What is the best course of treatment for a patient with severe iron deficiency anemia and leukopenia?

Management of Severe Iron Deficiency Anemia with Leukopenia

Start oral ferrous sulfate 200 mg once daily immediately with vitamin C 500 mg to enhance absorption, while investigating the underlying cause of blood loss or malabsorption. 1, 2 The leukopenia is likely related to the severe iron deficiency itself and should resolve with iron repletion. 3, 4

Immediate Treatment Strategy

First-Line Oral Iron Therapy

• Prescribe ferrous sulfate 200 mg (65 mg elemental iron) once daily—this is the gold standard due to effectiveness and low cost. 1, 2
• Add vitamin C (ascorbic acid) 500 mg with each iron dose to enhance absorption, particularly critical given severe iron depletion. 1, 2
• Take on an empty stomach for optimal absorption, though taking with food is acceptable if gastrointestinal side effects occur. 2
• Never prescribe multiple daily doses—once-daily dosing improves tolerance while maintaining equal or better iron absorption due to hepcidin regulation. 2
• Alternative formulations (ferrous gluconate or ferrous fumarate) are equally effective if ferrous sulfate is not tolerated. 1, 2

Understanding the Leukopenia

The leukopenia is most likely a manifestation of the severe iron deficiency itself and should resolve with iron repletion. 3, 4 This is an important clinical pearl that is often overlooked:

• Approximately one-third of patients with iron deficiency anemia present with mild leukopenia. 3
• Case reports document complete resolution of chronic unexplained neutropenia after iron supplementation, suggesting "iron deficiency-induced neutropenia" as an underrecognized entity. 4
• The leukopenia does not contraindicate iron therapy—in fact, iron therapy is the treatment. 4

Common pitfall: Do not delay iron therapy to pursue extensive hematologic workup for the leukopenia if iron deficiency is clearly documented. The leukopenia will likely resolve with iron repletion. 3, 4

Expected Response and Monitoring

• Check hemoglobin at 4 weeks—expect a rise of approximately 2 g/dL. 1, 2
• Monitor complete blood count including white blood cell count to document resolution of leukopenia alongside anemia correction. 3, 4
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores. 1, 2
• Monitor hemoglobin and red cell indices every 3 months for the first year, then again after another year. 1, 2

Failure to Respond After 4 Weeks

If hemoglobin fails to rise by 2 g/dL after 4 weeks, assess for: 1, 2

• Poor compliance with oral iron
• Continued blood loss
• Malabsorption (celiac disease, inflammatory bowel disease, post-bariatric surgery)
• Misdiagnosis

When to Switch to Intravenous Iron

Switch to IV iron if any of the following apply: 2, 5

• Intolerance to at least two different oral iron preparations
• Failure of ferritin levels to improve after 4 weeks of compliant oral therapy
• Active inflammatory bowel disease with hemoglobin <10 g/dL
• Post-bariatric surgery patients (disrupted duodenal absorption)
• Celiac disease with inadequate response despite gluten-free diet adherence
• Ongoing gastrointestinal blood loss exceeding oral replacement capacity

IV Iron Formulation and Dosing

For patients ≥50 kg: Ferric carboxymaltose (Injectafer) 750 mg IV in two doses separated by at least 7 days for a total cumulative dose of 1,500 mg per course. 5

For patients <50 kg: Ferric carboxymaltose 15 mg/kg body weight IV in two doses separated by at least 7 days. 5

Critical safety consideration: Monitor serum phosphate levels before and after IV iron, as ferric carboxymaltose carries risk of hypophosphatemia. 5, 6 Administer in a medical facility with resuscitation capabilities available, though true anaphylaxis is rare (0.6-0.7%). 2, 5

Investigation of Underlying Cause

While initiating iron therapy, simultaneously investigate the source of iron deficiency: 1, 2

In Premenopausal Women

• Assess menstrual blood loss first—menorrhagia, pregnancy, and breastfeeding account for iron deficiency in 5-10% of menstruating women. 1, 2
• Consider pictorial blood loss assessment charts (80% sensitivity and specificity for menorrhagia). 1
• Screen for celiac disease with antiendomysial antibody and IgA measurement. 2
• If age >45 years or alarm symptoms present: Proceed with upper endoscopy and colonoscopy. 1
• If age <45 years without alarm symptoms: Gastrointestinal investigation only if upper GI symptoms present or failure to respond to iron therapy. 1

In Men and Postmenopausal Women

• Always perform upper endoscopy and colonoscopy to exclude gastrointestinal malignancy. 1, 2
• Screen for celiac disease with antiendomysial antibody and IgA measurement. 2
• Exclude urinary tract bleeding if hematuria present. 1

Special Considerations for Leukopenia

Do not pursue extensive hematologic workup for isolated leukopenia in the setting of severe iron deficiency until after iron repletion. 3, 4 The diagnostic approach should be:

1. Document that leukopenia is present alongside severe iron deficiency
2. Initiate iron therapy as outlined above
3. Recheck complete blood count at 4 weeks
4. If leukopenia persists despite correction of iron deficiency, then pursue hematologic evaluation

Important caveat: If leukopenia worsens during IV iron therapy (occurs in 1.91% of patients), this is typically transient and clinically insignificant with minimal infection risk. 7 However, monitor for signs of infection and check complete blood count if symptoms develop.

Critical Pitfalls to Avoid

• Do not delay iron therapy while pursuing extensive workup for leukopenia—the leukopenia is likely secondary to iron deficiency. 3, 4
• Do not prescribe multiple daily doses of oral iron—this increases side effects without improving efficacy. 2
• Do not stop iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores. 1, 2
• Do not overlook vitamin C supplementation—this significantly enhances absorption in severe iron deficiency. 1, 2
• Do not fail to identify and treat the underlying cause—iron therapy alone is insufficient if blood loss continues. 1, 2
• Do not use parenteral iron as first-line unless specific contraindications to oral therapy exist—oral iron is safer and equally effective when tolerated. 1