Advertisement
Review Article| Volume 34, ISSUE 3, P479-501, September 2014

Measurement of Dabigatran in Standardly Used Clinical Assays, Whole Blood Viscoelastic Coagulation, and Thrombin Generation Assays

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hankey G.J.
        • Eikelboom J.W.
        Dabigatran etexilate: a new oral thrombin inhibitor.
        Circulation. 2011; 123: 1436-1450
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Connolly S.J.
        • Ezekowitz M.
        • Yusuf S.
        • et al.
        Newly identified events in the RE-LY trial.
        N Engl J Med. 2010; 363: 1875-1876
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Hylek E.M.
        The need for new oral anticoagulants in clinical practice.
        J Cardiovasc Med. 2009; 10: 605-609
        • 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
        • Mani H.
        • Kasper A.
        • Lindhoff-Last E.
        Measuring the anticoagulant effects of target specific oral anticoagulants – reasons, methods and current limitations.
        J Thromb Thrombolysis. 2013; 36: 187-194
        • Favaloro E.J.
        • Lippi G.
        The new oral anticoagulants and the future of haemostasis laboratory testing.
        Biochem Med (Zagreb). 2012; 22: 329-341
        • Greinacher A.
        • Warkentin T.E.
        The direct thrombin inhibitor hirudin.
        Thromb Haemost. 2008; 99: 819-829
        • Nowak G.
        The ecarin clotting time, a universal method to quantify direct thrombin inhibitors.
        Pathophysiol Haemost Thromb. 2003; 33: 173-183
      1. Haemosys Ecarin Chromogenic Assay. ECA-T Kit for quantitative determination of direct synthetic thrombin inhibitors in plasma [package Insert]. JenAffin GmbH, Jena, Germany; 2010.

        • Huisman M.V.
        • Lip G.Y.
        • Diener H.C.
        • et al.
        Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice.
        Thromb Haemost. 2012; 107: 838-847
        • Stangier J.
        • Stahle H.
        • Rathgen K.
        • et al.
        Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects.
        Clin Pharmacokinet. 2008; 47: 47-59
        • Stangier J.
        • Rathgen K.
        • Staehle H.
        • et al.
        Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open label, parallel group, single-centre study.
        Clin Pharmacokinet. 2010; 49: 259-268
        • Stangier J.
        • Rathgen K.
        • Stahle H.
        • et al.
        The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.
        Br J Clin Pharmacol. 2007; 64: 292-303
        • Douxfils J.
        • Dogné J.M.
        • 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
        • Dager W.E.
        • Gosselin R.C.
        • Kitchen S.
        • et al.
        Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study.
        Ann Pharmacother. 2012; 46: 1627-1636
        • Gosselin R.
        • Hawes E.
        • Moll S.
        • et al.
        Performance on various laboratory assays in the measurement of dabigatran in patients receiving therapeutic doses.
        Am J Clin Pathol. 2014; 141: 262-267
        • 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
        • Harenberg J.
        • Giese C.
        • Marx S.
        • et al.
        Determination of dabigatran in human plasma samples.
        Semin Thromb Hemost. 2012; 38: 16-22
        • Lindahl T.L.
        • Baghaei F.
        • Blixter I.F.
        • et al.
        Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays.
        Thromb Haemost. 2011; 105: 371-378
        • Hawes E.M.
        • Deal A.M.
        • Funk-Adcock D.
        • et al.
        Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels.
        J Thromb Haemost. 2013; 11: 1495-1502
        • Hapgood G.
        • Butler J.
        • Malan E.
        • et al.
        The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the hemoclot thrombin inhibitor assay in patient plasma samples.
        Thromb Haemost. 2013; 110: 308-315
        • Stangier J.
        • Feuring M.
        Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran.
        Blood Coagul Fibrinolysis. 2012; 23: 138-143
        • Avecilla S.T.
        • Ferrell C.
        • Chandler W.L.
        • et al.
        Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy.
        Am J Clin Pathol. 2012; 137: 572-574
        • Baruch L.
        • Sherman O.
        Potential inaccuracy of point-of-care INR in dabigatran-treated patients.
        Ann Pharmacother. 2011; 45: e40
        • Deremer C.E.
        • Gujral J.S.
        • Thornton J.W.
        • et al.
        Dabigatran falsely elevates point of care international normalized ratio results.
        Am J Med. 2011; 124: e5-e6
        • van Ryn J.
        • Baruch L.
        • Clemens A.
        Interpretation of point-of-care INR in patients treated with dabigatran.
        Am J Med. 2012; 125: 417-420
        • Lefemine A.A.
        • Lewis M.
        Activated clotting time for control of anticoagulation during surgery.
        Am Surg. 1985; 51: 274-278
        • Hartert H.
        Blutgerinnungstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren.
        Klin Wochenschr. 1948; 26: 557-583
        • Bolliger D.
        • Seeberger M.D.
        • Tanaka K.A.
        Principles and practice of thromboelastography in clinical coagulation management and transfusion practice.
        Transfus Med Rev. 2012; 26: 1-13
      2. Available at: http://www.rotem.de. Accessed January 21, 2014.

      3. Available at: http://www.haemonetics.com/en/. Accessed January 21, 2014.

        • Grottke O.
        Coagulation management.
        Curr Opin Crit Care. 2012; 18: 641-646
        • Hoffman M.
        • Monroe 3rd, D.M.
        A cell-based model of hemostasis.
        Thromb Haemost. 2001; 85: 958-965
        • Ganter M.T.
        • Hofer C.K.
        Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices.
        Anesth Analg. 2008; 106: 1366-1375
        • Rugeri L.
        • Levrat A.
        • David J.S.
        • et al.
        Diagnosis of early coagulation abnormalities in trauma patients by rotation thromboelastography.
        J Thromb Haemost. 2007; 5: 289-295
        • Roullet S.
        • Pillot J.
        • Freyburger G.
        • et al.
        Rotation thromboelastometry detects thrombocytopenia and hypofibrinogenaemia during orthotopic liver transplantation.
        Br J Anaesth. 2010; 104: 422-428
        • Ogawa S.
        • Szlam F.
        • Chen E.P.
        • et al.
        A comparative evaluation of rotation thromboelastometry and standard coagulation tests in hemodilution induced coagulation changes after cardiac surgery.
        Transfusion. 2012; 52: 14-22
        • Amukele T.K.
        • Ferrell C.
        • Chandler W.L.
        Comparison of plasma with whole blood prothrombin time and fibrinogen on the same instrument.
        Am J Clin Pathol. 2010; 133: 550-556
        • Ogawa S.
        • Szlam F.
        • Bolliger D.
        • et al.
        The impact of hematocrit on fibrin clot formation assessed by rotational thromboelastometry.
        Anesth Analg. 2012; 115: 16-21
        • Kashuk J.L.
        • Moore E.E.
        • Sawyer M.
        • et al.
        Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma.
        Ann Surg. 2010; 252: 434-442
        • Theusinger O.M.
        • Wanner G.A.
        • Emmert M.Y.
        • et al.
        Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma.
        Anesth Analg. 2011; 113: 1003-1012
        • Raza I.
        • Davenport R.
        • Rourke C.
        • et al.
        The incidence and magnitude of fibrinolytic activation in trauma patients.
        J Thromb Haemost. 2013; 11: 307-314
        • Fries D.
        • Haas T.
        • Klingler A.
        • et al.
        Efficacy of fibrinogen and prothrombin complex concentrate used to reverse dilutional coagulopathy – a porcine model.
        Br J Anaesth. 2006; 97: 460-467
        • Grottke O.
        • Braunschweig T.
        • Henzler D.
        • et al.
        Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury.
        Crit Care. 2010; 14: R62
        • Weber C.F.
        • Gorlinger K.
        • Meininger D.
        • et al.
        Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients.
        Anesthesiology. 2012; 117: 531-547
        • Gorlinger K.
        • Fries D.
        • Dirkmann D.
        • et al.
        Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy.
        Transfus Med Hemother. 2012; 39: 104-113
        • Rourke C.
        • Curry N.
        • Khan S.
        • et al.
        Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.
        J Thromb Haemost. 2012; 10: 1342-1351
        • Rahe-Meyer N.
        • Solomon C.
        • Hanke A.
        • et al.
        Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial.
        Anesthesiology. 2013; 118: 40-50
        • Schoechl H.
        • Nienaber U.
        • Maegele M.
        • et al.
        Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy.
        Crit Care. 2011; 15: R83
        • Schoechl H.
        • Forster L.
        • Woidke R.
        • et al.
        Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate.
        Anaesthesia. 2010; 65: 199-203
        • Fassl J.
        • Matt P.
        • Eckstein F.
        • et al.
        Transfusion of allogeneic blood products in proximal aortic surgery with hyopthermic circulatory arrest: effects of thromboelastometry-guided transfusion management.
        J Cardiothorac Vasc Anesth. 2013; 27: 1181-1188
        • Honickel M.
        • Rieg A.
        • Rossaint R.
        • et al.
        Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia.
        Thromb Haemost. 2011; 106: 724-733
        • Grottke O.
        • Braunschweig T.
        • Spronk H.M.
        • et al.
        Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury.
        Blood. 2011; 118: 1943-1951
        • Afshari A.
        • Wikkelsø A.
        • Brok J.
        • et al.
        Thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion.
        Cochrane Database Syst Rev. 2011; (CD007871)
        • Wikkelsoe A.J.
        • Afshari A.
        • Wetterslev J.
        • et al.
        Monitoring patients at risk of massive transfusion with thromboelastography or thromboelastometry: a systematic review.
        Acta Anaesthesiol Scand. 2011; 55: 1174-1189
        • 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; 9: 1-10
        • Davis P.K.
        • Musunuru H.
        • Walsh M.
        • et al.
        The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine.
        Thromb Haemost. 2012; 108: 586-588
        • 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: 332-338
        • Mosnier L.O.
        • Buijtenhuijs P.
        • Marx P.F.
        • et al.
        Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets.
        Blood. 2003; 101: 4844-4846
        • Engström M.
        • Rundgren M.
        • Schött U.
        An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin time.
        Acta Anaesthesiol Scand. 2010; 54: 86-89
        • Grottke O.
        • van Ryn J.
        • Spronk H.
        • et al.
        Prothrombin complex concentrates and a specific antidote (aDabi-Fab) are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model.
        Crit Care. 2014; 18: R27
        • Spronk H.M.
        • van der Voort D.
        • ten Cate H.
        Blood coagulation and the risk of atherothrombosis: a complex relationship.
        Thromb J. 2004; 2: 12
        • Loeffen R.
        • Spronk H.M.
        • ten Cate H.
        The impact of blood coagulability on atherosclerosis and cardiovascular disease.
        J Thromb Haemost. 2012; 10: 1207-1216
        • Hemker H.C.
        • Dieri al R.
        • de Smedt E.
        • et al.
        Thrombin generation, a function test of the haemostatic-thrombotic system.
        Thromb Haemost. 2006; 96: 553-561
        • Béguin S.
        • Lindhout T.
        • Hemker H.C.
        The mode of action of heparin in plasma.
        Thromb Haemost. 1988; 60: 457-462
        • Hemker H.C.
        Recollections on thrombin generation.
        J Thromb Haemost. 2008; 6: 219-226
        • Hemker H.C.
        • Giesen P.
        • AlDieri R.
        • et al.
        The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability.
        Pathophysiol Haemost Thromb. 2002; 32: 249-253
        • Hemker H.C.
        • Béguin S.
        Thrombin generation in plasma: its assessment via the endogenous thrombin potential.
        Thromb Haemost. 1995; 74: 134-138
        • Loeffen R.
        • Kleinegris M.C.
        • Loubele S.T.
        • et al.
        Preanalytic variables of thrombin generation: towards a standard procedure and validation of the method.
        J Thromb Haemost. 2012; 10: 2544-2554
        • Spronk H.M.
        • Dielis A.W.
        • de Smedt E.
        • et al.
        Assessment of thrombin generation II: validation of the calibrated automated thrombogram in platelet-poor plasma in a clinical laboratory.
        Thromb Haemost. 2008; 100: 362-364
        • Castoldi E.
        • Castoldi E.
        • Rosing J.
        • et al.
        Thrombin generation tests.
        Thromb Res. 2011; 127: S21-S25
        • Lutsey P.L.
        • Folsom A.R.
        • Heckbert S.R.
        • et al.
        Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study.
        J Thromb Haemost. 2009; 7: 1639-1648
        • Tripodi A.
        • Martinelli I.
        • Chantarangkul V.
        • et al.
        The endogenous thrombin potential and the risk of venous thromboembolism.
        Thromb Res. 2007; 121: 353-359
        • Hron G.
        • Kollars M.
        • Binder B.R.
        • et al.
        Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation.
        JAMA. 2006; 296: 397-402
        • Tripodi A.
        • Legnani C.
        • Chantarangkul V.
        • et al.
        High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism.
        J Thromb Haemost. 2008; 6: 1327-1333
        • Besser M.
        • Baglin C.
        • Luddington R.
        • et al.
        High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study.
        J Thromb Haemost. 2008; 6: 1720-1725
        • van Hylckama Vlieg A.
        • Christiansen S.C.
        • Luddington R.
        • et al.
        Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence.
        Br J Haematol. 2007; 138: 769-774
        • Cate-Hoek ten A.J.
        • Dielis A.W.
        • Spronk H.M.
        • et al.
        Thrombin generation in patients after acute deep-vein thrombosis.
        Thromb Haemost. 2008; 100: 240-245
        • ten Cate H.
        Thrombin generation in clinical conditions.
        Thromb Res. 2012; 129: 367-370
        • Páramo J.A.
        • Orbe J.
        • Beloqui O.
        • et al.
        Prothrombin fragment 1+2 is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease.
        Stroke. 2004; 35: 1085-1089
        • With Notø A.T.
        • Mathiesen E.B.
        • Østerud B.
        • et al.
        Increased thrombin generation in persons with echogenic carotid plaques.
        Thromb Haemost. 2008; 99: 602-608
        • Borissoff J.I.
        • Joosen I.A.
        • Versteylen M.O.
        • et al.
        Accelerated in vivo thrombin formation independently predicts the presence and severity of CT angiographic coronary atherosclerosis.
        JACC Cardiovasc Imaging. 2012; 5: 1201-1210
        • Smid M.
        • Dielis A.W.
        • Winkens M.
        • et al.
        Thrombin generation in patients with a first acute myocardial infarction.
        J Thromb Haemost. 2011; 9: 450-456
        • Smid M.
        • Dielis A.W.
        • Spronk H.M.
        • et al.
        Thrombin generation in the Glasgow Myocardial Infarction Study.
        PLoS One. 2013; 8: e66977
        • Orbe J.
        • Zudaire M.
        • Serrano R.
        • et al.
        Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test.
        Thromb Haemost. 2008; 99: 382-387
        • Winckers K.
        • Siegerink B.
        • Duckers C.
        • et al.
        Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study.
        J Thromb Haemost. 2011; 9: 2243-2250
        • Nair S.C.
        • Dargaud Y.
        • Chitlur M.
        • et al.
        Tests of global haemostasis and their applications in bleeding disorders.
        Haemophilia. 2010; 16: 85-92
        • Dargaud Y.
        • Lienhart A.
        • Negrier C.
        Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery.
        Blood. 2010; 116: 5734-5737
        • Wong P.C.
        • White A.
        • Luettgen J.
        Inhibitory effect of apixaban compared with rivaroxaban and dabigatran on thrombin generation assay.
        Hosp Pract (1995). 2013; 41: 19-25
        • Samama M.M.
        • Martinoli J.L.
        • LeFlem L.
        • et al.
        Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor.
        Thromb Haemost. 2010; 103: 815-825
        • Gerotziafas G.T.
        • Elalamy I.
        • Depasse F.
        • et al.
        In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban.
        J Thromb Haemost. 2007; 5: 886-888
        • Novak M.
        • Schlagenhauf A.
        • Bernhard H.
        • et al.
        Effect of rivaroxaban, in contrast to heparin, is similar in neonatal and adult plasma.
        Blood Coagul Fibrinolysis. 2011; 22: 588-592
        • Wienen W.
        • Stassen J.M.
        • Priepke H.
        • et al.
        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: 155-162
        • Serebruany V.
        • Sani Y.
        • Lynch D.
        • et al.
        Effects of dabigatran in vitro on thrombin biomarkers by calibrated automated thrombography in patients after ischemic stroke.
        J Thromb Thrombolysis. 2012; 33: 22-27
        • Furugohri T.
        • Sugiyama N.
        • Morishima Y.
        • et al.
        Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.
        Thromb Haemost. 2011; 106: 1076-1083
        • Wagenvoord R.J.
        • Deinum J.
        • Elg M.
        • et al.
        The paradoxical stimulation by a reversible thrombin inhibitor of thrombin generation in plasma measured with thrombinography is caused by alpha-macroglobulin-thrombin.
        J Thromb Haemost. 2010; 8: 1281-1289
        • Furugohri T.
        • Shiozaki Y.
        • Muramatsu S.
        • et al.
        Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models.
        Eur J Pharmacol. 2005; 514: 35-42
        • Mattsson C.
        • Menschik-Lundin A.
        • Nylander S.
        • et al.
        Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro.
        Thromb Res. 2001; 104: 475-486