title: Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation.
abstract: BACKGROUND
  Mechanisms 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Pujadas-Mestres
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Lopez-Vilchez
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arellano-Rodrigo
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Reverter
authors.affiliation: Department of Medicine, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Farre
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Diaz-Ricart
authors.affiliation: Atherothrombosis Research Unit, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Badimon
authors.affiliation: Department of Hemotherapy and Hemostasis, Hospital Clinic of Barcelona, Centre of Biomedical Diagnosis (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Gines
authors.initials: G
authors.lastname: Escolar
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors / Q000494:pharmacology; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D018056:Hemorheology; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D015539:Platelet Activation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D005337:Fibrin; D013917:Thrombin