Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor VII to Reverse Rivaroxaban in a Rabbit Model

Author:

Godier Anne1,Miclot Anastasia2,Le Bonniec Bernard3,Durand Marion4,Fischer Anne-Marie5,Emmerich Joseph6,Marchand-Leroux Catherine7,Lecompte Thomas8,Samama Charles-Marc9

Affiliation:

1. Staff Anaesthesiologist, Department of Anaesthesia and Critical Care, Paris Descartes University, Hôtel-Dieu University Hospital, Paris, France, and INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, France.

2. Research Fellow, INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, France.

3. Senior Research Scientist, INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, France.

4. Staff Surgeon, Thoracic Surgery Unit, Nancy University Hospital, CHU, Nancy, France, and INSERM U961, Nancy, France.

5. Professor and Chair, Laboratory of Haemostasis, Paris Descartes University, APHP Européen Georges Pompidou University Hospital, Paris, France.

6. Professor, INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, France.

7. Professor, Equipe de Recherche “Pharmacologie de la Circulation Cérébrale” (EA4475), Paris Descartes University, Paris, France.

8. Professor and Chair, Haemostasis, Laboratory Haematology, Nancy University Hospital, CHU, Nancy, France, and INSERM U961, Nancy, France.

9. Professor and Chair, Department of Anaesthesia and Critical Care, Paris Descartes University, Hôtel-Dieu University Hospital, Paris, France, and INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, France.

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. Conclusion rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

Reference38 articles.

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