Reversal of Factor Xa Inhibitors by Andexanet Alfa May Increase Thrombogenesis Compared to Pretreatment Values

Abstract

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.

Operative survival in patients with acute aortic disease in the era of newer oral anticoagulants

“…Apixaban is the most used anticoagulant in Norway and even though plasma level analyses are available at our institution, there are no clear guidelines as to what levels would be considered therapeutic. Furthermore, as andexanet alfa may have effects on antithrombin mediated anticoagulation, 8 the safety of andexanet alfa in open heart surgery requiring full-heparinisation remains to be demonstrated. In recent cases, we have used activated recombinant coagulation factors to reduce bleeding complications in DOAC users undergoing acute cardiac surgery.…”

“…Apixaban is the most used anticoagulant in Norway and even though plasma level analyses are available at our institution, there are no clear guidelines as to what levels would be considered therapeutic. Furthermore, as andexanet alfa may have effects on antithrombin mediated anticoagulation, 8 Adjusted operative survival for patients using DOAC versus patients not using DOAC (A). Adjusted operative survival for patients using warfarin versus patients not using warfarin (B).…”

Thrombin Generation Profile in Various Lymphoma Sub-Groups and Its Augmentation by Andexanet Alfa

“…However, andexanet alfa can also neutralize other direct anti-Xa agents such as betrixaban and edoxaban. 36 …”

“…However, andexanet alfa can also neutralize other direct anti-Xa agents such as betrixaban and edoxaban. 36 Andexanet Alfa (AA, coagulation FXa recombinant, inactivated Zh-Zo; Portola Pharmaceuticals, South San Francisco, CA) is a recombinant modified version of human activated FXa, which is designed to reverse the inhibition of FXa bleeding associated with newer oral anti-Xa agent. 30,31 In May 2018, the FDA approved andexanet alfa as an antidote for factor Xa inhibitors such as apixaban and rivaroxaban.…”

“…30 In the previous study the augmentation of thrombin generation associated with andexanet has been reported in plasma- based systems. 36 Thrombotic complications have been reported in both solid tumors and hematologic malignancies. 18 Thrombin generation plays an important role in mediating its responses in cancer patients.…”