AI Article Synopsis
- Andexanet alfa is a medication used to reverse the effects of FXa inhibitors like apixaban, but its impact on blood clotting and fibrinolysis hasn't been thoroughly studied.
- In experiments with plasma and blood from healthy volunteers, increasing levels of apixaban were shown to slow down thrombin generation and thrombus formation, while the addition of GDXa (a modified FXa analog) helped counteract these effects.
- Results suggested that GDXa can effectively reverse coagulation delays caused by apixaban, but its effect on fibrinolysis was limited, indicating that FXa still plays a role in generating plasmin despite apixaban's inhibition at high concentrations.
Article Abstract
Background: Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban.
Methods: Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa.
Results: Apixaban (250-800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500-800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations.
Conclusions: This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations.
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| http://dx.doi.org/10.1016/j.thromres.2023.08.018 | DOI Listing |
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