A patient on apixaban (Eliquis) presenting with hematuria—how should I manage the bleeding and anticoagulation?

Management of Hematuria in a Patient on Apixaban (Eliquis)

Stop apixaban immediately and assess bleeding severity using the ACC criteria: major bleeding is defined by hemodynamic instability, hemoglobin drop ≥2 g/dL, transfusion requirement ≥2 units RBCs, or bleeding at a critical site—isolated hematuria without these features is classified as non-major and should be managed with supportive care alone, without reversal agents. 1, 2

Initial Assessment of Bleeding Severity

The first step is to rapidly classify the hematuria as major versus non-major, which determines your entire management pathway. 1, 2

Major bleeding criteria (if ≥1 present): 1, 2

• Hemodynamic instability (systolic BP <90 mmHg, drop >40 mmHg, or tachycardia requiring intervention)
• Hemoglobin decrease ≥2 g/dL from baseline
• Transfusion requirement ≥2 units of red blood cells
• Bleeding at a critical site (urinary tract obstruction or renal pelvis involvement—isolated bladder bleeding typically does not qualify)

If none of these criteria are met, the hematuria is non-major. 2

Obtain vital signs, hemoglobin/hematocrit, renal function, and assess for ongoing bleeding. 1, 2 Check the timing of the last apixaban dose—this matters because apixaban has a half-life of 6–15 hours (extending to ~17 hours in elderly patients or those with renal impairment). 2, 3

Management of Non-Major Hematuria

For non-major hematuria, do NOT use reversal agents or hemostatic agents—this adds thrombotic risk without proven benefit. 1, 2

Immediate actions: 1, 2

• Stop apixaban immediately
• Provide local bladder irrigation if clots are present; use continuous irrigation for persistent bleeding
• Give intravenous fluids for volume resuscitation and maintain adequate urine flow
• Hold concomitant antiplatelet agents (aspirin, clopidogrel) because combined therapy markedly increases bleeding risk
• Do NOT give vitamin K—apixaban is not a vitamin K antagonist

Assess contributing factors: 1, 2

• Screen for thrombocytopenia, uremia, and liver disease
• Verify renal function—severe impairment prolongs apixaban half-life and increases bleeding propensity
• Confirm appropriate apixaban dosing (common errors include failure to adjust for renal function or body weight changes)

If the last apixaban dose was >12 hours ago and renal function is normal, supportive care alone is usually sufficient because drug levels will decline naturally. 2

Management of Major Hematuria

For major or life-threatening hematuria, escalate to aggressive intervention: 1, 2

• Immediately discontinue apixaban and all antiplatelet agents
• Provide aggressive supportive care: volume resuscitation, blood transfusion as needed, continuous bladder irrigation
• Consider cystoscopy for clot evacuation or identification of bleeding source
• Assess need for surgical or procedural intervention to control the bleeding source

Reversal strategy: 1, 2

• Administer andexanet alfa when bleeding is life-threatening or uncontrolled despite supportive measures (Class IIa recommendation from AHA/ACC/HRS)
• Andexanet alfa reduced median anti-FXa activity by 92% for apixaban in the ANNEXA-4 trial, with excellent or good hemostasis in the majority of patients 1
• If andexanet alfa is unavailable, use four-factor prothrombin complex concentrate (4F-PCC) or activated PCC at 50 U/kg (maximum 4,000 units) 1
• Activated charcoal (50 g) may be used if apixaban was ingested within 2–4 hours 1, 3

Critical pitfall: Do not rely on PT/aPTT or INR to assess apixaban effect—normal values do not exclude therapeutic or supratherapeutic levels. 4, 3 Anti-factor Xa assays are available only in specialized laboratories and are not useful for guiding reversal. 1

Urological Work-Up

Do not skip a urological evaluation—anticoagulation may unmask underlying pathology (bladder tumor, stones, infection) but does not replace diagnostic investigation. 2 Once bleeding is controlled and anticoagulation is held, proceed with cystoscopy and imaging as clinically indicated.

Restarting Apixaban After Hematuria

Delay restarting apixaban if: 1, 2

• Bleeding source not identified or definitively treated
• High risk of re-bleeding (e.g., bladder tumor pending resection)
• Planned urological surgery
• Patient declines continuation

Restart apixaban when: 1, 2

• Bleeding is controlled
• Source has been treated
• Patient has high thrombotic risk (atrial fibrillation with CHA₂DS₂-VASc ≥2 or recent venous thromboembolism)

Timing of restart: 2

• Generally 24 hours after bleeding control for low-risk scenarios
• 48–72 hours for higher-risk situations (e.g., major bleeding, critical site involvement)
• Within 7 days if high thrombotic risk and bleeding controlled

Key Pitfalls to Avoid

• Do not continue apixaban during active visible hematuria, even if mild 2
• Do not use reversal agents for non-major bleeding—this increases thrombotic risk without clear benefit 1, 2
• Always reassess renal function—impaired clearance prolongs apixaban exposure and increases bleeding duration 2, 3
• Do not assume hemostasis based on normal coagulation tests—PT, aPTT, and INR do not reliably reflect apixaban activity 4, 3
• Monitor for anticoagulant-related nephropathy—apixaban can aggravate acute kidney injury through glomerular hemorrhage and red blood cell cast formation 5

Note on comparative safety: Pharmacovigilance data suggest apixaban has a lower risk of hematuria compared to rivaroxaban and warfarin, with fewer fatal bleeding episodes than dabigatran or enoxaparin. 6 Apixaban also demonstrates a favorable bleeding profile in patients with mild to moderate renal impairment compared to conventional anticoagulants. 7, 8