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.

Keywords

dabigatran - point-of-care testing - ecarin clotting time - thrombolysis - anticoagulation

• References

• 1 Walter S, Kostopoulos P, Haass A. et al. Point-of-care laboratory halves door-to-therapy-decision time in acute stroke. Ann Neurol 2011; 69 (03) 581-586
• 2 Rizos T, Herweh C, Jenetzky E. et al. Point-of-care international normalized ratio testing accelerates thrombolysis in patients with acute ischemic stroke using oral anticoagulants. Stroke 2009; 40 (11) 3547-3551
• 3 Zantek ND, Hayward CP, Simcox TG, Smock KJ, Hsu P, Van Cott EM. An assessment of the state of current practice in coagulation laboratories. Am J Clin Pathol 2016; 146 (03) 378-383
• 4 Ebner M, Peter A, Spencer C. et al. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke 2015; 46 (10) 2741-2747
• 5 Ebner M, Birschmann I, Peter A. et al. Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants. Crit Care 2017; 21 (01) 32
• 6 Härtig F, Birschmann I, Peter A. et al. Point-of-care testing of coagulation in patients treated with edoxaban. J Thromb Thrombolysis 2020; 50 (03) 632-639
• 7 Kuhn J, Gripp T, Flieder T. et al. UPLC-MRM mass spectrometry method for measurement of the coagulation inhibitors dabigatran and rivaroxaban in human plasma and its comparison with functional assays. PLoS One 2015; 10 (12) e0145478
• 8 Novoa E, Seegers WH. Mechanisms of alpha-thrombin and beta-thrombin-E formation: use of ecarin for isolation of meizothrombin 1. Thromb Res 1980; 18 (05) 657-668
• 9 Ahmed N, Steiner T, Caso V, Wahlgren N. ESO-KSU session participants. Recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 13–15 November 2016. Eur Stroke J 2017; 2 (02) 95-102
• 10 Touzé E, Gruel Y, Gouin-Thibault I. et al. Intravenous thrombolysis for acute ischaemic stroke in patients on direct oral anticoagulants. Eur J Neurol 2018; 25 (05) 747-e52
• 11 Pernod G, Albaladejo P, Godier A. et al; Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis 2013; 106 (6–7): 382-393
• 12 Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (03) 623-627
• 13 Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998; 17 (08) 857-872
• 14 Steiner T, Freiberger A, Griebe M. et al. International normalised ratio normalisation in patients with coumarin-related intracranial haemorrhages--the INCH trial: a randomised controlled multicentre trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex--study design and protocol. Int J Stroke 2011; 6 (03) 271-277
• 15 Sykora M, Diedler J, Poli S. et al. Autonomic shift and increased susceptibility to infections after acute intracerebral hemorrhage. Stroke 2011; 42 (05) 1218-1223
• 16 Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982; 143 (01) 29-36
• 17 Krouwer JS. Why Bland-Altman plots should use X, not (Y+X)/2 when X is a reference method. Stat Med 2008; 27 (05) 778-780
• 18 Bossuyt PM, Cohen JF, Gatsonis CA, Korevaar DA. STARD group. STARD 2015: updated reporting guidelines for all diagnostic accuracy studies. Ann Transl Med 2016; 4 (04) 85
• 19 Eller T, Busse J, Dittrich M. et al. Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med 2014; 52 (06) 835-844
• 20 Seyve L, Richarme C, Polack B, Marlu R. Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int J Lab Hematol 2018; 40 (01) 84-93
• 21 Takeshita S, Tanaka KA, Sawa T, Sanda M, Mizobe T, Ogawa S. Whole blood point-of-care testing for incomplete reversal with idarucizumab in supratherapeutic dabigatran. Anesth Analg 2020; 130 (02) 535-541
• 22 Akman N, Braunschweig T, Honickel M. et al. Reversal of dabigatran by intraosseous or intravenous idarucizumab in a porcine polytrauma model. Br J Anaesth 2018; 120 (05) 978-987
• 23 Taune V, Skeppholm M, Ågren A. et al. Rapid determination of anticoagulating effects of dabigatran in whole blood with rotational thromboelastometry and a thrombin-based trigger. J Thromb Haemost 2018; 16 (12) 2462-2470
• 24 Harenberg J, Schreiner R, Hetjens S, Weiss C. Detecting anti-IIa and anti-Xa direct oral anticoagulant (DOAC) agents in urine using a DOAC dipstick. Semin Thromb Hemost 2019; 45 (03) 275-284