Direct Oral Anticoagulants Form Thrombus Different From Warfarin in a Microchip Flow Chamber System

Masanobu Ishii,Seiji Takashio,Seiji Hokimoto,Yasuhiro Izumiya,Eiichiro Yamamoto,Sunao Kojima,Hisao Ogawa,Koichi Kaikita,Kenichi Tsujita,Hiroshige Yamabe,Miwa Ito,Yuichiro Arima,Megumi Yamamuro,Daisuke Sueta

doi:10.1038/s41598-017-07939-6

Abstract

Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR10-AUC30 correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR10-AUC30 levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition.

Highlights

The prothrombin time-international normalized ratio (PT-INR) is widely used to assess the anticoagulant effects of warfarin
Total thrombus formation was suppressed in both warfarin- and Direct oral anticoagulants (DOACs)-treated groups compared to the Off-anticoagulants
The major findings of this study were as follows: (1) AR10-AUC30 could be a useful marker for monitoring the anticoagulant effects of warfarin and DOACs, it had weak negative correlation with plasma concentrations of DOACs; and (2) the area of thrombi during the early phase of thrombus formation was significantly larger in patients treated with rivaroxaban and apixaban compared to those on warfarin and dabigatran, indicating that these differential patterns of thrombus formation might explain the mechanism of volume reduction of ICH

Summary

Introduction

The prothrombin time-international normalized ratio (PT-INR) is widely used to assess the anticoagulant effects of warfarin. It is possible to measure blood concentrations of DOACs7, 8, there is currently no simple tool available to monitor the effects of DOACs9. The total thrombus-formation analysis system (T-TAS), a microchip-based flow chamber system designed to evaluate whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation. The T-TAS could be useful for monitoring the anticoagulant effects of DOACs and predicting periprocedural bleeding events[10,11,12,13]. The aim of the present study was to determine differences in the anticoagulation patterns of warfarin and DOACs using the T-TAS in patients with AF who had undergone radiofrequency catheter ablation (RFCA)

Objectives

Methods

Results

Conclusion