What is the approach to diagnosing and treating anemia?

Approach to Anemia

The approach to anemia requires determining the underlying etiology through systematic laboratory evaluation before initiating treatment, as treating the hemoglobin number alone without addressing the root cause increases morbidity and mortality. 1

Step 1: Confirm Anemia and Classify by MCV

• Confirm anemia using age-appropriate thresholds: Hemoglobin <13.5 g/dL in elderly men, <12.0 g/dL in elderly women and nonpregnant women of childbearing age, and <11.0 g/dL in pregnant women (varies by trimester). 2, 3
• Classify anemia by mean corpuscular volume (MCV): Microcytic (MCV <80 fL), normocytic (MCV 80-100 fL), or macrocytic (MCV >100 fL). 4
• A decrease of ≥2 g/dL from baseline warrants evaluation even if absolute values remain above anemia thresholds. 3

Step 2: Essential Initial Laboratory Workup

Before treating, obtain the following tests to identify reversible causes: 1

• Complete blood count with differential and red cell indices 1, 3
• Reticulocyte count and index to assess bone marrow response (low index = decreased production; high index = blood loss or hemolysis) 1, 4
• Comprehensive iron studies: serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT), and ferritin 1, 3
  • Absolute iron deficiency: TSAT <15% AND ferritin <30 ng/mL 1, 3
  • Functional iron deficiency (anemia of chronic disease): ferritin >100 μg/L with TSAT <20% 1, 3
  • Critical pitfall: Do not rely on ferritin alone in the presence of inflammation; use CRP/ESR to interpret iron studies correctly 1
• Peripheral blood smear review 1, 3
• Serum creatinine and estimated GFR to assess for chronic kidney disease 3
• Reserve vitamin B12 and folate testing for specific indicators: macrocytosis (MCV >100 fL) or neurological symptoms, as folate deficiency is rare in the US due to grain fortification and B12 deficiency occurs in only 3.9% of cancer patients 1, 4

Step 3: Additional Diagnostic Clues by MCV Category

Microcytic Anemia (MCV <80 fL)

• Red cell distribution width (RDW) >14% with low MCV suggests iron deficiency anemia 4
• RDW ≤14% with low MCV suggests thalassemia minor 4
• If iron studies are normal with persistent microcytosis, perform hemoglobin electrophoresis to evaluate for thalassemia trait 4
• Elevated ferritin with low TSAT suggests anemia of chronic disease 4

Macrocytic Anemia (MCV >100 fL)

• Check vitamin B12 and folate levels to confirm deficiency 4
• Review medications and alcohol intake as non-megaloblastic causes include alcoholism, certain medications, and myelodysplastic syndrome 4
• Check liver and thyroid function tests 4

Normocytic Anemia (MCV 80-100 fL)

• Evaluate for chronic kidney disease, anemia of chronic disease, or early iron deficiency 3
• Consider mixed anemias: microcytosis and macrocytosis can neutralize each other, resulting in a normal MCV 4

Step 4: Treat the Underlying Cause First

The American Society of Hematology emphasizes treating the etiology, not simply the hemoglobin number. 1

Iron Deficiency Anemia

• Identify and address the bleeding source first 1
• Oral iron supplementation (100-200 mg elemental iron daily) is first-line treatment 1
• Intravenous iron is preferred when oral iron is not tolerated or causes significant GI side effects 1
• Recheck hemoglobin 4 weeks after initiating iron therapy: An increase in Hb ≥1 g/dL or Hct ≥3% confirms the diagnosis 2, 1
• If anemia does not respond after 4 weeks despite compliance, further evaluate with MCV, RDW, and serum ferritin 2
• Continue iron treatment for 2-3 more months after confirming response, then recheck Hb/Hct 2

Anemia of Chronic Disease

• Treat the underlying inflammatory condition as the primary intervention 1
• Concurrent iron supplementation is usually necessary 1

Vitamin B12 Deficiency

• Parenteral vitamin B12 is the recommended treatment for pernicious anemia and will be required for life 5
• Dosing: 100 mcg daily IM or deep subcutaneous for 6-7 days, then alternate days for seven doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life 5
• Avoid the intravenous route, as almost all vitamin will be lost in urine 5

Folate Deficiency

• Treat with oral folate supplementation, though rarely needed in the US 1

Step 5: Determine Need for Immediate Intervention

• Assess symptoms, comorbidities, and clinical context rather than relying solely on hemoglobin thresholds 1
• Categorize patients: asymptomatic without significant comorbidities, asymptomatic with comorbidities or high risk, and symptomatic anemia 1
• Packed RBCs are preferred over whole blood and should be reserved for severe, symptomatic anemia with hemodynamic instability 1

Step 6: Special Populations

Pregnant Women

• Start oral, low-dose (30 mg/day) iron supplementation at the first prenatal visit 2
• Screen for anemia at the first prenatal visit using stage-specific criteria 2
• If Hb <9.0 g/dL or Hct <27.0%, refer to a physician familiar with anemia during pregnancy 2
• Treat anemia with 60-120 mg/day oral iron 2
• When Hb becomes normal for gestational stage, decrease iron dose to 30 mg/day 2

Infants and Children

• Screen high-risk populations (low-income, WIC-eligible, migrant, refugee children) at ages 9-12 months, 6 months later, and annually from ages 2-5 years 2
• Treat presumptive iron-deficiency anemia with 3 mg/kg per day of iron drops administered between meals 2
• Counsel parents about adequate dietary iron intake 2

Chronic Kidney Disease

• Initiate erythropoietin (PROCRIT) only when hemoglobin <10 g/dL in dialysis patients 6
• For non-dialysis CKD patients, consider initiating only when Hb <10 g/dL and the rate of decline indicates likelihood of requiring RBC transfusion 6
• Use the lowest dose to avoid RBC transfusions; do not target Hb >11 g/dL due to increased risks of death, cardiovascular events, and stroke 6
• Evaluate iron status before and during treatment and maintain iron repletion 6

Cancer Patients on Chemotherapy

• PROCRIT is indicated only for anemia due to myelosuppressive chemotherapy with a minimum of 2 additional months of planned chemotherapy 6
• ESAs are not indicated when the anticipated outcome is cure 6
• Discontinue following completion of chemotherapy course 6

Step 7: Long-Term Monitoring

• Monitor for anemia recurrence, which occurs in >50% of patients within one year 1
• Check hemoglobin every 12 months in patients in remission, every 6 months in patients with mild active disease 1
• Continue hemoglobin monitoring every 3 months in patients with chronic kidney disease 3

Critical Pitfalls to Avoid

• Never assume a single cause of anemia without comprehensive evaluation, as anemia is often multifactorial 1
• Do not rely on ferritin alone in the presence of inflammation 1
• Avoid intramuscular iron and erythropoiesis-stimulating agents without first excluding and treating reversible causes 1
• Do not use ESAs in cancer patients receiving chemotherapy when the anticipated outcome is cure 6