Can medications such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like ibuprofen or naproxen, warfarin, aspirin, and certain antibiotics like penicillin cause hematuria in patients?

Medications That Cause Hematuria

Yes, multiple medications commonly cause hematuria, with anticoagulants (warfarin, rivaroxaban, dabigatran, apixaban) and antiplatelet agents (aspirin, clopidogrel) being the most frequent culprits, followed by NSAIDs (ibuprofen, naproxen) which can cause hematuria through both direct nephrotoxicity and platelet dysfunction. 1, 2

Anticoagulants and Antiplatelet Agents

Anticoagulants are the leading medication class associated with hematuria:

• Rivaroxaban and warfarin pose the highest risk among anticoagulants, with significantly elevated proportional reporting ratios compared to other anticoagulants (PRR>1, P<0.05), while apixaban appears safest (PRR<1, P<0.05) 1
• Dabigatran and rivaroxaban carry increased risk of gastrointestinal bleeding specifically in patients ≥75 years with atrial fibrillation or VTE 3
• Warfarin-associated hematuria warrants full urological evaluation despite anticoagulation status, as 25% of patients presenting with gross hematuria while on warfarin or aspirin have an underlying tumor 3, 2
• Aspirin increases minor hematuria risk (OR 1.36,95% CI 1.13-1.64) but does not significantly increase severe hematuria, hemospermia, or rectal bleeding after procedures like prostate biopsy 3

Critical clinical context:

• Patients on warfarin had normal urological evaluations 38% of the time versus only 22% for aspirin patients, suggesting aspirin may cause more direct urothelial injury 2
• Hemorrhagic cystitis was diagnosed exclusively in aspirin users (12 patients), pointing to a specific bleeding diathesis in the urothelium 2
• The monthly incidence of hematuria in anticoagulated patients is 0.05% with prevalence of 3.2%, similar to non-anticoagulated controls (0.08% incidence, 4.8% prevalence) 3

NSAIDs (Ibuprofen, Naproxen)

NSAIDs cause hematuria through multiple mechanisms:

• NSAIDs were implicated in 54% of idiopathic hematuria cases versus only 1% of cases with identifiable causes (neoplasia, stones, infection), compared to 3.3% baseline prevalence in controls 4
• Direct nephrotoxicity manifests as acute kidney injury with proteinuria (60% of cases) and hematuria (80% of cases), including gross hematuria 5
• NSAIDs should be absolutely avoided in patients with cirrhosis and ascites due to extremely high risk of acute renal failure, hyponatremia, and diuretic resistance 3, 6

Specific NSAID considerations:

• Ibuprofen and naproxen inhibit platelet aggregation with quantitatively less effect than aspirin but still prolong bleeding time 7, 8
• Naproxen specifically increases incidence of rash and prolonged bleeding times in pediatric patients 7
• Renal toxicity risk is highest in patients with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly 7

Antibiotics

Penicillins in high doses increase bleeding risk by inhibiting platelet function, though this is less commonly associated with hematuria than anticoagulants 3

Clinical Management Approach

When hematuria occurs in patients on these medications:

• Do not defer urological evaluation based on medication use alone - 25% of patients with anticoagulant-associated gross hematuria have tumors 3, 2
• Patients on anticoagulants with hematuria require cystoscopy and either excretory urography or ultrasound 2
• Excessive anticoagulation (supratherapeutic INR) does not preclude pathologic findings - 18% of excessively anticoagulated patients still had tumors 2
• Mean hospitalization for gross hematuria in anticoagulated patients is 4.7 days with mean bladder irrigation duration of 3.1 days 9

Drug-drug interactions matter:

• DDIs occur in 31.9% of patients with hematuria on anticoagulants/antiplatelets and significantly impact irrigation duration (p=0.01) and volume of irrigation fluid required (p=0.05) 9
• Concurrent use of anticoagulants with NSAIDs, SSRIs, or SNRIs potentiates bleeding risk 3

Severity and Mortality

Fatal hematuria is rare but medication-specific:

• Overall fatality rate from hematuria is only 1.08% (162/15,007 cases) 1
• Cyclophosphamide (7.2%), enoxaparin (3%), and dabigatran (2.5%) have the highest fatal hematuria rates compared to other anticoagulants (<1%) 1