Specific Point-of-Care Testing of Coagulation in Patients Treated with Dabigatran

Abstract

Background and purpose: Accurate and rapid assessment of coagulation status is necessary to guide thrombolysis or reversal of anticoagulation in stroke patients, but commercially available point-of-care (POC) assays are not suited for coagulation testing in patients treated with direct oral anticoagulants (DOACs). We aimed to evaluate the direct thrombin monitoring (DTM) test card by Helena Laboratories (Texas, United States) for anti-IIa-specific POC coagulation testing, hypothesizing that its POC-ecarin clotting time (POC-ECT) accurately reflects dabigatran plasma concentrations.

Methods: A prospective single-center diagnostic study (ClinicalTrials.gov-identifier: NCT02825394) was conducted enrolling patients receiving a first dose of dabigatran and patients already on dabigatran treatment. Blood samples were collected before drug intake and 0.5, 1, 2, 8, and 12 hours after intake. POC-ECT was performed using whole blood (WB), citrated blood (CB), and citrated plasma (CP). Dabigatran plasma concentrations were determined by mass spectrometry.

Results: In total, 240 blood samples from 40 patients contained 0 to 275 ng/mL of dabigatran. POC-ECT with WB/CB/CP ranged from 20 to 186/184/316 seconds. Pearson's correlation coefficient showed a strong correlation between dabigatran concentrations and POC-ECT with WB/CB/CP (R2 = 0.78/0.90/0.92). Dabigatran concentrations >30 and >50 ng/mL (thresholds for thrombolysis, surgery, and reversal therapy according to clinical guidelines) were detected by POC-ECT with WB/CB/CP (>36/35/45 and >43/45/59 seconds) with 95/97/97 and 96/98/97% sensitivity, and 81/87/94 and 74/60/91% specificity.

Conclusion: This first study evaluating DOAC-specific POC coagulation testing revealed an excellent correlation of POC-ECT with actual dabigatran concentrations. Detecting clinically relevant dabigatran levels with high sensitivity/specificity, the DTM assay represents a suitable diagnostic tool in acute stroke, hemorrhage, and urgent surgery.

Conflict of interest statement

F.H. reports nonfinancial support from Helena Laboratories, during the conduct of the study; other from Bayer, other from Daiichi Sankyo, outside the submitted work. I.B. reports personal fees and other from Bristol-Myers Squibb/Pfizer, grants and personal fees from Siemens Healthcare, personal fees from CSL Behring, other from Aspen, other from LFB Biomedicaments, outside the submitted work. H.R. reports nonfinancial support from Helena Laboratories, during the conduct of the study. U.Z. reports nonfinancial support from Helena Laboratories, during the conduct of the study; grants and personal fees from Biogen Idec, personal fees from Bayer Vital, personal fees from Bristol-Myers Squibb/Pfizer, personal fees from CorTec, personal fees from Medtronic, grants from Servier, grants from Janssen Pharmaceutica NV, outside the submitted work. S.P. reports nonfinancial support from Helena Laboratories, during the conduct of the study; personal fees from Bayer, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb/Pfizer, grants and personal fees from Daiichi Sankyo, personal fees from Werfen, outside the submitted work.

The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Figures

Fig. 1

Diagnostic accuracy of point-of-care ecarin clotting time (POC-ECT), laboratory-based ECT, and laboratory-based Biophen Direct Thrombin Inhibitor (BDTI) assay. Scatter plots illustrate the correlation between dabigatran plasma concentrations determined by ultra-performance liquid chromatography/tandem mass spectrometry and (A) POC-ECT with whole blood (WB), (B) citrated blood (CB), (C) citrated plasma (CP) as well as (D) calibrated laboratory-based (lab.) ECT, and (E) calibrated laboratory-based (lab) BDTI.Green shaded barsindicate the treatment-relevant dabigatran plasma concentration thresholds of 30 (darker) and 50 ng/mL (lighter).Horizontal gray linesindicate suggested optimal cut-offs providing >95% sensitivity for detection of samples containing >30 (solid) and >50 ng/mL (dashed) of dabigatran.Diagonal black linesindicate regression lines with their respective equations and the squared Pearson's correlation coefficient (R 2) to be found in the upper left corner of the diagrams.

Fig. 2

Comparison of agreement with ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) between calibrated point-of-care ecarin clotting time (POC-ECT) and two calibrated laboratory-based anti-IIa assays. Bland–Altman plots are used to display the agreement level between UPLC-MS/MS and calibrated POC-ECT: (A) all data and (B) 0–100 ng/mL; calibrated laboratory-based (lab.) ECT: (C) all data and (D) 0–100 ng/mL; as well as calibrated laboratory-based (lab.) Biophen Direct Thrombin Inhibitor (BDTI) assay: (E) all data and (F) 0–100 ng/mL; all measurements were performed using citrated plasma.Gray horizontal linesindicate a distance of 1.96 standard deviations (short-dashed) from the mean (long-dashed).Green shaded barsindicate the dabigatran plasma concentration treatment-relevant thresholds of 30 and 50 ng/mL.Diagonal red linesindicate regression curves with their respective equations and the squared Pearson's correlation coefficient (R 2) to be found in the upper left corner of the diagrams.