Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood.
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.
Department of Hemotherapy-Hemostasis, Hospital Clinic, Centre de Diagnostic Biomedic, Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
Gines
G
Escolar
Victor
V
Fernandez-Gallego
Eduardo
E
Arellano-Rodrigo
Jaume
J
Roquer
Joan Carles
JC
Reverter
Victoria Veronica
VV
Sanz
Patricia
P
Molina
Irene
I
Lopez-Vilchez
Maribel
M
Diaz-Ricart
Ana Maria
AM
Galan
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000378:metabolism* / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013916:Thrombelastography / Q000379:methods
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D015942:Factor VIIa; D015951:Factor Xa