Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art

Abstract

Direct oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence-based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC-induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds.

Keywords

DOACs - thromboelastometry - thromboelastography - dabigatran - FXa inhibitors

• References

• 1 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103 (03) 572-585
• 2 Ruff CT, Giugliano RP, Braunwald E. , et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
• 3 Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 (11) 2012-2020
• 4 Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 2011; 10 (01) 61-75
• 5 Favaloro EJ, Lippi G. Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 2015; 41 (02) 208-227
• 6 Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogné JM. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107 (05) 985-997
• 7 Douxfils J, Tamigniau A, Chatelain B, Goffinet C, Dogné J-M, Mullier F. Measurement of non-VKA oral anticoagulants versus classic ones: the appropriate use of hemostasis assays. Thromb J 2014; 12: 24
• 8 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64 (03) 292-303
• 9 Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98 (01) 155-162
• 10 Stangier J, Stähle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48 (12) 1411-1419
• 11 Wang Y, Bajorek B. New oral anticoagulants in practice: pharmacological and practical considerations. Am J Cardiovasc Drugs 2014; 14 (03) 175-189
• 12 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. ; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e44S-e88S
• 13 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013; 11 (01) 10
• 14 Frost C, Wang J, Nepal S. , et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75 (02) 476-487
• 15 Ogata K, Mendell-Harary J, Tachibana M. , et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50 (07) 743-753
• 16 Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78 (04) 412-421
• 17 DeWald TA, Becker RC. The pharmacology of novel oral anticoagulants. J Thromb Thrombolysis 2014; 37 (02) 217-233
• 18 Lip GYH, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 2014; 35 (28) 1844-1855
• 19 Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther 2010; 88 (03) 375-382
• 20 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 (06) 1116-1127
• 21 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
• 22 Xu Y, Wu W, Wang L. , et al. Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro. Blood Coagul Fibrinolysis 2013; 24 (03) 332-338
• 23 Solbeck S, Meyer MA, Johansson PI. , et al. Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastography. Int J Cardiol 2014; 176 (03) 794-799
• 24 Solbeck S, Ostrowski SR, Stensballe J, Johansson PI. Thrombelastography detects dabigatran at therapeutic concentrations in vitro to the same extent as gold-standard tests. Int J Cardiol 2016; 208: 14-18
• 25 Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 2015; 139 (05) 665-673
• 26 Dinkelaar J, Patiwael S, Harenberg J, Leyte A, Brinkman HJM. Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate. Clin Chem Lab Med 2014; 52 (11) 1615-1623
• 27 Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med 2011; 365 (21) 2039-2040
• 28 Aron JL, Gosselin R, Moll S, Arkin CF, Mantha S. Effects of recombinant factor VIIa on thrombin generation and thromboelastography in a patient with dabigatran-associated intracranial hemorrhage. J Thromb Thrombolysis 2014; 37 (02) 76-79
• 29 Stein P, Bosshart M, Brand B, Schlicker A, Spahn DR, Bettex D. Dabigatran anticoagulation and Stanford type A aortic dissection: lethal coincidence: case report with literature review. Acta Anaesthesiol Scand 2014; 58 (05) 630-637
• 30 Davis PK, Musunuru H, Walsh M, Mitra R, Ploplis V, Castellino FJ. The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine. Thromb Haemost 2012; 108 (03) 586-588
• 31 Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111 (05) 989-995
• 32 Honickel M, Braunschweig T, van Ryn J. , et al. Prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model. Anesthesiology 2015; 123 (06) 1350-1361
• 33 Honickel M, Maron B, van Ryn J. , et al. Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model. Thromb Haemost 2016; 115 (02) 271-284
• 34 Martin AC, Gouin-Thibault I, Siguret V. , et al. Multimodal assessment of non-specific hemostatic agents for apixaban reversal. J Thromb Haemost 2015; 13 (03) 426-436
• 35 Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E. , et al. Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood. PLoS One 2013; 8 (11) e78696
• 36 Adelmann D, Wiegele M, Wohlgemuth RK. , et al. Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry. Thromb Res 2014; 134 (04) 918-923
• 37 Martin AC, Le Bonniec B, Fischer AM. , et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013; 168 (04) 4228-4233
• 38 Körber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann Cv. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014; 20 (07) 735-740
• 39 Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res 2014; 133 (04) 671-681
• 40 Escolar G, Arellano-Rodrigo E, Lopez-Vilchez I. , et al. Reversal of rivaroxaban-induced alterations on hemostasis by different coagulation factor concentrates – in vitro studies with steady and circulating human blood. Circ J 2015; 79 (02) 331-338
• 41 Godier A, Miclot A, Le Bonniec B. , et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116 (01) 94-102
• 42 Oswald E, Velik-Salchner C, Innerhofer P. , et al. Results of rotational thromboelastometry, coagulation activation markers and thrombin generation assays in orthopedic patients during thromboprophylaxis with rivaroxaban and enoxaparin: a prospective cohort study. Blood Coagul Fibrinolysis 2015; 26 (02) 136-144
• 43 Rathbun S, Tafur A, Grant R, Esmon N, Mauer K, Marlar RA. Comparison of methods to determine rivaroxaban anti-factor Xa activity. Thromb Res 2015; 135 (02) 394-397
• 44 Pollack Jr CV, Reilly PA, Eikelboom J. , et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (06) 511-520
• 45 Siegal DM, Curnutte JT, Connolly SJ. , et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
• 46 Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis 2015; 39 (03) 395-402
• 47 Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013; 118 (06) 1466-1474
• 48 Faraoni D, Levy JH, Albaladejo P, Samama C-M. ; Groupe d'Intérêt en Hémostase Périopératoire. Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants. Crit Care 2015; 19: 203
• 49 Grottke O, van Ryn J, Spronk HM, Rossaint R. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care 2014; 18 (01) R27
• 50 Neyens R, Bohm N, Cearley M, Andrews C, Chalela J. Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making. J Thromb Thrombolysis 2014; 37 (02) 80-83
• 51 Crapelli GB, Bianchi P, Isgrò G, Biondi A, De Vincentiis C, Ranucci M. A case of fatal bleeding following emergency surgery of an ascending aorta intramural hematoma in a patient under dabigatran treatment. J Cardiothorac Vasc Anesth 2016; 30 (04) 1027-1031
• 52 Rinehart DR, Lockhart NR, Hamilton LA, Langdon JR, Rowe AS. Management of apixaban-associated subdural hematoma: a case report on the use of factor eight inhibitor bypassing activity. Crit Care Med 2015; 43 (06) e203-e207
• 53 Brinkman HJ, Patiwael S, Tripathi S, Meijers JCM. Heparin supplement counteracts the prohemostatic effect of prothrombin complex concentrate and factor IX concentrate: an in vitro evaluation. Thromb Res 2016; 139: 102-110