title: Effects on platelet function of a direct acting antagonist of coagulation factor Xa.
abstract: Because novel direct acting anticoagulants are being tested in the secondary prevention of cardiovascular events, we assessed potential effects of a direct acting antagonist of Factor Xa on platelet function. Blood from patients with known coronary artery disease who were treated with aspirin but no other antithrombotic agent was spiked in vitro with rivaroxaban alone or in combination with a direct acting P2Y12 antagonist (cangrelor). To limit cofounding effects of anticoagulants and to enable interaction between coagulation factors, blood was anticoagulated only with a specific inhibitor of Factor XIIa, corn trypsin inhibitor. Polymerization of fibrin was prevented with the peptide GPRP. Activation of platelets was determined with the use of flow cytometry in response to lipidated tissue factor, thrombin, the collagen mimetic convulxin, and adenosine diphosphate (ADP). Rivaroxaban inhibited the activation of platelets induced by tissue factor and to a lesser extent activation induced by thrombin, effects that were accentuated when combined with cangrelor. Rivaroxaban did not attenuate convulxin-induced activation of platelets; however, a limited but consistent attenuation of ADP-induced platelet activation was seen with blood anticoagulated with rivaroxaban. Effects of rivaroxaban on ADP-induced platelet activation were not mediated by thrombin, tissue factor, or platelet-leukocyte aggregation. In conclusion, rivaroxaban attenuated in vitro the activation of platelets mediated by thrombin. In light of the pivotal role of thrombin in platelet activation after rupture of an atherosclerotic plaque, rivaroxaban should attenuate platelet activation in vivo, an effect that is accentuated by combination with a P2Y12 antagonist.
authors.affiliation: Cardiovascular Unit and Cardiovascular Research Institute, University of Vermont, 111 Colchester Ave, Burlington, VT, 05401, USA. sukit.ringwala@vtmednet.org
authors.forename: Sukit M
authors.initials: SM
authors.lastname: Ringwala
authors.forename: Peter M
authors.initials: PM
authors.lastname: Dibattiste
authors.forename: David J
authors.initials: DJ
authors.lastname: Schneider
mesh_terms: D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage; D001792:Blood Platelets / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy; D003435:Crotalid Venoms / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D037181:Lectins, C-Type; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage*; D010940:Plant Proteins / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D010979:Platelet Function Tests / Q000379:methods; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D003435:Crotalid Venoms; D065427:Factor Xa Inhibitors; D037181:Lectins, C-Type; D009025:Morpholines; C548576:P2RY12 protein, human; D010940:Plant Proteins; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; C052160:trypsin inhibitor, Zea mays; C028890:convulxin; D000249:Adenosine Monophosphate; C117446:cangrelor; D000069552:Rivaroxaban; D015951:Factor Xa; D001241:Aspirin