Methotrexate and Blood Clots
Methotrexate is not a recognized cause of blood clots (thromboembolism) in clinical practice. The major FDA-labeled and guideline-documented toxicities of methotrexate include hepatotoxicity, myelosuppression (thrombocytopenia, leukopenia, pancytopenia), pneumonitis, mucositis, and gastrointestinal toxicity—but thrombotic events are not listed among these established adverse effects 1.
Evidence Review
FDA Drug Label and Guidelines
- The FDA drug label for methotrexate extensively details hematologic toxicities including thrombocytopenia (low platelet counts), which would actually increase bleeding risk rather than clotting risk 1
- Major guidelines from the American Academy of Dermatology (2009) and the joint AAD-National Psoriasis Foundation (2020) comprehensively outline methotrexate's adverse event profile, with no mention of thrombotic complications 2
- The American College of Rheumatology 2021 guidelines for rheumatoid arthritis treatment detail extensive monitoring requirements and toxicity concerns for methotrexate, but do not identify thromboembolism as a recognized adverse effect 2
Hematologic Effects: Bleeding, Not Clotting
The documented hematologic effects of methotrexate work in the opposite direction from clot formation:
- Thrombocytopenia (decreased platelets) is a well-established toxicity that requires immediate discontinuation if platelet counts drop significantly 1
- In controlled trials in rheumatoid arthritis, thrombocytopenia (platelets <100,000/mm³) occurred in 6 of 128 patients 1
- Methotrexate can cause pancytopenia, leukopenia, and aplastic anemia—all conditions that impair normal hemostasis 1
Research Evidence on Coagulation
Limited research examining methotrexate's effects on coagulation actually suggests anticoagulant effects rather than prothrombotic effects:
- High-dose methotrexate in childhood leukemia transiently prolonged PT and aPTT, decreased fibrinogen, and reduced coagulation inhibitors (protein C, protein S, antithrombin III), but these changes did not cause clinical thrombotic complications 3
- One study found that plasma from RA patients on low-dose methotrexate enhanced platelet aggregation in vitro, but this laboratory finding has no established clinical correlation to thrombotic events 4
- Case reports of subdural hematomas (bleeding complications) have been associated with methotrexate combined with other agents, further supporting bleeding rather than clotting risk 5
Clinical Bottom Line
Methotrexate's hematologic toxicity profile is characterized by bone marrow suppression leading to cytopenias, which increases bleeding risk, not thrombotic risk. If a patient on methotrexate develops a blood clot, alternative explanations should be sought:
- Underlying inflammatory disease activity (RA, psoriasis, and other inflammatory conditions independently increase thrombotic risk)
- Other medications or comorbidities
- Standard thrombotic risk factors (immobility, malignancy, inherited thrombophilias, etc.)
The absence of thrombotic complications in major guidelines, FDA labeling, and decades of clinical experience with methotrexate strongly indicates this is not a drug-related adverse effect 2, 1.