Rivaroxaban Effects Illustrate the Underestimated Importance of Activated Platelets in Thrombin Generation Assessed by Calibrated Automated Thrombography.

Stephanie Makhoul,Véronique Regnault,Jeremy Lagrange,Philip Wenzel,Wolfram Ruf,Marina Panova-Noeva

doi:10.3390/jcm8111990

Abstract

Background: The direct oral anticoagulant rivaroxaban inhibiting specifically activated factor X (FXa) causes delayed thrombin generation (TG) as measured by calibrated automated thrombography (CAT). The implications of these changes for assessing bleeding or residual prothrombotic risks of patients are unclear in the absence of a better understanding of the underlying mechanism. Methods: We compared platelet rich plasma (PRP) without or with prior collagen-induced platelet aggregation (agPRP) in the CAT assay to better characterize TG in the presence of rivaroxaban. Results: In the presence of rivaroxaban, TG curves in agPRP showed a distinct profile with a rapidly ascending phase followed with a protracted phase. Inhibition of tissue factor pathway inhibitor amplified the first phase of the curve which was also modulated by procoagulant phospholipids. Inhibition of FXIIa-dependent FXI activation revealed that aggregated platelets influenced the first phase by a combination of extrinsic and intrinsic coagulation pathway initiations. Thrombin-dependent amplification of TG (even prior collagen activation) was responsible for the second phase of the TG curve. Conclusions: AgPRP fully includes platelet ability to support TG and reveal distinct TG phases in the presence of direct FXa inhibitors highlighting its potential use in an anticoagulated setting.

Highlights

Direct oral anticoagulants (DOACs) are increasingly used as first line treatment for venous thromboembolism (VTE) and for prevention of ischemic stroke in atrial fibrillation, but regular assessment of their anticoagulant effects remains challenging
Most of the thrombin generation (TG) occurs after the clot formation and total TG potential of a plasma can be assessed with calibrated automated thrombography (CAT), which gives a better overview of the coagulation system than clotting times [1,2,3,4]
TG was performed in platelet rich plasma (PRP) and collagen-induced agPRP from healthy volunteers in the absence or presence of rivaroxaban and initiated with 1 pM of tissue factor (TF) (Figure 1A)

Summary

Introduction

Direct oral anticoagulants (DOACs) are increasingly used as first line treatment for venous thromboembolism (VTE) and for prevention of ischemic stroke in atrial fibrillation, but regular assessment of their anticoagulant effects remains challenging. Most of the thrombin generation (TG) occurs after the clot formation and total TG potential of a plasma can be assessed with calibrated automated thrombography (CAT), which gives a better overview of the coagulation system than clotting times (prothrombin time or activated partial thromboplastin time) [1,2,3,4]. The direct oral anticoagulant rivaroxaban inhibiting activated factor X (FXa) causes delayed thrombin generation (TG) as measured by calibrated automated thrombography (CAT). The implications of these changes for assessing bleeding or residual prothrombotic risks of patients are unclear in the absence of a better understanding of the underlying mechanism. Conclusions: AgPRP fully includes platelet ability to support TG and reveal distinct TG phases in the presence of direct FXa inhibitors highlighting its potential use in an anticoagulated setting

Objectives

Results

Conclusion