How should anemia be defined, evaluated, and managed, including appropriate workup and treatment options?

Anemia: Evidence-Based Definition, Evaluation, and Management

Definition of Anemia

Anemia is defined as hemoglobin below 13.0 g/dL (130 g/L) in adult men and below 12.0 g/dL (120 g/L) in non-pregnant adult women, using the World Health Organization thresholds that should be applied across all age groups including the elderly. 1, 2

• In pregnant women during the second and third trimesters, the diagnostic cutoff is hemoglobin < 11.0 g/dL (110 g/L). 1
• Pediatric thresholds are age-specific: approximately 11.0 g/dL for ages 6 months to 5 years, 11.5 g/dL for ages 5–11 years, and 12.0 g/dL for ages 12–13 years. 1, 2
• Standard thresholds require adjustment in elderly men (≥ 70 years), high-altitude residents, smokers, non-Caucasian populations, patients with chronic lung disease, or hemoglobinopathies. 1
• Use the lower limit of the normal range for your specific laboratory, but these should align with WHO-defined lower limits. 3

Critical Pitfall: Elderly Patients

Despite common practice, do not use lower hemoglobin thresholds for elderly patients simply because of age—hemoglobin values below WHO reference values are associated with increased mortality and functional impairment even in advanced age, and a cause is found in over 80% of cases when properly investigated. 4

Initial Laboratory Workup

Order a complete blood count with red-cell indices (MCV, MCH, RDW), absolute reticulocyte count, serum ferritin, transferrin saturation, C-reactive protein, and differential blood count as the minimum initial panel. 1

• The reticulocyte count (corrected for degree of anemia) is essential to assess bone marrow response: low/normal indicates inadequate erythropoiesis, while elevated suggests hemolysis or blood loss. 1, 2
• C-reactive protein is mandatory because it affects interpretation of iron studies. 1
• Peripheral blood smear examination should be performed to identify red cell morphology abnormalities. 2

Diagnostic Algorithm by Mean Corpuscular Volume (MCV)

Microcytic Anemia (MCV < 80 fL)

Iron Studies Interpretation:

• Without inflammation (normal CRP): Serum ferritin < 30 µg/L confirms iron deficiency anemia. 1, 2
• With inflammation (elevated CRP): Ferritin up to 100 µg/L may still represent iron deficiency because ferritin is an acute-phase reactant. 3, 1
• Transferrin saturation < 20% (or < 15%) supports iron deficiency. 1, 2
• Elevated red-cell distribution width (RDW) provides an additional clue for iron deficiency. 1

If iron studies are normal:

• Consider thalassemia—requires hemoglobin electrophoresis for diagnosis. 1
• Consider anemia of chronic disease, which can present with microcytosis. 1

Clinical Response as Diagnostic Tool:

• A hemoglobin rise ≥ 10 g/L within 2 weeks of iron therapy is highly suggestive of absolute iron deficiency, even if iron study results are equivocal. 3

Normocytic Anemia (MCV 80–100 fL)

Algorithm Based on Reticulocyte Count:

Low or Normal Reticulocyte Count (Inadequate Marrow Response):

1. Check iron status:

   • Apply the same ferritin thresholds as above (< 30 µg/L without inflammation; ≤ 100 µg/L with inflammation). 1
   • Transferrin saturation < 20% indicates functional iron deficiency. 1

2. Assess renal function:

   • Measure serum creatinine and urea to identify chronic kidney disease, which commonly causes normocytic anemia through erythropoietin deficiency. 1, 5

3. Evaluate for anemia of chronic disease:

   • Elevated CRP with normal or high ferritin (typically > 100 µg/L) suggests anemia of chronic disease. 1, 5
   • Characteristic findings include low serum iron, low or normal transferrin, low transferrin saturation, and normal or elevated ferritin. 5

4. Investigate primary bone marrow pathology:

   • When other cell lines are abnormal (leukopenia, thrombocytopenia), consider malignancy, vasculitis, aplastic anemia, or myelodysplastic syndrome. 1
   • This warrants hematology consultation and possible bone marrow examination. 1, 5

Elevated Reticulocyte Count (Appropriate Response):

• Suggests hemolysis or acute blood loss. 1, 2
• Order haptoglobin (decreased in hemolysis), lactate dehydrogenase (elevated), and indirect bilirubin (elevated) to confirm hemolysis. 1, 2
• Direct Coombs test is positive in immune-mediated hemolysis. 2

Macrocytic Anemia (MCV > 100 fL)

Immediate measurement of vitamin B12 and folate is required; low levels confirm nutritional deficiency. 1, 2

• Elevated methylmalonic acid and homocysteine confirm B12 deficiency when serum B12 is borderline. 2
• Never give folic acid before checking B12 to prevent neurological complications. 1

When B12 and folate are normal, evaluate for:

• Medication-induced macrocytosis (hydroxyurea, antiretrovirals). 2
• Alcohol misuse. 2
• Hypothyroidism. 2
• Myelodysplastic syndrome, especially with additional cytopenias. 1, 2
• Reticulocytosis (which can elevate MCV). 1

Extended Diagnostic Tests for Unclear Cases

Test	Clinical Use
Soluble transferrin receptor	Differentiates iron deficiency from anemia of chronic disease [1]
Percentage of hypochromic red cells or reticulocyte hemoglobin content	Detects functional iron deficiency [1]
Haptoglobin, LDH, indirect bilirubin	Confirms hemolysis [1]
Serum creatinine and urea	Screens for renal disease contributing to anemia [1]
Bone marrow examination	Indicated for unexplained cytopenias across multiple lineages or suspected primary marrow disorder [1]

Referral to a hematology specialist is advised if the etiology remains unclear after the extended workup. 1

Management Based on Etiology

Iron Deficiency Anemia

Initiate oral iron supplementation as first-line therapy while treating the underlying cause. 1

• Confirm iron stores are restored after hemoglobin normalizes—do not stop therapy when hemoglobin corrects alone. 1
• Use intravenous iron for:
  • Intolerance to oral iron. 1
  • Chronic kidney disease with poor oral response. 1
  • Inflammatory bowel disease. 1

Investigation for source of blood loss:

• In men and postmenopausal women with iron deficiency anemia, perform bidirectional endoscopy (upper and lower GI). 1
• Test for H. pylori and celiac disease non-invasively before endoscopy. 1
• A gastrointestinal bleeding source is found in 60–70% of patients referred for endoscopy. 6

Vitamin B12 Deficiency

Treat immediately with hydroxocobalamin 1 mg intramuscularly. 1

• Give on alternate days until no further improvement. 1
• Then every 2 months for neurological involvement. 1
• Oral vitamin B12 can be as effective as intramuscular B12 in managing anemia due to B12 deficiency and is underused. 6

Anemia of Chronic Disease

Treat the underlying inflammatory, infectious, or neoplastic condition as the primary strategy. 1, 5

• Iron supplementation may be considered if there is evidence of concomitant iron deficiency. 5
• Consider erythropoiesis-stimulating agents only in severe symptomatic anemia, particularly in chronic kidney disease, but with caution and careful monitoring given safety concerns. 1, 5

Transfusion Thresholds

Reserve blood transfusions for:

• Hemoglobin ≤ 5.1 g/dL with hemodynamic instability or severe symptoms. 1
• Symptomatic patients with hemoglobin ≤ 8.0 g/dL. 1

Critical Pitfalls to Avoid

• Ferritin is falsely elevated during inflammation—use a higher cutoff (≤ 100 µg/L) when CRP is elevated rather than the standard < 30 µg/L threshold. 3, 1, 5
• Co-existing micro- and macrocytosis may normalize the MCV—a markedly increased RDW helps uncover this mixed picture. 1
• In chronic kidney disease patients with adequate iron, B12, and folate, a low reticulocyte count more often reflects insufficient erythropoietin production or inflammatory suppression rather than nutrient deficiency. 1
• Hemoglobin measurement is preferred over hematocrit for diagnosing anemia because it is less affected by sample storage time and plasma glucose levels. 1
• Investigation should be considered at any level of anemia in the presence of iron deficiency, though the case is stronger with more severe degrees of anemia, as they are more likely to have serious underlying GI pathology. 3