Can aspirin, clopidogrel, and enoxaparin cause hematuria?

Aspirin, Clopidogrel, and Enoxaparin as Causes of Hematuria

Yes, aspirin, clopidogrel, and enoxaparin can all cause hematuria, with anticoagulants like enoxaparin posing a higher risk than antiplatelet agents like aspirin and clopidogrel. 1, 2

Risk Profile of Individual Agents

Anticoagulants (Higher Risk)

• Enoxaparin (low molecular weight heparin) is associated with a higher risk of hematuria compared to antiplatelet agents, with studies showing anticoagulants are 76 times more likely to cause hematuria than antiplatelet medications 3
• Enoxaparin has been reported to have a relatively high rate (3%) of fatal hematuria episodes compared to other antithrombotic agents 1
• Higher doses of enoxaparin (80 mg or greater) are associated with a 4.1-fold increased risk of bleeding complications compared to lower doses (40 mg) 4

Antiplatelet Agents (Moderate Risk)

• Aspirin is more likely to cause hematuria than clopidogrel, with odds of hematuria with aspirin being 6.7 times higher than with clopidogrel 3
• Minor hematuria is statistically more frequent among patients taking aspirin than in control groups (p=0.001, OR 1.36) 4
• Clopidogrel causes irreversible platelet inhibition, and while it may not directly cause mucosal injury, it is associated with an increased risk of bleeding including hematuria 4

Combination Therapy Significantly Increases Risk

• Dual or triple antithrombotic therapy dramatically increases bleeding risk, including hematuria 5
• The combination of anticoagulant and antiplatelet therapy increases the rate of hematuria-related complications to 191.61 events per 1000 person-years compared to 80.17 events in unexposed patients 2
• Patients on dual antiplatelet therapy with aspirin and clopidogrel have a 70% increased relative risk of bleeding compared to monotherapy 4

Clinical Significance of Hematuria in Patients on Antithrombotics

• Patients exposed to antithrombotic agents have higher rates of hematuria-related complications requiring emergency department visits (IRR 2.80), hospitalizations (IRR 2.03), and urologic procedures (IRR 1.37) compared to unexposed patients 2
• Patients with gross hematuria who are on anticoagulants or antiplatelet drugs require significantly longer irrigation duration (p=0.01) and greater volumes of irrigation fluid (p=0.05) during hospitalization 6
• Importantly, hematuria in patients on antithrombotic therapy warrants thorough evaluation, as underlying urologic pathology is identified in 44% of cases, with malignancy found in 24% 3
• Patients exposed to antithrombotic agents are more likely to be diagnosed with bladder cancer within 6 months (0.70% vs 0.38%; OR 1.85) 2

Management Considerations

• For patients with active hematuria on dual antiplatelet therapy, the American Heart Association recommends continuing aspirin and temporarily withholding clopidogrel 7
• If clopidogrel must be temporarily discontinued (e.g., to treat bleeding), it should be restarted as soon as possible to reduce cardiovascular risk 8
• For patients on enoxaparin with serious bleeding, consider temporarily interrupting therapy until hemostasis is achieved 7
• Proton pump inhibitor therapy is recommended for patients on antithrombotic therapy with GI bleeding risk, though this primarily addresses upper GI bleeding rather than hematuria 7, 9

Risk Factors for Increased Bleeding with Antithrombotics

• Advanced age significantly increases the absolute risk of bleeding with antithrombotic agents 5, 9
• History of previous bleeding or peptic ulcer disease is the strongest risk factor for bleeding in patients taking antiplatelet agents 5
• Concurrent use of NSAIDs or steroids with antithrombotic agents further increases bleeding risk 5, 9
• Drug-drug interactions are relevant in 31.9% of patients with gross hematuria and may lead to adverse clinical events 6

Important Caveats

• Discontinuation of antithrombotic therapy, especially in patients taking these medications for secondary prevention, significantly increases the risk of cardiovascular events 7
• A full urologic evaluation is warranted in patients with hematuria on antithrombotic therapy, even when excessive anticoagulation is present, as underlying pathology is common 10
• The presence of hematuria in patients on antithrombotic therapy should not be automatically attributed to the medication without appropriate investigation 10, 3