Thromb Haemost 2017; 117(03): 519-528
DOI: 10.1160/TH16-08-0619
Coagulation and Fibrinolysis
Schattauer GmbH

Microfluidic coagulation assay for monitoring anticoagulant therapy in acute stroke patients

Annemarie Bluecher
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
,
Sascha Meyer dos Santos
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
2   Fraunhofer Institute IME, Project Group Translational Medicine and Pharmacology, Frankfurt am Main, Germany
,
Nerea Ferreirós
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
,
Sandra Labocha
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
,
Isabel Maria Rodrigues Meyer dos Santos
3   Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany
,
Bettina Picard-Willems
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
,
Sebastian Harder
1   Clinical Pharmacology, Goethe University Hospital, Frankfurt am Main, Germany
,
Oliver C. Singer
3   Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany
4   HELIOS Dr. Horst Schmidt Kliniken, Department of Neurology, Wiesbaden, Germany
› Author Affiliations
Financial support: This study was supported by a grant of Bayer Vital, Leverkusen, Germany.
Further Information

Publication History

Received: 10 August 2016

Accepted after major revision: 10 January 2016

Publication Date:
22 November 2017 (online)

Summary

Reliable detection of anticoagulation status in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) is challenging but of importance especially in the emergency setting. This study evaluated the potential of a whole-blood clotting time assay based on Surface Acoustic Waves (SAW-CT) in stroke-patients. The SAW-technology was used for quick and homogenous recalcification of whole blood inducing a surface-activated clotting reaction quantified and visualised by real-time fluorescence microscopy with automatic imaging processing. In 20 stroke or transient ischaemic attack (TIA)-patients taking NOACs kinetics of SAW-CT were assessed and correlated to other coagulation parameters (PT, aPTT) and NOAC-plasma concentration measured by tandem mass spectrometry (LC-MS/MS). In 225 emergency patients with suspicion of acute stroke or TIA, SAW-CT values were assessed. Mean (± SD) SAW-CT in non-anticoagulated stroke patients (n=180) was 124 s (± 21). In patients on dabigatran or rivaroxaban, SAW-CT values were significantly higher 2 and 8 hours (h) after intake rising up to 267 seconds (s) (dabigatran, 2 h after intake) and 250 s (rivaroxaban, 8 h after intake). In patients on apixaban, SAW-CT values were only moderately increased 2 h after intake (SAW-CT 153 s). In emergency patients, SAW-CT values were significantly higher in NOAC and vitamin K antagonist (VKA)-treated as compared to non-anticoagulated patients. In conclusion, the SAW-CT assay is capable to monitor anticoagulant level and effect in patients receiving dabigatran, rivaroxaban and the VKA phenprocoumon. It has a limited sensitivity for apixaban-detection. If specific SAW-CT results were used as cut-offs, SAW-CT yields high diagnostic accuracy to exclude relevant rivaroxaban and dabigatran concentrations in strokepatients.

 
  • References

  • 1 Rizos T. et al. Oral anticoagulants--a frequent challenge for the emergency management of acute ischaemic stroke. Cerebrovasc Dis 2012; 34: 411-418.
  • 2 Bouget J, Oger E. Emergency admissions for major haemorrhage associated with direct oral anticoagulants. Thromb Res 2015; 136: 1190-1194.
  • 3 Douxfils J. et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thrombosis Res 2012; 130: 956-966.
  • 4 Douxfils J. et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 2013; 110: 723-731.
  • 5 McGlasson DL. et al. Comparison of a chromogenic factor X assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagul Fibrinol 2008; 19: 513-517.
  • 6 Barrett YC. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
  • 7 Dale BJ. et al. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2016; 172: 315-336.
  • 8 Hillarp A. et al. Effects of the oral direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays. J Thromb Haemost 2014; 12: 1545-1553.
  • 9 Samama MM. et al. Monitoring plasma levels of factor Xa inhibitors: how. why and when? Expert Rev Hematol 2013; 06: 155-164.
  • 10 Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011; 49: 761-772.
  • 11 Bonar R. et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2016; 48: 60-71.
  • 12 Tripodi A. The laboratory and the direct oral anticoagulants. Blood 2013; 121: 4032-4035.
  • 13 Lindhoff-Last E. et al. Laboratory testing of rivaroxaban in routine clinical practice: when. how. and which assays. Ann Med 2013; 45: 423-429.
  • 14 Marshall RS. Progress in Intravenous Thrombolytic Therapy for Acute Stroke. JAMA Neurol 2015; 72: 928-934.
  • 15 Meyer dos Santos S. et al. A novel µ-fluidic whole blood coagulation assay based on Rayleigh surface-acoustic waves as a point-of-care method to detect anticoagulants. Biomicrofluidics 2013; 07: 56502.
  • 16 Ng VL. Prothrombin time and partial thromboplastin time assay considerations. Clin Lab Med 2009; 29: 253-263.
  • 17 Ray MJ, Hawson GA. A comparison of two APTT reagents which use silica activators. Clin Lab Haematol 1989; 11: 221-232.
  • 18 van den Besselaar AM. et al. Effect of synthetic phospholipids on the response of the activated partial thromboplastin time to heparin. Blood Coagul Fibrinol 1993; 04: 895-903.
  • 19 Graff J. et al. Effects of the oral direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47: 1398-1407.
  • 20 Mueck W. et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53: 1-16.
  • 21 Jourdi G. et al. Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban. Thromb Haemost 2015; 114: 78-86.
  • 22 Epple C, Steiner T. Acute stroke in patients on new direct oral anticoagulants: how to manage. how to treat? Expert Opin Pharmacother 2014; 15: 1991-2001.
  • 23 Ishihara H. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban. J Stroke Cerebrovasc Dis 2014; 23: e457-459.
  • 24 van Hooff RJ. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischaemic stroke in a patient treated with rivaroxaban. Clin Neurol Neurosurg 2014; 122: 133-134.
  • 25 Neal AJ. et al. Intravenous thrombolysis for acute ischaemic stroke in the setting of rivaroxaban use. J Clin Neurosci 2014; 21: 2013-2015.
  • 26 De Smedt A. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with apixaban. Int J Stroke 2014; 09: E31.
  • 27 Landais A, Ginoux C. Intravenous thrombolysis for acute ischaemic stroke in a patient receiving rivaroxaban. J Stroke Cerebrovasc Dis 2015; 24: e73-74.
  • 28 Ebner M. et al. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke 2015; 46: 2741-2747.
  • 29 Moll J. et al. Micro-optical prototyping of a surface acoustic wave-based point-of-care coagulation assay and first application in anticoagulated patients. Int J Clin Pharmacol Ther 2016; 54: 177-184.
  • 30 Cuker A. et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64: 1128-1139.
  • 31 Koscielny J, Rutkauskaite E. Rivaroxaban and hemostasis in emergency care. Emerg Med Internat 2014; 2014: 935474.
  • 32 Steiner T. et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs) apixaban dabigatran and rivaroxaban. Clin Res Cardiol 2013; 102: 399-412.
  • 33 Hillarp A. et al. Effects of the oral. direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 09: 133-139.
  • 34 Di Minno A. et al. Clinical judgment when using coagulation tests during direct oral anticoagulant treatment: a concise review. Semin Thromb Hemost 2013; 39: 840-846.
  • 35 Samama MM. et al. Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: Results of a multicenter field trial. Clin Appl Thromb Hem 2012; 18: 150-158.
  • 36 Jauch EC. et al. Guidelines for the early management of patients with acute ischaemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44: 870-947.