PB1090 - Modelling the effects of 4-factor prothrombin complex concentrate for the management of factor Xa inhibitor-associated bleeding

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

IM

Ineke Muir

Associate Director
CSL Innovation Ltd Pty
Parkville, Victoria, Australia

Co-Author(s)

EH

Eva Herzog

Executive Director
CSL Behring
King of Prussia, Pennsylvania, United States
MB

Markus Brechmann

Executive Director
CSL Behring Innovation GmbH
Marburg, Hessen, Germany

Presenting Author(s)

Oliver Ghobrial

Director
CSL Behring
King of Prussia, Pennsylvania, United States

Co-Author(s)

AR

Alireza Rezvani-Sharif

Senior Scientist
CSL Ltd Pty
Parkville, Victoria, Australia
MH

Maureane Hoffman

Professor
Duke University School of Medicine
Durham, North Carolina, United States

Background: The management of factor Xa (FXa) inhibitor-associated bleeding remains a clinical challenge. Massive bleeding is often associated with complex coagulopathy, so the sole reversal of FXa inhibitors might not be sufficient to restore haemostasis, requiring instead a multimodal approach. Four-factor prothrombin complex concentrate (4F-PCC) is widely recognized as a viable treatment option for FXa inhibitor-associated bleeding, but the exact mechanism of action is poorly understood.

Aims: To use a computational model to simulate a patient who has received a FXa inhibitor, explore the effects that 4F-PCC (and components thereof) has on restoration of thrombin and compare those to the effects of specific FXa inhibitor reversal agents.

Methods: Simulations were performed using a mathematical model of coagulation based on a modified, previously developed model1. The model was calibrated and validated using data from a phase 3 clinical trial of vitamin K antagonist (VKA) reversal with 4F-PCC.

Results: The model successfully simulated the effects, at various plasma levels, of rivaroxaban and apixaban on total thrombin generation. 4F-PCC doses of 15, 25 or 50 IU/kg resulted in either partial or complete normalization of INR. An investigation into the effects of individual and combinations of 4F-PCC components indicated that prothrombin alone or in combination with FVII or FIX had the greatest efficacy in restoring thrombin levels.

Conclusion(s): Our coagulation simulation model showed that 4F-PCC effectively increased thrombin generation in the presence of rivaroxaban or apixaban.