What is the significance of an elevated RDW in an adult patient with a history of autoimmune disease or organ transplantation, who has a normal MCV and is currently being treated with azathioprine?

Elevated RDW with Normal MCV in Azathioprine-Treated Patients

In a patient on azathioprine with normal MCV (93.10 fL) but elevated RDW (16.10%), this pattern most likely indicates either early iron deficiency, mixed nutritional deficiencies that are neutralizing each other's effect on MCV, or azathioprine-induced bone marrow effects with heterogeneous red cell populations—and you must obtain serum ferritin, transferrin saturation, CRP, vitamin B12, folate, and reticulocyte count immediately to differentiate these causes. 1

Understanding This Laboratory Pattern

Why This Combination Matters

• Azathioprine characteristically causes macrocytosis (elevated MCV), which typically develops after 3-6 months of therapy and stabilizes thereafter 2, 3
• Your patient's normal MCV despite azathioprine therapy is unusual and suggests a competing process is masking the expected drug-induced macrocytosis 1
• High RDW (>14.0%) with normal MCV indicates anisocytosis (variable red cell sizes), which occurs when microcytic and macrocytic populations coexist and cancel each other out in the MCV calculation 1, 4

The Diagnostic Algorithm

Step 1: Obtain Minimum Workup Immediately 1

• Serum ferritin (interpret based on inflammation status: <30 μg/L without inflammation, <100 μg/L with inflammation indicates iron deficiency)
• Transferrin saturation (<16-20% supports iron deficiency)
• CRP (to interpret ferritin correctly)
• Reticulocyte count (low/normal suggests deficiency; elevated suggests hemolysis or bleeding)
• Vitamin B12 and folate levels
• Complete blood count with differential

Step 2: Interpret Based on Results

If iron deficiency is confirmed (ferritin <30 μg/L or <100 μg/L with inflammation): 1

• The elevated RDW reflects iron-restricted erythropoiesis creating microcytic cells
• These microcytes are being masked by azathioprine-induced macrocytes, resulting in "normal" MCV
• This is the most common scenario in patients with autoimmune disease or transplant on azathioprine

If vitamin B12 or folate deficiency is present: 1

• Similar masking effect occurs but in reverse direction
• Less common but must be excluded

If hemolysis is suspected (elevated reticulocytes, low haptoglobin, elevated LDH): 1

• Azathioprine can rarely cause immune-mediated hemolysis
• The RDW elevation reflects both young reticulocytes and older damaged cells

Critical Management Decisions

Monitoring Azathioprine Hematologic Effects

Expected hematologic changes on azathioprine: 5

• MCV typically increases by ≥6 fL after 3-4 months of therapy 2
• This MCV increase correlates with therapeutic 6-thioguanine nucleotide (6-TGN) levels 2
• Your patient's normal MCV suggests either inadequate dosing OR a competing nutritional deficiency

Dangerous hematologic changes requiring immediate action: 1

• White blood cell count <4,000/mm³: reduce azathioprine dose by 50% or stop immediately 1
• Platelet count <100,000/mm³: reduce azathioprine dose by 50% or stop immediately 1
• Pancytopenia: stop azathioprine completely and consider TPMT/NUDT15 deficiency 5, 6

Treatment Algorithm

If iron deficiency is confirmed: 1

1. Initiate iron supplementation (oral or IV based on severity and tolerance)
2. Investigate source of blood loss, particularly gastrointestinal (common in autoimmune disease and transplant patients on immunosuppression)
3. Continue azathioprine at current dose unless other cytopenias present
4. Recheck CBC in 4 weeks—expect MCV to rise as iron stores replete and azathioprine effect becomes unmasked

If vitamin deficiencies are confirmed: 1

1. Supplement appropriately (B12 or folate)
2. Continue azathioprine
3. Monitor CBC monthly until normalized

If no deficiency is found: 1

1. Consider bone marrow evaluation if anemia is present or worsening
2. Evaluate for occult hemolysis (haptoglobin, LDH, indirect bilirubin)
3. Consider hematology consultation

Critical Pitfalls to Avoid

Common Errors in Interpretation

• Do NOT assume normal MCV excludes iron deficiency in azathioprine-treated patients 1, 4—the drug-induced macrocytosis masks microcytosis
• Do NOT empirically treat with iron without confirming deficiency 7—ferritin and transferrin saturation are essential
• Do NOT ignore elevated RDW as "nonspecific" 1, 4—in this context, it is a critical clue to mixed red cell populations
• Do NOT stop azathioprine based solely on elevated RDW 1—this is not a criterion for dose reduction

Monitoring Frequency

While investigating this abnormality: 1

• Check CBC weekly until diagnosis established and treatment initiated
• Monitor for development of leukopenia or thrombocytopenia (more concerning than isolated RDW elevation)
• Once stable, return to monthly CBC monitoring as standard for azathioprine therapy 1

Special Considerations in Autoimmune Disease/Transplant Patients

• Chronic inflammation elevates ferritin 1—use threshold of <100 μg/L (not <30 μg/L) to diagnose iron deficiency in these patients
• Multiple medications may interact 1—co-trimoxazole, trimethoprim increase myelotoxicity risk; aminosalicylates inhibit TPMT
• Chronic disease anemia is common 1—may coexist with iron deficiency (mixed anemia pattern)

The bottom line: This laboratory pattern demands immediate investigation for iron deficiency, which is being masked by azathioprine's macrocytic effect, and delaying workup risks missing a treatable cause of anemia in an already immunocompromised patient. 1, 4