Significant changes incorporated to this global amendment included: • Added more exploratory endpoints: - Relationship between hemostatic efficacy and anti fXa activity - Length of time from clinical presentation at the treating facility to the start of surgery - Time hospitalized in a post anesthesia care unit (PACU), assessed at the Day 30 visit - Time in the operating room (OR) • Clarified timing of FXa dosing in relation to surgery to allow enrollment of participants who received their last dose of a FXa inhibitor >15 hours before surgery if their anti fXa activity level is >100 ng/milliliter mL (or >0.5 IU/mL for participants taking enoxaparin) within 2 hours of consent • Clarified criteria for re-dosing and extended infusion • Clarified that only participants with effective levels of anticoagulation will be included in the efficacy analysis population • Updated eligibility criteria to exclude participants who have - acute overt bleeding that is potentially life threatening - overt bleeding associated with a fall in hemoglobin level by ≥ 2 grams (g)/deciliter (dL) or a hemoglobin level of ≤8 g/dL if no baseline hemoglobin is available - acute bleeding in a critical area or organ - a nonsurgical interventional procedure as the primary procedure of efficacy assessment - heparin-induced thrombocytopenia (with or without thrombosis) - inherited coagulopathy - last dose of apixaban <2.5 mg, rivaroxaban <10 mg, edoxaban <30 mg, or enoxaparin 40 mg • Increased sample size to account for possible attrition rates and rare events • Removed null and alternative hypotheses testing • Added ‘physical examination’ and ‘centrally adjudicated’ deaths to the safety assessments and clarified that all safety analyses will be performed in Safety Analysis Population

Significant changes incorporated to this global amendment included: • Revised study phase from Phase 3 to Phase 2 • Added that participants will be closely monitored during the period where they are most vulnerable, and the risk of thrombosis is highest • Added allowance of 2.5 mg of apixaban • Updated eligibility criteria to exclude participants who have - Known hypersensitivity to any component of andexanet - Known allergic reaction to hamster proteins - Known or suspected (that is, presumed positive) COVID-19 related illness at the time of Screening • Clarified the section on informed consent to include acknowledgement that proxy consents must be permissible by national regulatory authorities and that emergency consent is not permitted • Reduced the sample size from 200 participants to 100 participants to align with goals for a Phase 2 study