocytopenia with macro-ovalocytes in myelodysplastic

Acute gastrointestinal bleeding

Rupture of a vascular aneurysm

Vitamin B12 deficiency