title: Effects of Rivaroxaban on Platelet Activation and Platelet-Coagulation Pathway Interaction: In Vitro and In Vivo Studies.
abstract: BACKGROUND
  Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models.
  
  
  METHODS
  Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis.
  
  
  RESULTS
  Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect.
  
  
  CONCLUSIONS
  These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency.
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany elisabeth.perzborn@bayer.com.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perzborn
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heitmeier
authors.affiliation: Acute Care Diseases Research, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Laux
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000069552:Rivaroxaban / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000069552:Rivaroxaban; D000077144:Clopidogrel; D013917:Thrombin; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin
keywords: antiplatelet agents; combination drug therapy; platelet aggregation; rivaroxaban; thrombosis
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