Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood

PLoS One. 2013 Nov 11;8(11):e78696. doi: 10.1371/journal.pone.0078696. eCollection 2013.

Abstract

Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s(-1). The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / pharmacology*
  • Blood Coagulation / drug effects*
  • Dose-Response Relationship, Drug
  • Factor VIIa / metabolism*
  • Factor VIIa / pharmacology
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors
  • Female
  • Humans
  • Male
  • Platelet Adhesiveness / drug effects*
  • Pyrazoles / pharmacology*
  • Pyridones / pharmacology*
  • Rabbits
  • Thrombelastography / methods

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Pyrazoles
  • Pyridones
  • apixaban
  • Factor VIIa
  • Factor Xa

Grants and funding

This work was partially supported by grants FIS (CP04-00112, PS09/00664), SAF2009-10365, and Red HERACLES RD06/0009/1003-0015 from the Spanish Government and by an investigator sponsored award from BMS-Pfizer. Dr A.M. Galan belongs to the Miguel Servet Researcher's stabilization program of “Instituto de Salud Carlos III” from the Spanish government and “Direcció d'Estratègia i Coordinació del Departament de Salut” from the Generalitat de Catalunya. Dr Fernandez-Gallego is employed by Bristol-Myers Squibb, Madrid, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.