title: Rivaroxaban delivery and reversal at a venous flow rate.
abstract: OBJECTIVE
  Rivaroxaban is an oral anticoagulant that directly targets both free factor Xa and factor Xa in complex with its protein cofactor, factor Va, in the prothrombinase complex. It is approved in the United States for the prophylaxis of deep vein thrombosis and stroke in patients with atrial fibrillation; however, it also carries a black box warning regarding the risk of thrombosis after discontinuation of treatment. The purpose of this study was to determine the degree to which rivaroxaban, over a range of physiologically relevant free plasma concentrations, inhibits preassembled prothrombinase at a typical venous shear rate (100 s(-1)) and to determine the dynamics of rivaroxaban washout.
  
  
  RESULTS
  Prothrombinase was assembled on phospholipid-coated glass capillaries. Its activity was characterized with respect to the activation of prothrombin (mean plasma concentration, 1.4 μmol/L) in the absence and presence of rivaroxaban (2, 5, and 10 nmol/L). The degree of inactivation of preassembled prothrombinase is sensitive to the solution-phase rivaroxaban concentration; however, prothrombinase unmasking upon removal of rivaroxaban is concentration independent.
  
  
  CONCLUSIONS
  The model system presented suggests that when rivaroxaban plasma concentrations decrease after cessation of therapy, there will be an unmasking of thrombus-associated prothrombinase that may be related to the reported rebound phenomena.
authors.affiliation: Department of Biochemistry, University of Vermont College of Medicine, Colchester, VT 05446, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Haynes
authors.forename: Thomas
authors.initials: T
authors.lastname: Orfeo
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Mann
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000187:drug effects / Q000378:metabolism; D015943:Factor Va / Q000187:drug effects / Q000378:metabolism; D015951:Factor Xa / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects*; D012307:Risk Factors; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism; D020246:Venous Thrombosis / Q000453:epidemiology* / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; C022475:prothrombinase complex; D015943:Factor Va; D005165:Factor V; D013925:Thromboplastin; D000069552:Rivaroxaban; D015951:Factor Xa