High-dose antithrombin with heparin mitigated andexanet-induced heparin resistance in vitro, prolonging ACT to >400 s, though residual thrombin generation suggests ongoing thrombotic risk.
Does combined antithrombin and heparin supplementation restore heparin responsiveness in blood exposed to andexanet alfa during cardiopulmonary bypass?
High-dose antithrombin combined with heparin mitigates andexanet-induced heparin resistance in vitro, though residual thrombin generation suggests ongoing thrombotic risk.
ABSTRACT Background: Andexanet alfa, a Gla‐domainless mutant factor Xa (GDXa), reverses oral FXa inhibitors but can cause severe heparin resistance during cardiopulmonary bypass (CPB). Antithrombin (AT) supplementation may mitigate this effect, though dosing evidence is limited. Methods We evaluated in vitro the effectiveness of combined heparin and AT in restoring heparin responsiveness after andexanet exposure. Whole blood and platelet‐poor plasma from surgical patients on CPB were spiked with andexanet at target concentrations of 2.9 and 4 µM, respectively. Heparin responsiveness was assessed using kaolin‐activated clotting time (ACT), ellagic acid‐activated thromboelastometry (INTEM), and thrombin generation (TG) assays. Heparin alone or with AT (0.8–3.1 µM in whole blood; 1.1–4.4 µM in plasma) simulated clinical AT dosing (25–100 U/kg). Results Andexanet shortened ACT by 68% versus native on‐CPB blood. Heparin alone or low‐dose AT failed to restore ACT, while high‐dose AT with heparin prolonged ACT to > 400 s. INTEM showed a 102% increase in clotting time with moderate‐dose AT, with modest α ‐angle and MCF reductions (≤ 16%). In plasma, high‐dose AT plus heparin increased TG lag time ∼5‐fold, with thrombin peak and velocity reduced by 86%. Conclusion High‐dose AT with heparin mitigates andexanet‐induced heparin resistance in vitro, though residual TG and clot formation suggest ongoing thrombotic risk, warranting further study. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission
Butt et al. (Fri,) conducted a other in Andexanet alfa-induced heparin resistance during cardiopulmonary bypass. Combined heparin and antithrombin vs. Heparin alone or low-dose antithrombin was evaluated on Heparin responsiveness assessed by ACT, INTEM, and thrombin generation. High-dose antithrombin with heparin mitigated andexanet-induced heparin resistance in vitro, prolonging ACT to >400 s, though residual thrombin generation suggests ongoing thrombotic risk.