Anemia

Anemia is defined 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 deficiency. Clinical features, if present, are mostly nonspecific 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 deficiency anemia” for more information.

• Definition: 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
  • Pregnant women: Hb < 11 g/dL
  • Children
    • 6–59 months: < 11 g/dL
    • 5–11 years: < 11.5 g/dL
    • 12–14 years: < 12.0 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
• US National Health and Nutrition Examination Survey: children aged 12–35 months: Hb < 11 g/dL

Anemia may be classified into several subtypes based on the following methods:

RBC size and morphology ^[4]

The most widely used classification

Both iron deficiency 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.

Severity ^[1]

• Mild anemia
  • Hb level: below normal range based on age and sex, but > 10–11 g/dL
  • Presentation: usually asymptomatic; clinical features of anemia may be present
• Moderate anemia
  • Hb level: ∼ 7–10.9 g/dL
  • Presentation: clinical features of anemia may or may not be present.
• Severe anemia
  • Hb level: ∼ 7–8 g/dL
  • Presentation: clinical features of anemia typically present; hemodynamic compromise may be present.

Other classifications

• 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)

Microcytic anemia

• Defective heme synthesis
  • Iron deficiency anemia (IDA): the most common
  • Lead poisoning
  • Anemia of chronic disease (late phase)
  • Sideroblastic anemia
• Defective globin chain: Thalassemia

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

Normocytic anemia

Hemolytic anemia

• Intrinsic defects
  • Hemoglobinopathies
    • Sickle cell anemia
    • HbC disease
  • Enzyme deficiencies
    • Pyruvate kinase deficiency
    • G6PD deficiency
  • Membrane defects
    • Paroxysmal nocturnal hemoglobinuria
    • Hereditary spherocytosis
• Extrinsic defects
  • Autoimmune hemolytic anemia
  • Microangiopathic hemolytic anemia
  • Macroangiopathic hemolytic anemia
  • Infections
  • Mechanical destruction

Nonhemolytic normocytic anemia

• Blood loss
• Aplastic anemia
• Anemia of chronic kidney disease
• Iron deficiency anemia (early phase)
• Anemia of chronic disease (early phase)
• Dilutional anemia of pregnancy ^[5]

Macrocytic anemia

Megaloblastic anemia

• Vitamin B₁₂ deficiency
• Folate deficiency
• Medications
  • Phenytoin
  • Sulfa drugs
  • Trimethoprim
  • Hydroxyurea
  • MTX
  • 6-mercaptopurine
• Fanconi anemia
• Orotic aciduria

Nonmegaloblastic anemia

• Liver disease
• Alcohol use
• Diamond-Blackfan anemia
• Myelodysplastic syndrome
• Multiple myeloma
• Hypothyroidism

Clinical features of anemia

• Asymptomatic
• Exertional dyspnea; and fatigue
• Worsening of angina pectoris
• Pallor (e.g., on mucous membranes, conjunctivae)
• Growth impairment (chronic anemia)

Accompanying features

Vary depending on underlying etiology

• Clinical features of shock (if anemia is acute)
• Features of IDA: pica (craving for ice or dirt), brittle nails, angular cheilitis, atrophic glossitis
• Features of megaloblastic anemia: oral sores, mucosal bleeding, paresthesias, ataxia
• Clinical features of hemolysis
• Signs of hemorrhage: e.g., GI bleeding, menorrhagia (See also “Classification of hemorrhagic shock.”)
• Features of hyperdynamic state
  • Bounding pulses
  • Tachycardia/palpitations
  • Flow murmur
  • Pulsatile sound in the ear
  • Possibly heart failure (anemia-induced heart failure)
• Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g., thalassemia, myelofibrosis).
  • Hepatosplenomegaly
  • Paravertebral mass
  • Widening of diploic spaces of the skull

Tachycardia and narrowed pulse pressure are the first signs of hemodynamically relevant blood loss. ^[5]

Approach

• Initial evaluation
  • Unstable patients: Treat acute blood loss anemia immediately without waiting for diagnostic confirmation.
  • Stable patients: Check CBC to confirm anemia and assess severity.
  • Classify anemia by morphology and MCV to narrow down the causes of anemia and guide initial studies.
• Microcytic anemia: Obtain iron panel to screen for IDA; further evaluation depends on iron studies.
• Macrocytic anemia: Obtain PBS to visualize red cell morphology.
  • Megaloblastic anemia: Check serum vitamin B₁₂ and folate levels; if necessary, serum homocysteine and methylmalonic acid levels
  • Nonmegaloblastic anemia: Measure reticulocyte count (retic count) to narrow down causes of macrocytosis.
    • ↑ Retic count: suggests hemolysis or blood loss
    • ↓ Retic count: suggests drug or alcohol toxicity, myelodysplastic syndromes, or pure red cell aplasia.
• Normocytic anemia: Measure retic count to assess bone marrow response.
  • Retic count > 2%: reassess history for blood loss and consider FOBT for occult GI bleed; consider hemolysis workup.
  • Retic count < 2%: obtain iron studies, serum vitamin B₁₂ and folate levels; if normal, check BMP, LFTs, TFTs
• Advanced diagnostics (e.g., Hb-electrophoresis, bone marrow aspirate or biopsy): Consider as needed in consultation with hematology.

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 findings.

CBC with differential

Initial test to confirm 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. ^[6]
  • 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) ^[6][7]

• Iron studies: initial investigation for microcytic anemia
  • ↓ Ferritin OR normal/↑ ferritin and ↑ TIBC: iron deficiency anemia (see diagnosis of iron deficiency anemia)
  • Normal/↑ ferritin and ↓ TIBC: anemia of chronic disease ^[8]
  • Serum iron levels are decreased in iron deficiency anemia and anemia of chronic disease.
• Peripheral blood smear (PBS), reticulocyte count, RDW: not routinely required to evaluate microcytic anemia because findings are often nonspecific
  • PBS findings may suggest a specific etiology.
  • Reticulocyte count
    • Low reticulocyte count (< 2%): iron deficiency anemia, thalassemia trait, anemia of chronic disease, sideroblastic anemia, and lead poisoning
    • High reticulocyte count (> 2%): thalassemia
  • RDW: typically high in iron deficiency anemia and sideroblastic anemia
  • Mentzer index
• 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 identified ^[7]
  • 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)

Iron deficiency anemia and thalassemia trait are the most common causes of microcytic anemia. ^[7]

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 confirms the diagnosis of iron deficiency anemia, elevated serum ferritin does not rule it out.

Macrocytic anemia (MCV > 100 fL) ^{[6][9][10][11]}

• 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. ^[12][13]
  • Vitamin B₁₂ levels < 200 pg/mL: vitamin B₁₂ deficiency (see “Diagnosis of vitamin B12 deficiency” for further workup)
  • Folate < 2 ng/mL: folate deficiency
• Serum homocysteine and methylmalonic acid levels: obtain in patients with borderline serum vitamin B₁₂ and/or folate levels
  • Normal methylmalonic acid but ↑ homocysteine levels: folate deficiency
  • ↑ Methylmalonic acid, normal/↑ homocysteine: vitamin B₁₂ deficiency ^[10]
• Bone marrow biopsy: consider if any of the following are present ^[10]
  • 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 folate deficiency and elevated in vitamin B₁₂ deficiency. Serum homocysteine levels are elevated in both.

Evaluation of nonmegaloblastic macrocytic anemia ^[6][10]

• Reticulocyte count: Obtain in all patients with nonmegaloblastic macrocytic anemia to evaluate bone marrow response.
  • Normal/low reticulocyte count (< 2%)
    • Obtain a detailed drug and alcohol use history. ^[10]
    • 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-filled 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 deficiency, and certain medications. ^[10]

Normocytic anemia (MCV 80–100 fL) ^{[6][9][11][14]}

• 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 deficiency anemia and/or anemia of chronic disease (see microcytic anemia)
    • Vitamin B₁₂ and folate levels (see megaloblastic macrocytic anemia)
    • Basic metabolic panel (BMP), LFTs, thyroid studies: if iron studies and vitamin B₁₂ and folate levels are normal ^[6]
    • Serum erythropoietin levels: consider if BUN and/or creatinine levels are abnormal ^[15]
  • High reticulocyte count (> 2%) ^[11]
    • Reassess history for evidence of acute or chronic blood loss.
    • Check hemolysis labs: ↓ haptoglobin, ↑ LDH, and ↑ unconjugated bilirubin suggest a hemolytic anemia
• Bone marrow aspirate and biopsy: consider in hypoproliferative anemia with normal nutritional assays and metabolic panels ^[6]

Additional diagnostics

• 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: 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.

Management approach

• Identify and treat the underlying causes of anemia, e.g.:
  • Iron therapy for IDA
  • Hemostatic measures for acute hemorrhagic anemia
  • EPO for chronic kidney disease
  • Vitamin replenishment
    • Megaloblastic anemia: e.g., Vitamin B₁₂, folate
    • Sideroblastic anemia: Vitamin B₆
• Blood transfusion: See “Indications for pRBC transfusion” for details. ; ^[16][17][18]
  • Severe anemia; in any patient: e.g., Hb ≤ 7 g/dL; or Hb ≤ 8 g/dL in patients with perioperative or cardiac risk factors
  • Moderate anemia in high-risk or symptomatic patients.
• Consider bone marrow transplantation in select cases (e.g., aplastic anemia).

Disposition

Consider hospital admission or observation in: ^[16]

• Acutely symptomatic anemia
• Actively bleeding patient, as clinically indicated
• Patients requiring blood transfusion
• Anemia with WBC and/or platelet count abnormalities ^[19]

Patients with isolated anemia who are asymptomatic, nonbleeding, and hemodynamically stable with minimal comorbidities can be managed as outpatients. ^[19]

For hemodynamically unstable patients with acute blood loss, see “Hemorrhagic shock.”

• Establish IV access.
• Monitor the patient with serial blood pressures and continuous pulse oximetry.
• Consider indications for pRBC transfusion.
• Send type and screen with crossmatching.
• Obtain blood for further workup of anemia prior to initiating transfusion.
• Obtain patient consent for blood transfusion.
• Consider transfusion of other blood components, if indicated (e.g., platelets for thrombocytopenia; see “Transfusion”).
• Identify and treat the underlying cause.

• Description: anemia due to chronic inflammation
• Epidemiology: second most common anemia ^[20]
• Pathophysiology: inflammation → 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
  • Inflammation (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 total iron binding capacity (TIBC)
  • High 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:^[21]

• Description: : anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria ^[22]
• Etiology
  • Inherited: X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect
  • Acquired
    • Vitamin B₆ deficiency
    • Lead poisoning
    • Alcohol use disorder
    • Drugs (e.g., chloramphenicol, isoniazid , linezolid)
    • Copper deficiency
    • 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: ^[23]

General

• Description: normocytic, normochromic anemia characterized by a severe reduction in circulating reticulocytes and marked reduction or absence of erythroid precursors in the bone marrow ^[24]
• Pathophysiology: : thought to be related to abnormal T-cell function and IgG antibodies that target erythroblasts and erythropoietin
• Etiology
  • Acquired
    • Most often idiopathic
    • Possible associated conditions
      • Thymoma
      • Myelodysplastic syndrome
      • Adverse drugs effects (e.g., from phenytoin, chloramphenicol)
      • Parvovirus B19 infection
      • Autoimmune disorders (e.g., type 1 diabetes, thyroiditis, rheumatoid arthritis)
  • Congenital: Diamond-Blackfan anemia (DBA): see below
• Diagnostics
  • 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)

Diamond-Blackfan anemia ^[25]

• Description
  • Intrinsic defect of erythroid progenitor cells → ↑ apoptosis
  • Usually autosomal dominant inheritance or associated with impaired ribosome synthesis mutations
  • Rapid onset of macrocytic (nonmegaloblastic) anemia in infancy (usually diagnosed within the first year of life)
• Additional clinical features: physical abnormalities manifest in ∼50% of affected individuals
  • Fatigue, poor feeding
  • Short stature, webbed neck
  • Upper extremity malformations (e.g., triphalangeal thumbs)
  • Microcephaly, micrognathia
  • Hypertelorism, flat nasal bridge, cleft palate
  • Congenital cataracts or glaucoma
  • Atrial and ventricular septal defects
• Diagnostics
  • Electrophoresis
    • Elevated HbF levels
    • Low total Hb levels
  • Specific laboratory findings
    • Elevated erythrocyte adenosine deaminase levels (eADA)
    • Increased expression of i antigen in RBCs
• Treatment ^[26]
  • Corticosteroids (first-line treatment)
  • Chronic red cell transfusions: individuals who do not respond to corticosteroids
  • Hematopoietic stem cell transplantation
• Complications
  • Increased risk of malignancy: acute myelogenous leukemia, myelodysplastic syndrome, solid tumors (e.g., colon cancer, osteogenic sarcoma)
  • Treatment-associated complications: iron overload due to repeated transfusions, corticosteroid-induced hyperglycemia
  • Endocrine dysfunction: adrenal insufficiency, hypogonadism, vitamin D deficiency

• Description: acute anemia due to blood loss
• Etiology: any cause of bleeding can cause acute blood loss anemia
• Clinical features: May be asymptomatic or have symptoms of anemia (see above) ^[14]
• Diagnostics ^[6][14]
  • 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 soft tissue if there is concern for intramuscular bleeding
    • CT abdomen and pelvis if there is concern for intraabdominal bleeding
    • CXR and/or CT chest if there is concern for a pulmonary source (see “Diagnosis” in “Pleural effusion” and in “Hemothorax”)
    • Endoscopy and/or colonoscopy if there is concern for a GI bleed (see ''Diagnosis'' in “Gastrointestinal bleeding”)
• Treatment
  • Identify and treat the underlying cause.
    • Prioritize hemostatic control.
    • Consult a specialist for definitive care based on the source of bleeding.
  • Emergency blood transfusion
    • Consider indications for anticoagulation reversal.
    • For hemodynamically unstable patients, see “Hemorrhagic shock” and “Massive transfusion protocol.”

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

Patients on anticoagulants have an increased risk of bleeding and may require anticoagulant reversal for hemodynamic instability or bleeding at a critical site (e.g., intracerebral, airway, retroperitoneal). ^[27]

• One-Minute Telegram 88-2023-3/3: A heart-racking dilemma: transfusions in myocardial infarction and anemia
• One-Minute Telegram 31-2021-1/3: Bariatric surgery associated with very high risk of long-term anemia

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