What is the approach to diagnosing and managing anemia?

Diagnostic Approach to Anemia

Begin with a complete blood count (CBC) with red cell indices, reticulocyte count, and peripheral blood smear—these three tests form the foundation for classifying anemia and directing subsequent workup. 1, 2, 3

Initial Classification by MCV

The mean corpuscular volume (MCV) provides the primary framework for differential diagnosis 1, 2:

Microcytic Anemia (MCV < 80 fL)

Order iron studies immediately: serum ferritin, transferrin saturation (TSAT), and total iron-binding capacity (TIBC). 1, 2

• Iron deficiency anemia is diagnosed when serum ferritin is < 30 μg/L (or < 15 μg/L without inflammation). 1, 2
• If ferritin is elevated (> 100 μg/L) with low TSAT (< 20%), consider anemia of chronic disease/inflammation and measure C-reactive protein (CRP). 4, 1
• When ferritin is elevated AND TSAT is elevated or when TSAT is low with ferritin 20-100 μg/L, suspect genetic disorders of iron metabolism or heme synthesis (sideroblastic anemia, IRIDA, hemochromatosis). 4
• Hemoglobin electrophoresis should be ordered if iron studies are normal to evaluate for thalassemia. 4, 1

Common pitfall: Do not assume normal ferritin excludes iron deficiency—ferritin 20-100 μg/L can represent iron deficiency in the presence of inflammation. 2

Normocytic Anemia (MCV 80-100 fL)

The reticulocyte count distinguishes between production defects and hemolysis/blood loss. 1, 3, 5

• Elevated reticulocyte count (> 2%): Indicates hemolysis or acute blood loss. Order peripheral smear for red cell morphology, direct antiglobulin test (Coombs), haptoglobin, LDH, and indirect bilirubin. 3, 5
• Low/normal reticulocyte count (< 2%): Suggests impaired production. Evaluate for:
  • Anemia of chronic disease: Check CRP, ferritin (typically > 100 μg/L with low TSAT < 20%). 1, 2
  • Chronic kidney disease: Measure creatinine and estimated GFR. 1, 2
  • Early iron deficiency: Ferritin < 30 μg/L. 1, 2
  • Bone marrow pathology if other causes excluded. 3, 5

Macrocytic Anemia (MCV > 100 fL)

Order vitamin B12 and folate levels immediately. 1, 2

• B12 deficiency is confirmed with low serum B12; consider methylmalonic acid and homocysteine if B12 is borderline. 2, 3
• Folate deficiency is diagnosed with low serum or red cell folate. 2, 3
• If vitamin levels are normal, evaluate for:
  • Medication effects (methotrexate, hydroxyurea, antiretrovirals). 1
  • Alcohol use. 4, 1
  • Myelodysplastic syndrome (especially if age > 60 or cytopenias in other cell lines). 4, 1

Essential Laboratory Tests for All Patients

Beyond the CBC with indices, obtain 1, 2:

• Reticulocyte count: Distinguishes production defects from hemolysis/blood loss. 1, 3
• Peripheral blood smear: Provides morphologic clues (target cells, spherocytes, schistocytes, ringed sideroblasts). 2, 3
• Iron studies: Ferritin, TSAT, TIBC—essential even in normocytic anemia. 1, 2
• Inflammatory markers: CRP helps identify anemia of chronic disease. 4, 1

Special Population Considerations

Chronic Kidney Disease (CKD)

• Monitor hemoglobin every 3 months when GFR < 30 mL/min. 1
• Complete workup is required if hemoglobin < 12 g/dL in women or < 13 g/dL in men. 1
• Correct iron deficiency (ferritin < 100 μg/L or TSAT < 20%) before considering erythropoietin therapy. 1, 6
• Do NOT target hemoglobin > 11 g/dL with erythropoiesis-stimulating agents—this increases risk of death, stroke, and cardiovascular events. 6

Inflammatory Bowel Disease (IBD)

• Anemia is typically multifactorial: iron deficiency from blood loss plus anemia of chronic disease. 4
• Minimum screening includes CBC, CRP, and serum ferritin at regular intervals based on disease activity. 4
• Check vitamin B12 and folate annually in patients with extensive small bowel disease or resection. 4

Elderly Patients

• Never attribute anemia to "normal aging"—always investigate the cause. 1
• Screen for combined nutritional deficiencies (iron AND B12 deficiency can coexist). 1

When to Refer

Urgent hematology referral is indicated for: 2

• Abnormalities in two or more cell lines (bicytopenia or pancytopenia)
• Severe anemia (hemoglobin < 8 g/dL) without obvious cause
• Suspected hemolysis
• Unexplained anemia after complete workup

Gastroenterology referral for: 2

• Iron deficiency anemia with hemoglobin < 11 g/dL in men or < 10 g/dL in non-menstruating women
• Any iron deficiency anemia in adults without significant non-GI blood loss
• Suspected colorectal malignancy

Genetic Microcytic Anemias: Red Flags

Consider genetic disorders when 4:

• Microcytic anemia is refractory to iron supplementation
• Family history of anemia
• Ferritin > 100 μg/L with elevated TSAT (suggests iron loading disorders)
• Low TSAT with ferritin 20-100 μg/L (suggests IRIDA)
• Neurologic symptoms (suggests mitochondrial disorders)
• Photosensitivity (suggests erythropoietic protoporphyria)

For X-linked sideroblastic anemia (XLSA), screen male probands' mothers, sisters, and daughters—female carriers can develop phenotype later in life. 4

Critical Pitfalls to Avoid

• Do not transfuse based solely on hemoglobin threshold—use the lowest dose to avoid transfusion needs, especially in CKD and cancer patients. 1, 6
• Do not miss combined deficiencies—iron and B12 deficiency frequently coexist, particularly in elderly patients. 1
• Do not overlook inflammation—ferritin can be falsely elevated in inflammatory states, masking iron deficiency. 4, 2
• Do not delay workup in elderly patients—anemia always warrants investigation regardless of age. 1