title: Multimodal assessment of non-specific hemostatic agents for apixaban reversal.
abstract: BACKGROUND
  Non-specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off-label, to reverse the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban.
  
  
  METHODS
  Healthy volunteer whole blood was spiked with therapeutic or supra-therapeutic apixaban concentrations and two doses of aPCC, PCC or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time.
  
  
  RESULTS
  aPCC generated a dense clot constituting thin and branched fibers similar to those of a control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters.
  
  
  CONCLUSIONS
  aPCC was more effective than PCC or rFVIIa in reversing in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only a partial effect.
authors: Faculté de Pharmacie, Inserm UMR-S1140, Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Service de Cardiologie, Hôpital du Val de Grâce, Paris, France.
authors: A-C
authors: AC
authors: Martin
authors: I
authors: I
authors: Gouin-Thibault
authors: V
authors: V
authors: Siguret
authors: A
authors: A
authors: Mordohay
authors: C-M
authors: CM
authors: Samama
authors: P
authors: P
authors: Gaussem
authors: B
authors: B
authors: Le Bonniec
authors: A
authors: A
authors: Godier
mesh_terms: D000931:Antidotes / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000494:pharmacology; D015942:Factor VIIa / Q000494:pharmacology; D065427:Factor Xa Inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D005337:Fibrin / Q000378:metabolism / Q000648:ultrastructure; D064368:Healthy Volunteers; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D010314:Partial Thromboplastin Time; D058105:Polymerization; D011517:Prothrombin Time; D011720:Pyrazoles / Q000633:toxicity*; D011728:Pyridones / Q000633:toxicity*; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism
chemical_list: D000931:Antidotes; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D006490:Hemostatics; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; C522181:apixaban; D005337:Fibrin; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin
keywords: apixaban; factor eight inhibitor bypassing activity; fibrin; prothrombin complex concentrates; recombinant FVIIa