What is the recommended workup and management plan for a patient presenting with symptoms of anemia, such as fatigue, weakness, or shortness of breath, considering their medical history, physical examination findings, and demographic information, including age, sex, and potential comorbidities like gastrointestinal bleeding, menorrhagia, or neurological symptoms?

Anemia Workup: Systematic Diagnostic Approach

Begin the anemia workup when hemoglobin falls below 13 g/dL in men or 12 g/dL in non-pregnant women, using a structured morphologic classification based on mean corpuscular volume (MCV) and reticulocyte count to guide targeted testing. 1, 2

Initial Laboratory Assessment

Order the following tests immediately when anemia is detected:

• Complete blood count (CBC) with red cell indices including MCV, MCH, MCHC, and RDW 1, 2
• Reticulocyte count to distinguish regenerative from non-regenerative anemia 1, 3
• Iron studies: serum ferritin, transferrin saturation (TSAT), and total iron-binding capacity 1, 2
• Inflammatory markers: C-reactive protein (CRP) to interpret ferritin accurately 2

The reticulocyte count is critical for initial classification: elevated reticulocytes (>100 × 10⁹/L) suggest hemolysis or acute blood loss, while low/normal counts indicate impaired erythropoiesis. 3

Morphologic Classification and Targeted Workup

Microcytic Anemia (MCV < 80 fL)

Iron deficiency is the most common cause. 2 Confirm with:

• Ferritin < 30 μg/L confirms absolute iron deficiency without inflammation 1, 3
• Transferrin saturation < 15-20% supports the diagnosis 1, 2
• MCH is more reliable than MCHC for detecting iron deficiency as it's less affected by storage conditions 2

Critical pitfall: Ferritin is an acute-phase reactant and can be falsely elevated with inflammation, chronic disease, malignancy, or liver disease. 2 In these contexts, ferritin up to 100 μg/L may still represent iron deficiency if TSAT is low. 3

Additional microcytic workup:

• Screen for celiac disease with tissue transglutaminase antibody (approximately 5% of iron deficiency cases) 3
• Consider thalassemia trait if iron studies are normal, particularly in appropriate ethnic backgrounds 2
• Evaluate for chronic inflammatory conditions if ferritin >100 μg/L but TSAT <20% (functional iron deficiency) 3

Normocytic Anemia (MCV 80-100 fL)

Check reticulocyte count first to distinguish causes: 3

If reticulocytes elevated (>100 × 10⁹/L):

• Evaluate for hemolysis: measure haptoglobin, LDH, indirect bilirubin, and examine peripheral smear for schistocytes 2, 3
• Consider acute blood loss if clinical context supports it 2

If reticulocytes low/normal:

• Measure serum creatinine and calculate GFR in all patients—chronic kidney disease is a common cause 3
• Check thyroid-stimulating hormone (TSH) to exclude hypothyroidism 3
• Consider anemia of chronic inflammation/disease if CRP elevated 2
• Evaluate for bone marrow disorders if other causes excluded 4

Macrocytic Anemia (MCV > 100 fL)

Order the following:

• Vitamin B12 level: <150 pmol/L indicates deficiency 4
• Folate level: serum folate <10 nmol/L or RBC folate <305 nmol/L indicates deficiency 4
• TSH and free T4 to exclude hypothyroidism 4, 3

Important consideration: High-dose folic acid supplementation can mask vitamin B12 deficiency symptoms, particularly neurologic manifestations. 2 Always check B12 before treating isolated folate deficiency.

If vitamin levels are normal, consider myelodysplastic syndrome, alcohol use, liver disease, or medication effects. 4

Special Population Considerations

Chronic Kidney Disease Patients

• Initiate anemia workup when hemoglobin <12 g/dL in women or <13 g/dL in men with GFR <30 mL/min/1.73 m² 1
• Monitor hemoglobin at least every 3 months in patients with GFR <30 mL/min/1.73 m² 1
• Do not routinely measure serum erythropoietin levels—it adds little diagnostic value in CKD patients with normochromic, normocytic anemia 1
• Ensure adequate iron stores (ferritin >100 μg/L, TSAT >20%) before initiating erythropoietin therapy 4, 3

Elderly Patients

Never assume anemia is "normal aging"—always investigate the cause. 1 Elderly patients frequently have combined deficiencies and require comprehensive evaluation. 1

Patients with Gastrointestinal Symptoms or Risk Factors

All adult men and postmenopausal women with confirmed iron deficiency require gastroenterology referral to exclude gastrointestinal malignancy, regardless of anemia severity. 2, 3 This is particularly urgent if hemoglobin <12 g/dL in men or <10 g/dL in postmenopausal women. 3

Dual pathology (upper and lower GI bleeding sources) occurs in 1-10% of patients, so do not delay comprehensive endoscopic evaluation. 3

Management Based on Etiology

Iron Deficiency Anemia

Oral iron supplementation is first-line treatment: 3

• Start with 35-65 mg elemental iron daily 4
• If inadequate response or intolerance, increase to twice daily or try alternate oral preparations 4
• Assess response at 1 month: expect hemoglobin rise ≥1.0 g/dL and normalization of ferritin/TSAT 4

Intravenous iron is indicated for: 4, 3

• Oral iron intolerance or malabsorption
• Chronic inflammatory conditions with functional iron deficiency
• Need for rapid repletion
• Dose: 1 gram total empiric dose or calculate using Ganzoni formula 4

Regularly-scheduled iron infusions may be needed if chronic bleeding cannot be halted. 4

Vitamin B12 Deficiency

Parenteral vitamin B12 is required for pernicious anemia and malabsorption: 5

• Initial: 100 mcg daily intramuscularly or deep subcutaneous for 6-7 days 5
• Then: same dose on alternate days for 7 doses 5
• Then: every 3-4 days for 2-3 weeks 5
• Maintenance: 100 mcg monthly for life 5

Oral B12 is not dependable for pernicious anemia but may be used for dietary deficiency with normal intestinal absorption. 5

Folate Deficiency

Treat with oral folate supplementation, but exercise caution to avoid masking B12 deficiency symptoms. 1, 2

Anemia of Chronic Kidney Disease

• Treat iron deficiency first: for CKD patients not on dialysis with TSAT ≤30% and ferritin ≤500 ng/mL, trial oral or intravenous iron for 1-3 months 2
• If anemia persists despite adequate iron stores (ferritin >100 μg/L, TSAT >20%), consider erythropoietin therapy 4, 3

Red Blood Cell Transfusion Indications

Transfuse in the following settings: 4

• Hemodynamic instability or shock
• Comorbidities requiring higher hemoglobin target (e.g., coronary artery disease)
• Need to increase hemoglobin acutely (pre-surgery, pregnancy)
• Inability to maintain adequate hemoglobin despite frequent iron infusions
• Symptomatic patients with hemoglobin ≤8 g/dL 6

Use leukoreduced products; for potential transplant candidates, consider CMV-negative (if patient CMV-negative) and irradiated products. 4

Referral Indications

Gastroenterology referral: 3

• All adult men and postmenopausal women with iron deficiency (ferritin <30 μg/L or TSAT <20%)
• Immediate referral if hemoglobin <12 g/dL in men or <10 g/dL in postmenopausal women

Nephrology referral: 3

• GFR <30 mL/min/1.73 m² with anemia

Hematology referral: 3

• Unexplained anemia after initial workup
• Suspected hemolysis
• Suspected bone marrow disorder or myelodysplastic syndrome

Common Pitfalls to Avoid

• Watch for combined deficiencies, especially in elderly patients and those with inflammatory bowel disease 1
• Elevated RDW with normal MCV suggests early iron deficiency or mixed nutritional deficiencies—proceed with iron studies 2
• Low MCH is more sensitive than low MCV for detecting early iron deficiency 2
• Ferritin interpretation requires clinical context—inflammation can falsely elevate levels 2
• Do not delay gastroenterology evaluation in patients with iron deficiency due to risk of dual pathology 3