title: Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model.
abstract: BACKGROUND
  As a potent anticoagulant agent, rivaroxaban exposes a risk of bleeding. An effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of an overdose of rivaroxaban in a rabbit model of bleeding and thrombosis.
  
  
  METHODS
  First, a dose-ranging study assessed the minimal rivaroxaban dose that increased bleeding. Then, 48 anesthetized and ventilated rabbits were randomized into four groups: control (saline), rivaroxaban (rivaroxaban and saline), rFVIIa (rivaroxaban and rFVIIa), and PCC (rivaroxaban and PCC). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis, detected as cyclic flow reductions, which were recorded over 20 min. Then the following were measured: ear immersion bleeding time, clotting times, anti-Xa activity, thrombelastometric parameters, and thrombin generation test. Ultimately, a hepatosplenic section was performed and the total amount of blood loss after 15 min was evaluated as primary endpoint.
  
  
  RESULTS
  Rivaroxaban increased blood loss (17 g [8-32] vs. 7 g [5-18] for control (median [range]), P = 0.0004), ear bleeding time, clotting times, thrombelastographic clotting time, and decreased thrombin generation. In contrast, rFVIIa decreased ear bleeding time (92 s [65-115] vs. 140 s [75-190], P < 0.02), but without efficacy on blood loss. PCC and rFVIIa decreased activated partial thromboplastin time as well as thrombelastographic clotting time. Regarding safety, neither rFVIIa nor PCC increased cyclic flow reductions.
  
  
  CONCLUSIONS
  rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.
authors: Department of Anaesthesia and Critical Care, Paris Descartes University, Hôtel-Dieu University Hospital, Paris, France. anne.godier@htd.aphp.fr
authors: Anne
authors: A
authors: Godier
authors: Anastasia
authors: A
authors: Miclot
authors: Bernard
authors: B
authors: Le Bonniec
authors: Marion
authors: M
authors: Durand
authors: Anne-Marie
authors: AM
authors: Fischer
authors: Joseph
authors: J
authors: Emmerich
authors: Catherine
authors: C
authors: Marchand-Leroux
authors: Thomas
authors: T
authors: Lecompte
authors: Charles-Marc
authors: CM
authors: Samama
mesh_terms: D000758:Anesthesia; D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001760:Bleeding Time; D001780:Blood Coagulation Tests; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000008:administration & dosage / Q000627:therapeutic use*; D006470:Hemorrhage / Q000097:blood; D008099:Liver / Q000098:blood supply; D008297:Male; D008991:Monitoring, Physiologic; D009025:Morpholines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011516:Prothrombin / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012121:Respiration, Artificial; D000069552:Rivaroxaban; D013154:Spleen / Q000098:blood supply; D013876:Thiophenes / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000096:biosynthesis; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D011994:Recombinant Proteins; D013876:Thiophenes; D011516:Prothrombin; D000069552:Rivaroxaban; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin