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 < 13.5 g/dL
  • Women: Hb < 12 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:

• Morphology/size of RBCs (the classification 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)

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.

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

References:^[5][6][7]

• Asymptomatic
• Pallor; (e.g., on mucous membranes, conjunctivae)
• Exertional dyspnea; and fatigue
• Pica (craving for ice or dirt)
• Jaundice (in hemolytic anemia)
• Muscle cramps
• Growth impairment (chronic anemia)
• Worsening of angina pectoris
• 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

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

Approach

1. Check CBC to confirm 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 deficiency anemia; further evaluation depends on iron panel findings.
   • 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 deficiency and/or folate deficiency
     • 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 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. ^[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 deficiency anemia (see diagnosis of iron deficiency anemia)
  • Normal/↑ ferritin and ↓ TIBC: anemia of chronic disease ^[10]
  • 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
• 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 ^[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)

Iron deficiency 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 confirms the diagnosis of iron deficiency 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 deficiency (see “Diagnostics” in 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: folic acid deficiency
  • ↑ Methylmalonic acid, normal/↑ homocysteine: vitamin B₁₂ deficiency ^[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 deficiency and elevated in vitamin B₁₂ deficiency. 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%)
    • Obtain a detailed drug and alcohol use history. ^[12]
    • 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. ^[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 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 B₁₂ and folate levels are normal ^[8]
    • Serum erythropoietin levels: consider if BUN and/or creatinine levels are abnormal ^[17]
  • High reticulocyte count (> 2%) ^[13]
    • 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.

• 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).

• IV access
• IV fluid resuscitation if the patient is hypotensive or tachycardic
• Type and screen with crossmatching
• Consent patient for blood transfusion.
• 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

• Description
  • Pancytopenia caused by bone marrow insufficiency ^[19]
  • Should not be confused with aplastic crisis, a condition in which erythropoiesis is temporarily suppressed (e.g., due to parvovirus B19 infection in patients with hemolytic anemias)
• 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: HBV, EBV, CMV, HIV
  • Fanconi anemia ; ^[20][21]
    • 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. ^[22]
• 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 findings
    • Hypocellular fat-filled 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, eltrombopag)
  • Immunosuppressive therapy
    • Cyclosporine
    • Antithymocyte globulin (ATG)
    • Tacrolimus
    • Alemtuzumab
  • Consider hematopoietic cell transplantation (HCT) in young patients. ^[23]

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

• Description: anemia due to chronic inflammation
• Epidemiology: second most common anemia ^[24]
• 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:^[25]

• Description: : anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria ^[26]
• 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: ^[27]

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 ^[28]
• 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 ^[29]

• 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 ^[30]
  • 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) ^[16]
• Diagnostics ^[8][16]
  • 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 significant blood loss. They will eventually decrease after plasma volume has been restored either spontaneously or via IV fluid resuscitation.

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