A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa

  title={A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa},
  author={Genmin Lu and Francis R Deguzman and Stanley J. Hollenbach and Mark J. Karbarz and Keith Abe and Gail Lee and Peng Luan and Athiwat Hutchaleelaha and Mayuko Inagaki and Pamela B. Conley and David R. Phillips and Uma Sinha},
  journal={Nature Medicine},
Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight… 
A rapid pro-hemostatic approach to overcome direct oral anticoagulants
It is shown that a variant coagulation factor, FXaI16L, rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors, and is more potent than a noncatalytic antidote that is currently in clinical development.
Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy
Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding.
Reversal of Factor Xa Inhibitors by Andexanet Alfa May Increase Thrombogenesis Compared to Pretreatment Values
  • Fakiha Siddiqui, A. Tafur, J. Fareed
  • Biology
    Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
  • 2019
Recombinant coagulation factor Xa, inactivated Zh-zo, also known as andexanet alfa, is a modified version of human FXa that has been developed to neutralize FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems.
Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies.
An overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.
Reversing factor Xa inhibitors – clinical utility of andexanet alfa
Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, and indirect FXa inhibitors such as low-molecular-weight heparins.
Inactivated antithrombins as fondaparinux antidotes: a promising alternative to haemostatic agents as assessed in vitro in a thrombin-generation assay.
Evaluated in vitro the effectivity of inactive ATs to reverse anticoagulation by heparin derivatives and to compare them with non-specific fondaparinux reversal agents, like recombinant-activated factor VII (rFVIIa) or activated prothrombin-complex concentrate (aPCC), in a throm bin-generation assay (TGA).
FXa-α2-Macroglobulin Complex Neutralizes Direct Oral Anticoagulants Targeting FXa In Vitro and In Vivo.
GDFXa-α2M is an attractive candidate for xaban neutralization neither pro- nor anticoagulant in vitro as well as in vivo and did not increase D-dimer or thrombin-antithrombin complex formation, suggesting a lack of pro-thrombotic potential.
Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors
Andexanet alfa shows promise to become a highly effective, novel antidote for factor Xa anticoagulation, and its biochemical profile and mechanism of action are immediately more attractive than other drugs on the market and under development due to its inert nature within the normal coagulation cascade.


Antithrombotic Activity of PRT54021, a Potent Oral Direct Factor Xa Inhibitor, Can Be Monitored Using a Novel Prothrombinase Inhibition Bioassay.
It is established that this new prothrombinase bioassay predicts in vivo antithrombotic activity, and currently in clinical development, PRT021, an orally bioavailable fXa inhibitor in advanced stages of clinical development (Phase II), was used to validate this hypothesis.
Recombinant factor VIIa as an antidote for anticoagulant treatment.
Recombinant factor VIIa infusion results in a prohemostatic response in vivo in patients receiving treatment with factor Xa- or TF-specific anticoagulants, suggesting that rFVIIa may be a good candidate as an antidote for new anticoAGulants in cases of (severe) bleeding or in patients scheduled for emergency surgery.
Development of a recombinant antithrombin variant as a potent antidote to fondaparinux and other heparin derivatives.
Results clearly demonstrate that AT-N135Q-Pro394 can reverse the anticoagulant activity of fondaparinux and thus could be used as an antidote for this drug.
Mechanism by Which Exosites Promote the Inhibition of Blood Coagulation Proteases by Heparin-activated Antithrombin*
Comparisons of the reactions of catalytically inactive S195A and active proteases with site-specific fluorophore-labeled antithrombins that allow monitoring of these reaction steps show that exosites generated by heparin activation of antithromabin function both to promote the formation of an initial antithrubin-protease Michaelis complex and to favor the subsequent acylation of this complex.
Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor VII to Reverse Rivaroxaban in a Rabbit Model
RFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding and safety, respectively.
Kinetics of Blood Coagulation Factor Xaα Autoproteolytic Conversion to Factor Xaβ
The data support a model where FXaα is predominantly responsible for thrombin generation and where slow conversion to FXaβ coordinates coagulation and the initiation of fibrinolysis at sites of prothrombinase assembly.
In vitro and in vivo studies of the novel antithrombotic agent BAY 59‐7939—an oral, direct Factor Xa inhibitor
BAY 59‐7939 inhibited endogenous FXa more potently in human and rabbit plasma than rat plasma, correlating with the 14‐fold lower IC50 ofFXa inhibition in rabbit compared with rat plasma; this may suggest a correlation between FXa inhibition and antithrombotic activity.
Fondaparinux Sodium Mechanism of Action
At clinically relevant concentrations, fondaparinux sodium is highly and specifically bound to ATIII in human plasma, suggesting that potential interaction with drugs via albumin or α1-acid glycoprotein displacement is unlikely.
Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects
Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticonvulsant action of dabigatran at the PCC dose used in this study.
Autoproteolysis or Plasmin-mediated Cleavage of Factor Xaα Exposes a Plasminogen Binding Site and Inhibits Coagulation*
The data provide the first evidence for a functional difference between the FXa subforms and suggest a mechanism where autoproteolysis and plasmin-mediated cleavage modulate the function of FXaα from a procoagulant enzyme to a profibrinolytic plAsminogen receptor.