Abstract
IntroductionMechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions.MethodsWe assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets.ResultsIn studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated.ConclusionsOur studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.
Highlights
Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories
Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban
Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis
Summary
The aim of the present study was to assess the effects of apixaban at therapeutic and subtherapeutic doses in different models of hemostasis: 1) Modifications in the adhesive-cohesive properties of platelets and in fibrin formation were evaluated with perfusion devices, using whole blood circulated through damaged vascular segments, and a shear rate similar to those found at medium-sized arteries; 2) changes in thromboelastometry parameters during clot formation of citrated blood; and 3) contribution of platelets to kinetics of local thrombin generation, using an in house cell-based model of thrombin generation primed by platelets, in a fluorimetric assay with a fluorogenic substrate (Technoclone GmBH, Austria)
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