What is the differential diagnosis for an elderly male with primary hypertension and atrial fibrillation on Eliquis (apixaban) and losartan, presenting with urinary frequency and hematuria?

Differential Diagnosis and Workup for Hematuria in an Elderly Male on Anticoagulation

The most critical priority in this patient is urgent urologic evaluation to exclude bladder cancer, as anticoagulation-associated hematuria in elderly males is significantly associated with genitourinary malignancy, particularly bladder cancer, which requires early detection. 1

Differential Diagnosis

Primary Considerations

Anticoagulant-related hematuria is the leading consideration given apixaban therapy. Apixaban and other anticoagulants are among the most frequently implicated medications causing hematuria, though apixaban appears safer than rivaroxaban or warfarin in comparative analyses. 2 However, anticoagulation unmasks rather than causes most hematuria—the bleeding reveals underlying pathology that requires investigation. 1

Bladder cancer must be considered first-line in any elderly male with new-onset hematuria, particularly with concurrent urinary frequency. Research demonstrates that atrial fibrillation patients on oral anticoagulation with hematuria have significantly higher rates of genitourinary cancer (1.6% vs 0.7% in non-anticoagulated patients), with bladder cancer being the most common malignancy (1.2% vs 0.5%). 1 Importantly, anticoagulation may facilitate earlier detection of lower-grade tumors. 1

Benign prostatic hyperplasia (BPH) with bladder outlet obstruction is highly probable given the 3-4 weeks of urinary frequency in an elderly male. The combination of storage symptoms (frequency) and new hematuria suggests either prostatic bleeding or secondary bladder pathology from chronic obstruction. 3

Urinary tract infection (UTI) or prostatitis should be considered, though the absence of fever, dysuria, or suprapubic pain makes this less likely. 3

Nephrolithiasis remains possible despite absent flank pain, as elderly patients may have atypical presentations. 3

Medication-induced causes beyond anticoagulation include losartan, which has uricosuric effects that theoretically could contribute to crystalluria, though this is uncommon and losartan is generally safe in this context. 4

Secondary Considerations

• Renal parenchymal disease (glomerulonephritis, IgA nephropathy)
• Renal cell carcinoma or upper tract urothelial carcinoma
• Radiation cystitis (if prior pelvic radiation)
• Anticoagulant-related nephropathy leading to glomerular bleeding 5

Workup Algorithm

Immediate Laboratory Evaluation

Obtain urinalysis with microscopy immediately to characterize the hematuria (glomerular vs non-glomerular pattern), assess for pyuria, bacteria, casts, and crystals. 3

Check complete metabolic panel including creatinine to assess renal function, as apixaban dosing depends on kidney function and chronic kidney disease increases bleeding risk. Apixaban 5 mg is associated with higher bleeding rates in severe CKD (stage 4/5) compared to 2.5 mg dosing. 6 Additionally, direct oral anticoagulants including apixaban are associated with lower AKI risk than warfarin, but renal function must be monitored. 5

Obtain complete blood count to quantify blood loss and assess for anemia requiring intervention. 3

Send urine culture even without dysuria, as UTI can present atypically in elderly patients. 3

Check PSA level given age and urinary frequency, though recognize that acute urinary retention, instrumentation, or prostatitis can falsely elevate PSA. 3

Imaging Studies

Obtain renal and bladder ultrasound as the initial imaging modality to assess for hydronephrosis, bladder masses, stones, and post-void residual volume. This is non-invasive and provides immediate information about upper tract obstruction and bladder pathology. 3

CT urography (without and with contrast) is the gold standard for evaluating hematuria in patients >35 years with risk factors for malignancy. This provides comprehensive evaluation of the entire urinary tract including kidneys, ureters, and bladder. 3 However, assess renal function first—if creatinine is significantly elevated, contrast administration may be contraindicated.

Urologic Referral

Urgent urology consultation for cystoscopy is mandatory in this patient. Direct visualization of the bladder is essential to exclude bladder cancer, which is the most concerning diagnosis given the patient's demographics and anticoagulation status. 1 Cystoscopy should not be delayed pending other workup results.

Cystoscopy can typically be performed safely without interrupting anticoagulation for diagnostic purposes, though this decision should be made in consultation with urology. The European Heart Rhythm Association guidelines indicate that diagnostic cystoscopy is generally low bleeding risk. 3

Anticoagulation Management Considerations

Do not discontinue apixaban precipitously unless life-threatening bleeding occurs. The patient's CHA₂DS₂-VASc score is elevated (age ≥65, hypertension, likely ≥2 points), making stroke risk substantial if anticoagulation is interrupted. 3

If cystoscopy or biopsy is required, coordinate with urology and cardiology regarding timing of apixaban interruption. For procedures with moderate bleeding risk, apixaban is typically held for 24-48 hours preprocedure (approximately 2 half-lives). 3

Ensure blood pressure is well-controlled (<140/90 mmHg), as hypertension significantly increases both stroke and bleeding risk in anticoagulated patients with atrial fibrillation. 3

Additional Diagnostic Considerations

If urinalysis shows dysmorphic RBCs, RBC casts, or proteinuria >500 mg/day, consider nephrology referral for evaluation of glomerular disease, though this is less likely given the clinical presentation. 3

Assess for other bleeding manifestations (gingival bleeding, easy bruising, melena) that might suggest supratherapeutic anticoagulation effect or underlying coagulopathy. 3

Critical Pitfalls to Avoid

Never attribute hematuria solely to anticoagulation without complete urologic evaluation. While anticoagulants increase bleeding risk, they typically unmask underlying pathology rather than causing isolated hematuria. Failure to investigate can result in delayed cancer diagnosis. 1

Do not assume absence of fever excludes infection in elderly patients, who may have blunted inflammatory responses. 3

Avoid nephrotoxic agents including NSAIDs, which can worsen renal function and increase bleeding risk in anticoagulated patients. 3

Do not delay cystoscopy for "conservative management" in an elderly male with new hematuria—the pretest probability of significant pathology is too high. 1

Monitor renal function closely if contrast imaging is performed, as elderly patients on losartan and with potential volume depletion from hematuria are at increased AKI risk. 5