Can azathioprine cause anemia (low hemoglobin)?

Can Azathioprine Cause Low Hemoglobin?

Yes, azathioprine can cause low hemoglobin through multiple mechanisms including bone marrow suppression, pure red cell aplasia, autoimmune hemolytic anemia, and macrocytosis with mild anemia. 1, 2

Mechanisms of Azathioprine-Induced Anemia

Azathioprine causes anemia through several distinct pathways:

• Bone marrow toxicity is the most common mechanism, typically presenting as pancytopenia (affecting all blood cell lines) rather than isolated anemia. 1
• Pure red cell aplasia is a rare but serious complication where only red blood cell production is selectively suppressed, occurring almost exclusively in transplant recipients on long-term therapy. 3
• Autoimmune hemolytic anemia has been documented as an azathioprine-associated adverse event. 1
• Macrocytosis with mild anemia is common and occurs through interference with DNA synthesis; this is typically mild and can actually serve as a marker of patient compliance. 1, 4

Clinical Presentation and Frequency

The pattern of hematologic toxicity follows a predictable sequence:

• Leukopenia develops first and is the most common hematologic adverse effect, occurring in approximately 3.2% of patients. 1
• Thrombocytopenia typically follows as bone marrow suppression progresses. 1
• Isolated severe anemia is rare with azathioprine monotherapy, though megaloblastic changes in bone marrow are frequent (16-82% of aspirates). 3, 5

Critical Drug Interactions That Worsen Anemia

Several medications dramatically increase the risk of azathioprine-induced anemia:

• ACE inhibitors or ARBs combined with azathioprine cause significant anemia in renal transplant recipients. In one study, hematocrit dropped from 41±7% to 36±6% and hemoglobin from 14.0±2.3 g/dL to 11.3±1.5 g/dL when ACE inhibitors were added. 6
• Allopurinol increases azathioprine toxicity by inhibiting xanthine oxidase, requiring dose reduction to 25-33% of the usual azathioprine dose to prevent severe bone marrow suppression including anemia. 2, 7
• Ribavirin causes severe pancytopenia when combined with azathioprine by inhibiting inosine monophosphate dehydrogenase, leading to accumulation of toxic metabolites. 2
• Captopril may increase the risk of anemia and leukopenia when used with azathioprine. 1

Monitoring Requirements

To detect azathioprine-induced anemia early:

• Weekly complete blood counts (including hemoglobin) for the first month of therapy. 2
• Twice monthly monitoring for months 2-3. 2
• Monthly or more frequent monitoring thereafter, or whenever dose changes occur. 2
• Consider TPMT genotyping or phenotyping before starting therapy, as patients with low or absent TPMT activity are at highest risk for severe myelosuppression, though 73% of patients who develop severe toxicity have normal TPMT activity. 2

Management Approach

When anemia develops on azathioprine:

• Evaluate for drug interactions first, particularly ACE inhibitors, allopurinol, or ribavirin, as these are reversible causes. 2, 6
• Assess the pattern of cytopenia: isolated anemia suggests pure red cell aplasia or drug interaction, while pancytopenia indicates bone marrow suppression. 1, 3
• For mild anemia with downward trend, increase monitoring frequency and consider dose reduction. 8
• For severe anemia or pure red cell aplasia, complete drug withdrawal is typically required for recovery; dose reduction alone is often insufficient. 3
• Rule out other causes including active inflammatory bowel disease, infections, malignancies, and iron deficiency, as these commonly coexist. 1

Common Pitfalls

• Do not assume TPMT testing eliminates the need for monitoring, as most patients who develop severe myelosuppression have normal TPMT activity. 2
• Do not overlook ACE inhibitor or ARB use as a contributing factor to anemia in patients on azathioprine, particularly in transplant recipients. 6
• Do not continue azathioprine at reduced doses in cases of pure red cell aplasia, as complete withdrawal is necessary for recovery. 3
• Do not attribute all anemia to azathioprine without excluding iron deficiency, active disease, or other medications, as these are common in the populations receiving azathioprine. 1