Can azathioprine induce thrombocytopenia?

Azathioprine-Induced Thrombocytopenia

Yes, azathioprine can induce thrombocytopenia as a manifestation of its bone marrow suppressive effects, though isolated thrombocytopenia is less common than leukopenia and is typically not clinically severe when it occurs alone.

Mechanism and Incidence

Azathioprine causes dose-dependent myelosuppression that can affect all blood cell lines, including platelets 1. The FDA drug label explicitly lists thrombocytopenia as a known hematologic adverse effect, noting it may occur late in the course of therapy and is dose-dependent 2.

Key epidemiologic data:

• Isolated thrombocytopenia (platelet count <100,000 × 10⁶/L) occurs in approximately 2% of patients treated with azathioprine 3
• In a large 27-year study of 739 inflammatory bowel disease patients, 15 patients (2%) developed thrombocytopenia, with 9 cases occurring in isolation (not associated with leukopenia) 3
• Importantly, isolated thrombocytopenia was never clinically severe in this cohort, unlike leukopenia which caused life-threatening complications 3
• Thrombocytopenia can develop at any time during treatment, ranging from 2 weeks to 11 years after starting the drug 3

Risk Factors for Myelosuppression

TPMT (Thiopurine Methyltransferase) deficiency significantly increases risk:

• Patients with absent TPMT activity (homozygous variant alleles) have an 86% risk of developing myelosuppression with conventional azathioprine doses 1
• Patients with intermediate TPMT activity (heterozygous) have a 4.2-fold increased risk (OR 4.2,95% CI 3.2-5.5) of developing leucopenia compared to those with normal activity 1
• However, 73% of patients who developed severe myelosuppression had normal TPMT activity, indicating that TPMT testing cannot replace regular hematologic monitoring 1

Drug interactions that increase risk:

• Ribavirin co-administration induces severe pancytopenia by inhibiting inosine monophosphate dehydrogenase (IMDH), leading to accumulation of the toxic metabolite 6-MTITP 2
• Trimethoprim-sulfamethoxazole enhances marrow suppression through antifolate action, potentially causing life-threatening hematotoxicity 4
• Infliximab combined with azathioprine has been associated with severe neutropenia and thrombocytopenia 5

Clinical Context: Azathioprine for ITP Treatment

Paradoxically, azathioprine is sometimes used to treat immune thrombocytopenic purpura (ITP), though its efficacy is modest 1. In this context:

• About 20% of ITP patients achieve normal platelet counts sustained for months to years 1
• An additional 50% may improve but require continuous treatment 1
• One concerning study of 53 ITP patients reported 5 deaths from hemorrhage with severe thrombocytopenia, though it remains uncertain whether this was due to azathioprine-induced marrow suppression, disease severity, or lack of efficacy 1
• A more recent 2021 study showed azathioprine had a 38.1% overall response rate at day 90 in chronic ITP patients, with leucopenia being the most frequent adverse event 6

Monitoring Requirements

The FDA drug label mandates specific monitoring schedules 2:

• Weekly complete blood counts (including platelet counts) during the first month
• Twice monthly for the second and third months
• Monthly or more frequently thereafter if dosage changes occur

The British Association of Dermatologists recommends similar monitoring, with at least 3-monthly monitoring once patients are stable on a fixed dose 1.

Management of Thrombocytopenia

When thrombocytopenia develops:

• Dose reduction or temporary withdrawal typically results in reversal of the toxicity 2
• The severity and clinical significance depend on whether thrombocytopenia occurs in isolation or as part of pancytopenia 3
• Severe pancytopenia (affecting all three cell lines) carries significant mortality risk, with 2 deaths from sepsis reported in one large series 3

Critical Clinical Pitfall

Do not rely solely on TPMT testing to predict myelotoxicity risk. While TPMT deficiency strongly predicts severe myelosuppression, the majority of patients who develop bone marrow toxicity have normal TPMT activity 1. Regular complete blood count monitoring remains essential regardless of TPMT status and cannot be substituted by genetic testing 2.