Thromb Haemost 2015; 113(01): 154-164
DOI: 10.1160/TH14-02-0161
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Influence of dabigatran and rivaroxaban on routine coagulation assays

A nationwide Belgian survey
Marjan Van Blerk
1   Department of Quality of Medical Laboratories, Scientific Institute of Public Health, Brussels, Belgium
,
Els Bailleul
2   EQA Advisory Board, Belgium
,
Bernard Chatelain
2   EQA Advisory Board, Belgium
,
Anne Demulder
2   EQA Advisory Board, Belgium
,
Katrien Devreese
2   EQA Advisory Board, Belgium
,
Jonathan Douxfils
2   EQA Advisory Board, Belgium
,
Kristin Jochmans
2   EQA Advisory Board, Belgium
,
François Mullier
2   EQA Advisory Board, Belgium
,
Walter Wijns
2   EQA Advisory Board, Belgium
,
Mohamed Rida Soumali
1   Department of Quality of Medical Laboratories, Scientific Institute of Public Health, Brussels, Belgium
,
Wim Coucke
1   Department of Quality of Medical Laboratories, Scientific Institute of Public Health, Brussels, Belgium
,
Kris Vernelen
1   Department of Quality of Medical Laboratories, Scientific Institute of Public Health, Brussels, Belgium
,
Philippe Van de Walle
1   Department of Quality of Medical Laboratories, Scientific Institute of Public Health, Brussels, Belgium
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 20. Februar 2014

Accepted after major revision: 02. August 2014

Publikationsdatum:
27. November 2017 (online)

Summary

The Belgian national External Quality Assessment Scheme performed a nationwide survey using lyophilised plasma samples spiked with dabigatran or rivaroxaban to demonstrate to the Belgian clinical laboratories how these drugs affect their routine coagulation assays prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin. Virtually all Belgian laboratories performing routine coagulation testing (189/192) participated in the survey. Both, dabigatran and rivaroxaban significantly prolonged the PT and aPTT in a concentration- and reagent-dependent manner. PT reagents were more influenced by rivaroxaban than by dabigatran and aPTT reagents more influenced by dabigatran than by rivaroxaban. Among PT reagents, Neoplastin R® was the most sensitive to rivaroxaban and Innovin ® and Thromborel S® the least sensitive. Converting PT results to INR only increased the variability between reagents. Among aPTT reagents, Actin FSL® was the least sensitive to dabigatran while the other aPTT reagents showed slightly higher sensitivities. The presence of dabigatran led to falsely reduced fibrinogen concentrations when measured with a low thrombin concentration reagent. The presence of dabigatran caused an overestimation of the antithrombin level when measured with a thrombin-based activity assay and the presence of rivaroxaban an overestimation of the antithrombin level when measured with a FXa-based assay. Instrument-related differences were found for all tested parameters. In conclusion, this paper provides detailed information on the effect of dabigatran and rivaroxaban on routine coagulation assays as performed with a large number of reagent/instrument combinations.

 
  • References

  • 1 Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011; 123: 1436-1450.
  • 2 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
  • 3 Baglin T. The role of the laboratory in treatment with new oral anticoagulants. J Thromb Haemost 2013; 11 (Suppl. 01) 122-128.
  • 4 Baglin T, Keeling D, Kitchen S. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or riva-roxaban: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2012; 159: 427-429.
  • 5 Baglin T, Hillarp A, Tripodi A. et al. Measuring oral direct inhibitors of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Antico-agulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11: 756-760.
  • 6 Quick AJ, Stanley-Brown M, Bancroft FW. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sci 1935; 190: 501-511.
  • 7 Quick AJ. The prothrombin time in haemophilia and in obstructive jaundice. J Biol Chem 1935; 109: 73-74.
  • 8 EMA. Boehringer Ingelheim International GmbH: Pradaxa* (dabigatran etexilate) Summary of Product Characteristics.. Available at http://www.ema.europa.eu/docs/en_GB/documentlibrary/EPAR_-_ProductInformationhuman/000829/WC500041059.pdf Accessed February 11, 2014.
  • 9 EMA. Bayer Pharma AG: Xarelto* (rivaroxaban) Summary of Product Characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed February 11, 2014.
  • 10 Helin TA, Pakkanen A, Lassila R. et al. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem 2013; 59: 807-814.
  • 11 Hillarp A, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 09: 133-139.
  • 12 Lindahl TL, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011; 105: 371-378.
  • 13 Owren PA. Thrombotest. A new method for controlling anticoagulant therapy. Lancet 1959; 02: 754-758.
  • 14 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring riva-roxaban: their suitability and limitations. Ther Drug Monit 2010; 32: 673-679.
  • 15 Samama MM, Contant G, Spiro T. et al. Laboratory assessment of rivaroxaban: a review. Thromb J 2013; 11: 11.
  • 16 Asmis LM, Alberio L, Angelillo-Scherrer A. et al. Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests. A study in 9 Swiss laboratories. Thromb Res 2012; 129: 492-498.
  • 17 Dager WE, Gosselin RC, Kitchen S. et al. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fi-brinogen: a multicentre, in vitro study. Ann Pharmacother 2012; 46: 1627-1636.
  • 18 Douxfils J, Mullier F, Robert S. et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107: 985-997.
  • 19 Douxfils J, Mullier F, Loosen C. et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of riva-roxaban and review of the literature. Thromb Res 2012; 130: 956-966.
  • 20 Harenberg J, Giese C, Marx Svetlana et al. Determination of dabigatran in human plasma samples. Semin Thromb Hemost 2012; 38: 16-22.
  • 21 Harenberg J, Erdle S, Marx S. et al. Determination of rivaroxaban in human plasma samples. Semin Thromb Hemost 2012; 38: 178-184.
  • 22 Harenberg J, Marx S, Erdle S. et al. Determination of the anticoagulant effects of new oral anticoagulants: an unmet need. Expert Rev Hematol 2012; 05: 107-113.
  • 23 Mani H, Hesse C, Stratmann G. et al. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost 2011; 106: 156-164.
  • 24 Samama MM, Martinoli JL, Le Flem L. et al. Assessment of laboratory assays to measure rivaroxaban - on oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
  • 25 Van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
  • 26 Smith SA, Morissey JH. Thromboplastin composition affects the sensitivity of prothrombin time clotting tests to direct factor Xa inhibitors. Blood. 2007 110. Abstract 928.
  • 27 Kluft C, van Leuven K, Laterveer R. et al. Evidence that the effects of riva-roxaban are dependent on the degree of activation of the coagulation system. ISTH Amsterdam July 2013, 4th, oral communication 81.3 www.eventure-online.com/eventure/publicAbstractView.do?id=216647&congres-sId=6839
  • 28 Kitchen S, Cartwright I, Woods TAL. et al. Lipid composition of seven APTT reagents in relation to heparin sensitivity. Br J Haematol 1999; 106: 801-808.
  • 29 Okuda M, Yamamoto Y. Usefulness of synthetic phospholipid in measurement of activated partial thromboplastin time: a new preparation procedure to reduce batch difference,. Clin Lab Haem 2004; 26: 215-223..
  • 30 Bowyer A, Kitchen S, Makris M. The responsiveness of different APTT reagents to mild factor VIII, IX and XI deficiencies. Int J Lab Hematol 2011; 33: 154-158.
  • 31 Fritsma GA, Dembitzer FR, Randhawa A. et al. Recommendations for appropriate activated partial thromboplastin time reagent selection and utilization. Am J Clin Pathol 2012; 137: 904-908.
  • 32 Pengo V, Tripodi A, Reber G. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 07: 1737-1740.
  • 33 Halbmayer WM, Weigel G, Quehenberger P. et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med 2012; 50: 1601-1605.
  • 34 Adcock DM, Gosselin R, Kitchen S. et al. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 2013; 139: 102-109.
  • 35 Tripodi A. The laboratory and the new oral anticoagulants. Clin Chem 2012; 59: 353-362.
  • 36 Qari MH. High throughput coagulation analyzers review. Comb Chem High Througput Screen 2005; 08: 353-360.
  • 37 Douxfils J, Dogné JM, Mullier F. et al. Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate. Thromb Haemost 2013; 110: 543-549.
  • 38 Douxfils J, Tamigniau A, Chatelain B. et al. Comparison of calibrated chromo-genic 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.
  • 39 Freyburger G, Macouillard G, Labrouche S. et al. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 2011; 127: 457-465.
  • 40 Hawes EM, Deal AM, Funk-Adcock D. et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacody-namic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11: 1493-1502.
  • 41 Molenaar PJ, Dinkelaar J, Leyte A. Measuring rivaroxaban in a clinical laboratory setting, using common coagulation assays, Xa inhibition and thrombin generation. . Clin Chem Lab Med 2012; 50: 1799-1807.
  • 42 Samama MM, Guinet C, Le Flem L. et al. Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study. J Thromb Thrombolysis 2013; 35: 140-146.