What is the risk of arterial or venous thrombosis after administering andexanet alfa (Andexxa) and how should this risk influence its use for reversal of factor Xa inhibitors?

Risk of Thrombosis with Andexanet Alfa

Andexanet alfa carries a substantial thrombotic risk of approximately 10-18% within 30 days of administration, with the majority of events occurring in patients who did not resume anticoagulation; therefore, prompt reinitiation of therapeutic anticoagulation as soon as hemostasis is secured is essential to mitigate this risk. 1, 2, 3, 4

Magnitude and Timing of Thrombotic Risk

The thrombotic burden following andexanet alfa administration is clinically significant and well-documented across multiple sources:

• Incidence: Thromboembolic or ischemic events occur in 10-18% of patients within 30 days after andexanet alfa treatment 1, 2, 3, 4, 5
• Timing: The median time to first thrombotic event is 7 days, though 21 patients experienced events within the first 3 days in the FDA safety database 4
• Event types: These include arterial thrombosis, venous thromboembolism, ischemic stroke, and cardiac arrest 4

The FDA label specifically documents that among 352 bleeding subjects who received andexanet alfa, 63 patients (18%) experienced 88 thromboembolic or ischemic events 4. A meta-analysis found the thromboembolism rate with andexanet to be particularly elevated at 10.7% (95% CI: 6.5-15.7%), which was notably higher than with other reversal agents 5.

Comparative Evidence: Randomized Trial Data

The most recent and highest-quality evidence comes from the ANNEXA-I trial (2025), which provides Level 1 evidence comparing andexanet alfa to usual care:

• Thromboembolic events were significantly more frequent with andexanet alfa: 10.3% versus 5.6% with usual care (absolute increase 4.6 per 100 patients; 95% CI 0.1-9.2; P=0.048) 2
• Ischemic stroke specifically occurred in 6.5% of the andexanet group versus only 1.5% of usual care patients 2
• Despite this increased thrombotic risk, 30-day mortality was similar between groups (27.8% vs 25.5%) 2

This randomized evidence confirms that the thrombotic risk is not merely a reflection of the underlying patient population but represents a real treatment-related hazard.

Critical Risk Mitigation Strategy

The single most important intervention to reduce thrombotic risk is early resumption of anticoagulation 1, 2, 3, 4:

• Among the 223 patients in the FDA database who received at least one anticoagulation dose within 30 days after andexanet treatment, only 8% experienced a thrombotic event 4
• In contrast, the majority of thrombotic events occurred in patients who did not restart anticoagulation 2, 3
• The Association of Anaesthetists guidelines explicitly state: "when any form of anticoagulation was commenced within 30 days post-andexanet therapy, no thrombotic events occurred" 1

Practical Timing for Anticoagulation Resumption

Resume therapeutic anticoagulation as soon as medically appropriate after hemostasis is secured 4. The FDA label mandates monitoring for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest 4.

If immediate therapeutic anticoagulation must be delayed, consider bridging with prophylactic low-molecular-weight heparin until the patient is stable 2.

Mechanism of Thrombotic Risk

Andexanet alfa's prothrombotic effects are multifactorial 1:

• It binds tissue factor pathway inhibitor (TFPI) to form a non-productive complex, reducing TFPI activity 1
• This produces a transient increase in prothrombin fragment 1.2, thrombin-antithrombin complexes, and D-dimer 1
• The drug reverses anticoagulation in patients with underlying prothrombotic conditions (atrial fibrillation, recent VTE), exposing them to their baseline thrombotic risk 4

Clinical Scenarios Requiring Special Caution

The FDA label specifically notes that andexanet alfa safety has not been evaluated in 4:

• Patients who experienced thromboembolic events or disseminated intravascular coagulation within 2 weeks prior to the bleeding event
• Patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days prior to bleeding

The ACC/AHA guidelines note that andexanet alfa may not be indicated for patients with thromboembolic events in the previous 3 months 1.

Comparative Thrombotic Risk with Alternative Agents

When andexanet alfa is unavailable, 4-factor prothrombin complex concentrate (4F-PCC) is recommended at 50 U/kg IV (maximum 4,000-5,000 U) or a fixed 2,000-U dose 2, 3. One comparison showed no significant difference in thrombotic events between andexanet alfa and 4F-PCC, though larger studies are needed 1. The meta-analysis found overall thromboembolism rates with 4F-PCC to be lower than with andexanet 5.

Common Pitfalls to Avoid

• Do not delay anticoagulation resumption beyond what is necessary for hemostatic stability; this is the primary modifiable risk factor for thrombosis 1, 2, 3, 4
• Do not use andexanet alfa in patients requiring ongoing anticoagulation during surgery (e.g., cardiopulmonary bypass) as it can interfere with heparin 1, 4
• Do not assume the thrombotic risk is solely due to patient factors; the ANNEXA-I trial proves andexanet itself increases thrombotic events compared to usual care 2
• Monitor closely for at least 30 days after administration, as events can occur throughout this period 4