title: Thrombin generation induced by tissue factor plus ADP in human platelet rich plasma: A potential new measurement to assess the effect of the concomitant use of an oral factor Xa inhibitor edoxaban and P2Y12 receptor antagonists.
abstract: BACKGROUND
  Patients with atrial fibrillation undergoing percutaneous coronary intervention may require combination therapy with anticoagulants and antiplatelet agents. The objectives of this study were to establish an assay which can evaluate the effects of both anticoagulants and P2Y12 receptor antagonists and determine the effects of edoxaban, a direct factor Xa inhibitor, and P2Y12 receptor antagonists (clopidogrel and ticagrelor) alone and when combined.
  
  
  METHODS
  Human platelet-rich plasma (PRP) from healthy subjects was stimulated with adenosine diphosphate (ADP) plus tissue factor. Thrombin generation was measured by means of calibrated automated thrombography.
  
  
  RESULTS
  Combination of 10μM ADP and low concentration (0.25 pM) tissue factor induced reproducible thrombin generation in human PRP. Edoxaban (40 and 80ng/mL), active metabolite of clopidogrel (AM-clopidogrel, 10 and 20μg/mL), and ticagrelor (3μg/mL) alone inhibited ADP plus tissue factor-induced thrombin generation. Edoxaban suppressed all 5 parameters (lag time, peak, time to peak, endogenous thrombin potential, and maximum rate), whereas AM-clopidogrel and ticagrelor inhibited 4 and 3 parameters, respectively. Concomitant treatment with edoxaban and AM-clopidogrel or ticagrelor produced an additive inhibition of thrombin generation compared to the single treatments.
  
  
  CONCLUSIONS
  The thrombin generation assay induced by ADP plus tissue factor can detect the activities of both edoxaban and P2Y12 receptor antagonists. Combination of edoxaban and a P2Y12 receptor antagonist shows additive inhibition. These results suggest that ADP plus tissue factor-induced thrombin generation may be a useful measurement to assess the combination effects of anticoagulants and P2Y12 receptor antagonists in a single assay.
authors: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors: Yuko
authors: Y
authors: Honda
authors: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
authors: Yoshiyuki
authors: Y
authors: Morishima
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D006801:Humans; D053657:Platelet-Rich Plasma / Q000187:drug effects* / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*; D000077486:Ticagrelor
chemical_list: D065427:Factor Xa Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011725:Pyridines; D013844:Thiazoles; D000244:Adenosine Diphosphate; D013925:Thromboplastin; D013917:Thrombin; D000077486:Ticagrelor; D000241:Adenosine; C552171:edoxaban
keywords: ADP; Edoxaban; Factor Xa inhibitor; P2Y(12) receptor antagonist; Thrombin generation; Tissue factor