Coagulation Factor Concentrates Restore Alterations in Hemostasis Induced by a High Dose of Apixaban: Studies in Vitro with Circulating Human Blood.
Authors: Escolar Gines , Arellano-Rodrigo Eduardo , Reverter Joan Carles , Villalta Jaume , Sanz Victoria Veronica , Molina Patricia , Diaz-Ricart Maribel , Galan Ana M 
Published: October 2019

Abstract
Abstract 2263

Background:
Newly developed oral anticoagulants require less frequent controls, have fewer interactions with other medications and effects are more reliable. Despite these advantages, bleeding is still a frequent complication for patients on treatment with oral anticoagulants and reversal of their effects remains an unsolved issue for the newer agents. Apixaban is a new oral anticoagulant with inhibitory action on FXa. It has showed a very good efficacy/safety profile in studies in prophylaxis of thrombotic complications after mayor orthopaedic surgery and in atrial fibrillation (AF).

Aims:
To explore the effects of concentrations of apixaban in excess of those achieved after standard approved dosage, on platelet and coagulation mediated mechanisms of hemostasis. To evaluate the effectiveness of different factor concentrates at reversing the alterations of hemostatic mechanism induced by apixaban.

Methods:
Apixaban was added in vitro to blood alliquots from healthy donors. Concentrations of apixaban tested (200 ng/ml) doubled the average Cmax reached at steady state with standard approved treatment for AF. Modifications in platelet reactivity towards surfaces were measured at elevated shear rates in a cone and plate analyzer (Impact R®). Effects on thrombin generation (TG) and on thromboelastometry parameters (TEM) were also assessed. Changes in platelet adhesive, aggregating and procoagulant activities were additionally evaluated in perfusion studies through vascular surfaces in a system producing results that correlate with clinical situations (Transfus Med Rev 15:144, 2001). The potential action of prothrombin complex concentrates (PCCs) (50 IU/kg), activated PCCs (aPCCs) at 75 IU/kg, or rFVIIa at 270 μg/kg reversing the anticoagulant actions of apixaban were evaluated.

Results:
Apixaban did not affect the reactivity of platelets to surfaces in the Impact R®. Apixaban caused a moderate reduction in TG as confirmed by delayed lag phase, prolonged time to peak and reduced velocity index. Thrombin peak and velocity indexes in TG were improved by concentrates with the following order of efficacy PCC≥aPCC>rFVIIa. Apixaban prolonged clotting time (CT) and reduced maximal clot firmness (MCF) in TEM studies using tissue factor as activator. Alterations in these parameters were corrected by the different concentrates according to the following order of efficacy rFVIIa≥aPCC>PCC. Apixaban quantitatively reduced fibrin and platelet interactions with damaged vascular surfaces (p<0.05) in perfusion studies. These alterations were counteracted by the different concentrates with efficacies following this order rFVIIa>PCC>aPCC.

Conclusions:
Apixaban at 200 ng/ml did not show a direct antiplatelet effect in studies in the cone plate analyzer, but demonstrated evident alterations in hemostasis related to its recognized anticoagulant action. These alterations were variably compensated or even reversed by the different factor concentrates. 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 tests. Studies with flowing blood that reproduce conditions closer to the bleeding situation indicate that current coagulation factor concentrates can effectively restore the impairement in fibrin formation on damaged vascular surfaces resulting from apixaban overdose.

Disclosures:
Escolar: BMS: Honoraria, Research Funding; Bayer: Honoraria; Boehringer Ingelheim: Honoraria.