What is the best approach to evaluate and manage anemia in a patient with suspected anemia, considering demographic, medical history, and potential underlying chronic conditions or nutritional deficiencies?

Evaluation of Anemia: A Structured Diagnostic Approach

Begin with a complete blood count (CBC) with differential, peripheral blood smear, reticulocyte count with reticulocyte index, and iron studies (serum ferritin, transferrin saturation, total iron-binding capacity) to systematically classify the anemia and guide targeted investigation. 1, 2

Initial Laboratory Assessment

Hemoglobin is the preferred measure over hematocrit due to superior reproducibility across laboratories and lack of interference from storage time or patient-specific variables. 3

Define Anemia by Gender-Specific Thresholds:

• Men: Hemoglobin <13.0 g/dL 1, 2
• Non-pregnant women: Hemoglobin <12.0 g/dL 1, 2

Critical caveat: These standard definitions do not apply to pregnant women, menstruating women, individuals living at high altitude, smokers, men ≥70 years, non-Caucasian populations, patients with chronic lung disease, or those with hemoglobinopathies. 3, 4

Step 1: Classify by Mean Corpuscular Volume (MCV)

Microcytic Anemia (MCV <80 fL)

Check serum ferritin first. If ferritin <45 ng/mL (or <30 μg/L without inflammation), diagnose iron deficiency anemia. 3, 1

Major pitfall: Ferritin is an acute phase reactant and may be falsely elevated in chronic kidney disease, inflammatory states, or infection despite true iron deficiency. In these contexts, interpret ferritin in conjunction with transferrin saturation <15% and elevated total iron-binding capacity. 3, 1, 4

For confirmed iron deficiency anemia, proceed with GI evaluation:

• Test non-invasively for H. pylori and celiac disease before endoscopy 3, 4
• Bidirectional endoscopy is strongly recommended for men and postmenopausal women (strong recommendation, moderate quality evidence) 3
• For premenopausal women, particularly younger patients, bidirectional endoscopy is a conditional recommendation; empiric iron supplementation alone may be reasonable if they prioritize avoiding endoscopy risks over detecting rare neoplasia 3

If ferritin is adequate but MCV remains low, consider thalassemia, anemia of chronic disease, or sideroblastic anemia. 1, 2

Normocytic Anemia (MCV 80-100 fL)

Calculate the reticulocyte index to differentiate production versus destruction:

• Reticulocyte index <1.0 indicates decreased RBC production, suggesting iron deficiency, vitamin B12/folate deficiency, aplastic anemia, bone marrow dysfunction, chronic kidney disease, or chronic inflammatory conditions 2, 4
• Reticulocyte index >2.0 indicates adequate bone marrow response despite anemia, suggesting ongoing blood loss or hemolysis 2, 4

For low reticulocyte count:

• Assess renal function (creatinine, estimated GFR) to evaluate for chronic kidney disease 1, 4
• Check inflammatory markers (CRP, ESR) for anemia of chronic disease 4
• Consider bone marrow evaluation if other causes excluded 1

For elevated reticulocyte count:

• Perform hemolysis workup: direct Coombs test, lactate dehydrogenase, haptoglobin, indirect bilirubin, peripheral blood smear 4
• Evaluate for acute or chronic blood loss 1

Macrocytic Anemia (MCV >100 fL)

Measure vitamin B12 and folate levels immediately. 1, 4

Critical pitfall: Never administer folic acid before checking vitamin B12 levels, as this can precipitate or worsen neurological complications of B12 deficiency. 4

If B12 is low, confirm with methylmalonic acid and homocysteine levels (both elevated in B12 deficiency). 1

Step 2: Obtain Targeted Clinical History

Focus on these specific elements:

• Duration and onset: Acute versus chronic, lifelong history suggesting inherited disorder 1, 5
• Symptoms of severity: Syncope, exercise dyspnea, chest pain, headache, vertigo, fatigue 2
• Blood loss: Menstrual history (volume, duration), gastrointestinal symptoms (melena, hematochezia, dyspepsia), use of antiplatelet or anticoagulant therapy 3, 2
• Nutritional factors: Dietary restrictions, malabsorption symptoms, prior gastric surgery 1, 4
• Chronic conditions: Chronic kidney disease, inflammatory bowel disease, rheumatologic disease, malignancy, HIV infection 1, 4
• Medications: NSAIDs, proton pump inhibitors, metformin, anticonvulsants 2
• Family history: Thalassemia, sickle cell disease, hereditary spherocytosis 5

Step 3: Peripheral Blood Smear Examination

Review the peripheral smear immediately to visually confirm RBC size, shape, and color, and identify specific morphologic abnormalities. 2

Key findings:

• Hypochromic microcytes: Iron deficiency or thalassemia 1
• Target cells: Thalassemia, liver disease 5
• Schistocytes: Microangiopathic hemolytic anemia 5
• Spherocytes: Hereditary spherocytosis, autoimmune hemolysis 5
• Hypersegmented neutrophils: Megaloblastic anemia (B12 or folate deficiency) 1

Step 4: Treatment Based on Etiology

Iron Deficiency Anemia

Initiate oral iron supplementation as first-line therapy (ferrous sulfate 324 mg tablets contain 65 mg elemental iron) while simultaneously treating the underlying cause. 6, 7

Use intravenous iron when:

• Intolerance to oral iron develops 7
• Chronic kidney disease with poor oral response 7
• Inflammatory bowel disease (oral absorption impaired) 7
• Rapid hematologic response is required 7

Monitor hemoglobin at 4 weeks (goal: increase ≥2 g/dL). After hemoglobin normalizes, confirm iron stores are restored (ferritin >100 ng/mL). 3, 1

Vitamin B12 Deficiency

Treat immediately with hydroxocobalamin 1 mg intramuscularly:

• Daily for 6-7 days 1
• Then on alternate days for 7 doses 1
• Then every 2 months for life if neurological involvement, or monthly if no neurological symptoms 1, 4

Administer folic acid concomitantly only after B12 deficiency is excluded or treatment initiated. 4

Anemia of Chronic Disease/Inflammation

Treat the underlying inflammatory, infectious, or neoplastic condition as the primary strategy. 4

Consider erythropoiesis-stimulating agents only:

• In chronic kidney disease when hemoglobin <10 g/dL and iron stores are adequate 3
• Use the lowest dose to reduce transfusion need; targeting hemoglobin >11 g/dL increases mortality, cardiovascular events, and stroke risk 1

Sideroblastic Anemia

Initiate pharmacological doses of pyridoxine (50-200 mg daily). If responsive, continue lifelong supplementation with pyridoxine 10-100 mg daily. 1

Step 5: Transfusion Considerations

Reserve red blood cell transfusions for:

• Hemoglobin ≤5.1 g/dL with hemodynamic instability or severe symptoms 4
• Symptomatic patients with hemoglobin ≤8 g/dL 4

Special Populations

Chronic Kidney Disease Patients

Screen annually at minimum for anemia (hemoglobin <13.5 g/dL in men, <12.0 g/dL in women). 3

More frequent monitoring is indicated in diabetic patients, who develop anemia at earlier CKD stages and have higher prevalence regardless of kidney function level. 3

The anemia of CKD is normochromic and normocytic, indistinguishable from other chronic conditions; do not assume CKD is the sole cause without excluding other etiologies. 3

Common Diagnostic Pitfalls

Never rely on serum iron alone—always calculate transferrin saturation and check ferritin. 2

Mixed anemia can present with normal MCV when microcytosis and macrocytosis coexist (e.g., combined iron and B12 deficiency). 1

A hemoglobin drop of ≥2 g/dL from baseline warrants evaluation even if the absolute value remains above standard anemia thresholds. 2

Avoid erythropoietin therapy without adequate iron stores, as iron demands exceed availability during erythropoietin treatment. 2