9/1/2020 Anemia - AMBOSS

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Anemia Last updated: 3.06.2020

Summary
Anemia is de ned as a decrease in the quantity of circulating red blood cells (RBC), represented by a reduction in hemoglobin
concentration (Hb), hematocrit (Hct), or RBC count. It is a common condition that can be caused by inadequate RBC production,
excessive RBC destruction, or blood loss. The most common cause is iron de ciency. Clinical features, if present, are mostly nonspeci c
and may include fatigue, dyspnea, conjunctival pallor, and tachycardia. Once anemia has been established, the mean corpuscular volume
(MCV) should be checked to distinguish between microcytic, normocytic, and macrocytic anemia and to determine the next diagnostic
steps. Reticulocyte count can also be used to evaluate the bone marrow response. Treatment depends on the form of anemia and
underlying condition. Acute and/or severe cases of anemia may require transfusion of packed red blood cells.
See basics of hematology, transfusion, and iron de ciency anemia for more information.

De nition
De nition: a decrease in the absolute number of circulating RBCs; exact cutoffs vary from source to source.

WHO criteria for anemia [1]

Men: Hb < 13 g/dL

Women: Hb < 12 g/dL

Revised WHO/National Cancer Institute [2]

Men: Hb < 14 g/dL
Women: Hb < 12 g/dL

American Society of Hematology [3]

Men: Hb < 13.5 g/dL

Women: Hb < 12 g/dL

Classi cation
Anemia may be classi ed into several subtypes based on the following methods:

Morphology/size of RBCs (the classi cation most widely used) [4]

Time course: acute vs. chronic
Inheritance: inherited vs. acquired

Etiology: primary vs. secondary

RBC proliferation: hypoproliferative (decreased RBC production) vs. hyperproliferative (increased RBC destruction or blood loss)

Classi cation of anemia by morphology

Microcytic anemia Normocytic anemia Macrocytic anemia

MCV (fL) < 80 80–100 > 100

Mechanism Insuf cient hemoglobin Decreased blood volume and/or Insuf cient nucleus maturation relative to cytoplasm
production decreased erythropoiesis expansion due to
Defective DNA synthesis
Defective DNA repair

Differential Defective heme synthesis Hemolytic anemia Megaloblastic anemia: impaired DNA synthesis and/or repair
Iron de ciency anemia Intrinsic defects with hypersegmented neutrophils
diagnosis
(the most common) Hemoglobinopathies Vitamin B12 de ciency
Sickle cell anemia
Lead poisoning Folate de ciency
Anemia of chronic HbC disease
Medications
disease (late phase) Enzyme de ciencies Phenytoin
Pyruvate kinase de ciency
Sideroblastic anemia Sulfa drugs
G6PD de ciency
Defective globin chain Trimethoprim
Membrane defects
Hydroxyurea
Thalassemia Paroxysmal nocturnal
hemoglobinuria MTX

Hereditary spherocytosis 6-mercaptopurine

Extrinsic defects Fanconi anemia

Autoimmune hemolytic Orotic aciduria
anemia
Nonmegaloblastic anemia: normal DNA synthesis without
Microangiopathic hemolytic hypersegmented neutrophils
anemia Liver disease
Macroangiopathic hemolytic Alcohol use
anemia
Diamond-Blackfan anemia
Infections
Myelodysplastic syndrome
Mechanical destruction
Multiple myeloma
Nonhemolytic anemia
Hypothyroidism
Blood loss
Aplastic anemia
Anemia of chronic kidney
disease
Iron de ciency anemia (early
phase)
Anemia of chronic disease (early
phase)

Both iron de ciency anemia and anemia of chronic disease can manifest with normocytic anemia in the initial phase and
microcytic anemia later on.

Bone marrow failure (e.g., due to myeloproliferative malignancy, myelodysplastic syndrome) can manifest with microcytic,
normocytic, or macrocytic anemia.

The causes of microcytic anemia can be remembered with IRON LAST: IRON de ciency, Lead poisoning, Anemia of chronic
disease, Sideroblastic anemia, Thalassemia.

References:[5][6][7]

Clinical features
Asymptomatic
Pallor; (e.g., on mucous membranes, conjunctivae)

Exertional dyspnea; and fatigue

Pica (craving for ice or dirt)

Jaundice (in hemolytic anemia)

Muscle cramps

Worsening of angina pectoris

Features of hyperdynamic state

Bounding pulses
Tachycardia/palpitations
Flow murmur

Pulsatile sound in the ear

Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., thalassemia, myelo brosis).
Hepatosplenomegaly

Paravertebral mass
Widening of diploic spaces of the skull

Pulse acceleration is often the rst sign of hemodynamically relevant blood loss.

Diagnostics

Approach

1. Check CBC to con rm anemia and assess severity.

If acute blood loss anemia is suspected → see acute blood loss anemia
2. Based on MCV, classify into microcytic, macrocytic, and normocytic anemia.
3. Order initial tests to evaluate the underlying cause of anemia.

Microcytic anemia: iron panel to evaluate for iron de ciency anemia; further evaluation depends on iron panel ndings.
Macrocytic anemia: peripheral blood smear to differentiate megaloblastic anemia from nonmegaloblastic anemia.
Megaloblastic anemia: serum B12 and folate levels and, if necessary, serum homocysteine and methylmalonic acid levels to
identify vitamin B12 de ciency and/or folate de ciency

Nonmegaloblastic anemia: reticulocyte count to differentiate macrocytosis due to hemolysis/blood loss (high reticulocyte count)
from macrocytosis due to drugs, alcohol, myelodysplastic syndromes, or pure red cell aplasia (low reticulocyte count).

Normocytic anemia: reticulocyte count to assess bone marrow response.

Reticulocyte count > 2%: reassess history for blood loss, consider FOBT (see GI bleeding); obtain LDH, haptoglobin, and
unconjugated bilirubin to evaluate for hemolytic anemia

Reticulocyte count < 2%: obtain iron studies, serum vitamin B12 and folate levels; if normal, obtain a metabolic panel

4. Consider advanced diagnostics such as hemoglobin electrophoresis and bone marrow aspirate and biopsy as needed and with the
guidance of a hematologist.

Blood for further tests (e.g., iron studies, vitamin B12, folate levels) should be drawn before the patient receives a blood transfusion
because blood products can alter the study ndings.

CBC with differential

Initial test to con rm and classify anemia.

RBC indices: MCV is the most important parameter in the diagnostic workup of anemia.

Based on MCV, further testing should be performed to determine the underlying cause.

Abnormalities in platelet count, WBC count, and WBC differential may provide signs of the underlying diagnosis. [8]
Abnormal leukocytes may suggest bone marrow failure or bone marrow malignancy (e.g., aplastic anemia, leukemia,
myelodysplastic).
Pancytopenia can result from several etiologies (e.g., peripheral cell destruction or sequestration in hypersplenism, aplastic anemia,
infection).

Microcytic anemia (MCV < 80 fL) [8][9]

Iron studies: initial investigation for microcytic anemia

↓ Ferritin OR normal/↑ ferritin and ↑ TIBC: iron de ciency anemia (see diagnosis of iron de ciency anemia)

Normal/↑ ferritin and ↓ TIBC: anemia of chronic disease [10]

Serum iron levels are decreased in iron de ciency anemia and anemia of chronic disease.
Peripheral blood smear (PBS), reticulocyte count, RDW: not routinely required to evaluate microcytic anemia because ndings are
often nonspeci c
PBS ndings may suggest a speci c etiology.

Reticulocyte count
Low reticulocyte count (< 2%): iron de ciency anemia, thalassemia trait, anemia of chronic disease, sideroblastic anemia, and lead
poisoning

High reticulocyte count (> 2%): thalassemia

RDW: typically high in iron de ciency anemia and sideroblastic anemia
Hemoglobin electrophoresis: obtain if serum iron levels, TIBC, and TfS are normal or elevated

Normal hemoglobin A2: sideroblastic anemia, α-thalassemia trait

Increased hemoglobin A2: β-thalassemia trait
Other hemoglobinopathies (e.g., hemoglobin E, hemoglobin C)

Bone marrow biopsy: consider if the following are identi ed [9]

Ringed sideroblasts on PBS (see sideroblastic anemia, myelodysplastic syndromes)
Unexplained thrombocytopenia, leukocytopenia, or pancytopenia

Numerous immature forms of blood cells on CBC and/or PBS

Serum lead level: consider in patients with basophilic stippling but no ringed sideroblasts on PBS (see lead poisoning)

Serum laboratory ndings in microcytic anemia

Iron Ferritin Transferrin Transferrin or Reticulocyte Red cell distribution

saturation TIBC count width
(TfS) (RDW)

Iron de ciency ↓ ↓ ↓ ↑ ↓ ↑

Anemia of chronic disease ↓ ↑ Normal to ↓ ↓ Normal

↓

Thalassemia Normal to Normal to Normal to Normal to ↓* ↑ Normal (occasionally ↑)

↑* ↑* ↑*

Sideroblastic anemia ↑ ↑ ↑ ↓ ↓ ↑

Pregnancy or use of oral Normal to Normal ↓ ↑ Normal Normal

↓
contraceptive pills

* If there is iron overload (e.g., due to multiple transfusions, ineffective erythropoiesis, increased GI iron absorption)

Iron de ciency anemia and thalassemia trait are the most common causes of microcytic anemia. [9]

Basophilic stippling on peripheral blood smear suggests lead poisoning or sideroblastic anemia. Because ringed sideroblasts are
not usually seen in lead poisoning, they can help to distinguish between this condition and sideroblastic anemia.

While decreased ferritin con rms the diagnosis of iron de ciency anemia, elevated serum ferritin does not rule it out.

Macrocytic anemia (MCV > 100 fL) [8][11][12][13]

Peripheral blood smear (PBS): initial investigation for macrocytic anemia to look for megaloblastic changes (hypersegmented
neutrophils)

Hypersegmented neutrophils (> 5 lobes): megaloblastic anemia

No hypersegmented neutrophils: nonmegaloblastic anemia

Evaluation of megaloblastic macrocytic anemia

Vitamin B12 and folate levels: obtain in all patients with megaloblastic changes on PBS. [14][15]

Vitamin B12 levels < 200 pg/mL: vitamin B12 de ciency (see “Diagnostics” in vitamin B12 de ciency for further workup)

Folate < 2 ng/mL: folate de ciency

Serum homocysteine and methylmalonic acid levels: obtain in patients with borderline serum vitamin B12 and/or folate levels

Normal methylmalonic acid but ↑ homocysteine levels: folic acid de ciency

↑ Methylmalonic acid, normal/↑ homocysteine: vitamin B12 de ciency [12]

Bone marrow biopsy: consider if any of the following are present [12]
Normal vitamin B12 and folate levels

Normal methylmalonic acid and homocysteine levels

Unexplained thrombocytopenia, leukocytopenia, or pancytopenia

Numerous immature forms of blood cells on CBC and/or PBS

Additional evaluation: : consider urine orotic acid levels if orotic aciduria is suspected (extremely rare)

Serum methylmalonic acid levels are normal in folic acid de ciency and elevated in vitamin B12 de ciency. Serum homocysteine
levels are elevated in both.

Evaluation of nonmegaloblastic macrocytic anemia [8][12]

Reticulocyte count: in all patients with nonmegaloblastic macrocytic anemia to evaluate bone marrow response
Normal/low reticulocyte count (< 2%)
[12]
Obtain a detailed drug and alcohol use history.

Consider TSH, hepatic panel.

High reticulocyte count (> 2%)

Reassess history for evidence of acute or chronic blood loss.

Check hemolysis labs: ↓ haptoglobin, ↑ LDH, ↑ unconjugated bilirubin suggest a hemolytic anemia

Additional evaluation: consider the following if reticulocyte count and metabolic panels are normal and there is no history of
drug/alcohol use

Hemoglobin electrophoresis: ↑ HbF level indicates Diamond-Blackfan anemia

Bone marrow biopsy

Hypercellular marrow with dysplasia of all three cell lines: myelodysplastic syndrome

Hypocellular fat- lled marrow : aplastic anemia

Absent or sparse erythroid precursors: pure red cell aplasia

The most common causes of macrocytosis are chronic alcohol consumption, vitamin B12 and/or folate de ciency, and certain
medications. [12]

Normocytic anemia (MCV 80–100 fL) [8][11][13][16]

Reticulocyte count: in all patients with normocytic anemia to evaluate bone marrow response
Normal/low reticulocyte count (< 2%) indicates ineffective or decreased RBC production (hypoproliferative anemia)

Iron studies: to evaluate for iron de ciency anemia and/or anemia of chronic disease; (see microcytic anemia)

Vitamin B12 and folate levels (see megaloblastic macrocytic anemia)

[8]
Basic metabolic panel (BMP), LFTs, thyroid studies: if iron studies and B12 and folate levels are normal

[17]
Serum erythropoietin levels: consider if BUN and/or creatinine levels are abnormal
[13]
High reticulocyte count (> 2%)

Reassess history for evidence of acute or chronic blood loss.

Check hemolysis labs: ↓ haptoglobin, ↑ LDH, ↑ unconjugated bilirubin suggest a hemolytic anemia

Bone marrow aspirate and biopsy: consider in hypoproliferative anemia with normal nutritional assays and metabolic panels [8]

Additional diagnostics

Peripheral blood smear

Manual examination of a peripheral blood sample under a microscope

May reveal classic pathologic RBC forms, which can be used to identify certain types of anemia that automated RBC indices cannot
(e.g., schistocytes in hemolytic anemia)

See erythrocyte morphology.

Bone marrow biopsy

Manual examination of bone marrow aspirate sample under a microscope

Rarely used in the workup of anemia

Indications include pancytopenia and/or abnormal cells on the CBC or peripheral blood smear (e.g., blasts)

Prussian blue staining if sideroblastic anemia is suspected (see above)

Can be used to diagnose:

Aplastic anemia

Myelodysplastic syndromes

Myeloproliferative neoplasm
Malignant invasion of the bone marrow

Imaging

Imaging is not routinely indicated for the workup of anemia unless bleeding is suspected.

Consider endoscopy and/or colonoscopy in patients with anemia and positive FOBT.

Consider abdominal ultrasound to evaluate for hypersplenism, liver disease, or renal disease.
Consider CT and/or PET scan if malignancy is suspected.

Treatment
Identify and treat the underlying cause

Blood transfusion with RBCs for severe anemia:

Hb ≤ 7 g/dL
Hb ≤ 8 g/dL if the patient either has a preexisting cardiovascular disease or is undergoing cardiac or orthopedic surgery

See transfusion for further details

Consider hospital admission or observation in: [18]

Acutely symptomatic anemia

Actively bleeding patient, as clinically indicated

Patients requiring blood transfusion

Bone marrow transplantation may be indicated in certain cases (e.g., aplastic anemia).

Acute management checklist

IV access

IV uid resuscitation if the patient is hypotensive or tachycardic

Type and screen with crossmatching

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Consent patient for blood transfusion.
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Obtain blood for further diagnostic workup of anemia before initiating transfusion.

Consider indications for transfusion of packed RBCs.

Consider transfusion of other blood components, if indicated (e.g., platelets, fresh frozen plasma; see transfusion).
Identify and treat the underlying cause.

Serial blood pressure monitoring, continuous pulse oximetry

Supplemental oxygen as needed

Aplastic anemia

Description: pancytopenia caused by bone marrow insuf ciency [19]

Etiology

Idiopathic in > 50% of cases

Possibly immune-mediated

May follow acute hepatitis (hepatitis-associated aplastic anemia)

Medication side effects: carbamazepine, methimazole, NSAIDs, chloramphenicol, propylthiouracil, sulfa drugs, cytostatic drugs (esp.
alkylating agents and antimetabolites)
Toxins: benzene, cleaning solvents, insecticides, toluene

Ionizing radiation
Viruses: parvovirus B19, HBV, EBV, CMV, HIV
[20][21]
Fanconi anemia

Hereditary autosomal recessive disorder due to a DNA crosslink repair defect resulting in bone marrow failure
Skeletal and organ abnormalities: short stature, hypo- and hyperpigmentation, cafe-au-lait spots, microcephaly, developmental
delay, thumb and forearm malformations, kidney, GI, heart, eye, and ear abnormalities

Laboratory tests show pancytopenia and normocytic or macrocytic anemia.

∼ 50% of patients with Fanconi anemia will develop acute myeloid leukemia or myelodysplastic syndromes in early adulthood.

Clinical features

Fatigue, malaise
Pallor

Purpura, petechiae, mucosal bleeding

Infection
Diagnostics

CBC:

Pancytopenia (in contrast to aplastic crisis characterized by anemia only)

Normocytic or macrocytic anemia

Reticulocyte count: low

EPO level: high

Bone marrow biopsy ndings

Hypocellular fat- lled marrow (dry bone marrow tap)

RBCs normal morphology

Treatment

Cessation of the causative agent

Supportive therapy
Treatment of infections

Blood transfusion

Platelet transfusion
Bone marrow stimulants (e.g., GM-CSF)

Immunosuppressive therapy

Cyclosporine
Antithymocyte globulin (ATG)

Tacrolimus

Eltrombopag
Alemtuzumab

Consider hematopoietic cell transplantation (HCT) in young patients. [22]

Agents that can cause aplastic anemia: Can't Make New Blood Cells Properly = Carbamazepine, Methimazole, NSAIDs,
Benzenes, Chloramphenicol, Propylthiouracil

References: [23][24][25][26][27]

Anemia of chronic disease

Description: anemia due to chronic in ammation

Epidemiology: second most common anemia [28]

Pathophysiology: in ammation → increase in cytokines (esp. IL-6) and hepcidin → results in the outcomes listed below:

Reduced iron release from macrophages in the reticuloendothelial system and reduced intestinal iron absorption → reduced iron
available systemically
Reduced response (of production) to erythropoietin (EPO) and relative reduction of EPO levels → reduced RBC synthesis

Reduced erythrocyte survival and lifespan

Etiology
In ammation (e.g., rheumatoid arthritis, systemic lupus erythematosus)

Malignancy (e.g., lung cancer, breast cancer, lymphoma)

Chronic infections (e.g., tuberculosis)

Diagnostics

CBC: normocytic anemia (early phase) → microcytic anemia (later phase)

Low iron
Low iron saturation

Low TIBC

Elevated serum ferritin

Low reticulocyte count

Treatment:

Treat the underlying cause

Blood transfusion if required (see transfusion for indications for blood transfusion)

EPO in chronic incurable diseases (e.g., chronic kidney disease)

References:[29]

Sideroblastic anemia

Description: : anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria [30]
Etiology

Inherited: X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect

Acquired
Vitamin B6 de ciency

Lead poisoning

Alcohol use disorder

Drugs (e.g., chloramphenicol, isoniazid , linezolid)

Copper de ciency

Myelodysplastic syndrome

Malignancy
Diagnostics

CBC: microcytic anemia

Serum iron studies

High ferritin

High iron

High transferrin saturation

Normal/low TIBC

Peripheral blood smear

Basophilic stippling of RBCs

Normocytes/macrocytes (more common in acquired etiologies)

Prussian blue staining of bone marrow: ringed sideroblasts

Treatment
Cessation of the offending agent

Pyridoxine (B6) supplementation (a cofactor for δ-ALA synthase)

References: [31]

Pure red cell aplasia

Description: normocytic, normochromic anemia characterized by a severe reduction in circulating reticulocytes and marked reduction
or absence of erythroid precursors in the bone marrow [32]

Pathophysiology: : thought to be related to abnormal T-cell function and IgG antibodies that target erythroblasts and erythropoietin

Etiology

Acquired: most often idiopathic, but can be associated with

Thymoma

Myelodysplastic syndrome

Drugs (e.g., phenytoin, chloramphenicol)

Parvovirus B19 infection

Autoimmune disorders (e.g., type 1 diabetes, thyroiditis, rheumatoid arthritis)

Congenital: Diamond-Blackfan anemia (DBA)

Intrinsic defect of erythroid progenitor cells → increased apoptosis

Rapid onset of macrocytic (non-megaloblastic) anemia in infancy (usually diagnosed within the rst year of life)

Additional clinical features (physical abnormalities manifest in ∼ 50% of patients)

Short stature, webbed neck

Upper extremity malformations (e.g., triphalangeal thumbs)

Microcephaly, micrognathia

Hypertelorism, at nasal bridge, cleft palate

Electrophoresis

Elevated HbF levels

Low total Hb levels

Diagnosis

Low reticulocyte count

Bone marrow biopsy shows marked reduction or absence of erythroid precursors.

Treatment

Treatment of the underlying cause (e.g., cessation of possible offending agents, thymectomy)
Red blood cell transfusion for symptomatic patients

Immunosuppressive and/or cytotoxic agents (e.g., glucocorticoids, cyclosporine, cyclophosphamide)

References:[33][23][24][25][26][27][34][35][32]

Acute blood loss anemia

Description: acute anemia due to blood loss

Etiology: any cause of bleeding can cause acute blood loss anemia
[16]
Clinical features: May be asymptomatic or have symptoms of anemia (see above)

Diagnostics [16][8]

Routine laboratory studies

CBC: ↓ or normal Hb
Usually normocytic anemia

Compare to prior studies, if available.

Check platelets for thrombocytopenia.

Type and screen with crossmatching

Coagulation panel

Blood for potential further studies based on CBC should be drawn before blood transfusion (draw and hold).
Imaging: Modality depends on the pretest probability of the suspected site of bleeding.

CT of soft tissue if there is concern for intramuscular bleeding.

Abdominal/pelvic CT if there is concern for intra-abdominal bleeding.

Chest radiography and/or chest CT if there is concern for a pulmonary source (See “Diagnostics” in pleural effusion and in
hemothorax).

Endoscopy and/or colonoscopy if there is concern for a GI bleed. (See ''Diagnostics'' in gastrointestinal bleeding)
Treatment

Identify and treat the underlying cause

Blood transfusion

Hemoglobin and hematocrit levels can initially be normal in acute hemorrhage, even if there has already been signi cant blood
loss. They will eventually decrease after plasma volume has been restored either spontaneously or via IV uid resuscitation.

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