Measurement of dabigatran in standardly used clinical assays, whole blood viscoelastic coagulation, and thrombin generation assays

Clinics in Laboratory Medicine

Volumn 34, Issue 3, 2014, Pages 479-501

  van Ryn, Joanne ^a   Grottke, Oliver ^b   Spronk, Henri ^c  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^c MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

Anticoagulation; Dabigatran; Measurement; Thrombin generation; Thromboelastometry

Indexed keywords

ACTIVATED PROTEIN C; ANTIVITAMIN K; D DIMER; DABIGATRAN; DABIGATRAN ETEXILATE; HEPARIN; THROMBIN INHIBITOR; ANTITHROMBIN; BENZIMIDAZOLE DERIVATIVE; BETA ALANINE;

ACTIVATED CLOTTING TIME; ANTICOAGULATION; BLEEDING TENDENCY; BLOOD CLOTTING; BLOOD CLOTTING DISORDER; BLOOD CLOTTING TIME; DIAGNOSTIC PROCEDURE; DILUTED THROMBIN TIME; DISEASE ASSOCIATION; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG DETERMINATION; DRUG MONITORING; HEPARINIZATION; INTERNATIONAL NORMALIZED RATIO; LIQUID CHROMATOGRAPHY; PARTIAL THROMBOPLASTIN TIME; PRIORITY JOURNAL; PROTHROMBIN TIME; REVIEW; SENSITIVITY ANALYSIS; TANDEM MASS SPECTROMETRY; THROMBIN TIME; THROMBOELASTOGRAPHY; THROMBOSIS; VENOUS THROMBOEMBOLISM; VISCOELASTIC COAGULATION TEST; VISCOELASTICITY; ANALOGS AND DERIVATIVES; ANIMAL; BLOOD; BLOOD CLOTTING TEST; COMPARATIVE STUDY; DRUG EFFECTS; HUMAN; ORAL DRUG ADMINISTRATION; PERSONALIZED MEDICINE; PROCEDURES;

ADMINISTRATION, ORAL; ANIMALS; ANTITHROMBINS; BENZIMIDAZOLES; BETA-ALANINE; BLOOD COAGULATION; BLOOD COAGULATION TESTS; DRUG MONITORING; HUMANS; INDIVIDUALIZED MEDICINE;

EID: 84906934289     PISSN: 02722712     EISSN: 15579832     Source Type: Journal    
DOI: 10.1016/j.cll.2014.06.008     Document Type: Review

References (102)

1. Hankey G.J., Eikelboom J.W. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011, 123:1436-1450.
2. Connolly S.J., Ezekowitz M.D., Yusuf S., et al. Dabigatran versus warfarin in patients with atrial fibrillation. NEngl J Med 2009, 361:1139-1151.
3. Connolly S.J., Ezekowitz M., Yusuf S., et al. Newly identified events in the RE-LY trial. NEngl J Med 2010, 363:1875-1876.
4. Patel M.R., Mahaffey K.W., Garg J., et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEngl J Med 2011, 365:883-891.
5. Granger C.B., Alexander J.H., McMurray J.J., et al. Apixaban versus warfarin in patients with atrial fibrillation. NEngl J Med 2011, 365:981-992.
6. Giugliano R.P., Ruff C.T., Braunwald E., et al. Edoxaban versus warfarin in patients with atrial fibrillation. NEngl J Med 2013, 369:2093-2104.
7. Hylek E.M. The need for new oral anticoagulants in clinical practice. JCardiovasc Med 2009, 10:605-609.
8. 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.
9. Mani H., Kasper A., Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants - reasons, methods and current limitations. JThromb Thrombolysis 2013, 36:187-194.
10. Favaloro E.J., Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb) 2012, 22:329-341.
11. Greinacher A., Warkentin T.E. The direct thrombin inhibitor hirudin. Thromb Haemost 2008, 99:819-829.
12. Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003, 33:173-183.
13. Haemosys Ecarin Chromogenic Assay. ECA-T Kit for quantitative determination of direct synthetic thrombin inhibitors in plasma [package Insert]. JenAffin GmbH, Jena, Germany; 2010.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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, invitro study. Ann Pharmacother 2012, 46:1627-1636.
20. 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.
21. 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.
22. Harenberg J., Giese C., Marx S., et al. Determination of dabigatran in human plasma samples. Semin Thromb Hemost 2012, 38:16-22.
23. 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.
24. 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. JThromb Haemost 2013, 11:1495-1502.
25. 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.
26. Stangier J., Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012, 23:138-143.
27. 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.
28. Baruch L., Sherman O. Potential inaccuracy of point-of-care INR in dabigatran-treated patients. Ann Pharmacother 2011, 45(7-8):e40.
29. 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(9):e5-e6.
30. 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.
31. Lefemine A.A., Lewis M. Activated clotting time for control of anticoagulation during surgery. Am Surg 1985, 51:274-278.
32. Hartert H. Blutgerinnungstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschr 1948, 26:557-583.
33. 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.
34. Available at: Accessed January 21, 2014. http://www.rotem.de.
35. Available at: Accessed January 21, 2014. http://www.haemonetics.com/en/.
36. Grottke O. Coagulation management. Curr Opin Crit Care 2012, 18:641-646.
37. Hoffman M., Monroe D.M. Acell-based model of hemostasis. Thromb Haemost 2001, 85:958-965.
38. 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.
39. Rugeri L., Levrat A., David J.S., et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thromboelastography. JThromb Haemost 2007, 5:289-295.
40. 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.
41. Ogawa S., Szlam F., Chen E.P., et al. Acomparative evaluation of rotation thromboelastometry and standard coagulation tests in hemodilution induced coagulation changes after cardiac surgery. Transfusion 2012, 52:14-22.
42. 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.
43. 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.
44. 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.
45. 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.
46. Raza I., Davenport R., Rourke C., et al. The incidence and magnitude of fibrinolytic activation in trauma patients. JThromb Haemost 2013, 11(2):307-314.
47. 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.
48. 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(2):R62.
49. 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.
50. 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.
51. Rourke C., Curry N., Khan S., et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. JThromb Haemost 2012, 10:1342-1351.
52. 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.
53. 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.
54. 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.
55. 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. JCardiothorac Vasc Anesth 2013, 27:1181-1188.
56. 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.
57. 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.
58. 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, (3). CD007871.
59. 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.
60. 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.
61. Davis P.K., Musunuru H., Walsh M., et al. The exvivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine. Thromb Haemost 2012, 108:586-588.
62. 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 invitro. Blood Coagul Fibrinolysis 2013, 24:332-338.
63. 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.
64. 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.
65. 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(1):R27.
66. 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.
67. Loeffen R., Spronk H.M., ten Cate H. The impact of blood coagulability on atherosclerosis and cardiovascular disease. JThromb Haemost 2012, 10:1207-1216.
68. 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.
69. Béguin S., Lindhout T., Hemker H.C. The mode of action of heparin in plasma. Thromb Haemost 1988, 60:457-462.
70. Hemker H.C. Recollections on thrombin generation. JThromb Haemost 2008, 6:219-226.
71. 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.
72. Hemker H.C., Béguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995, 74:134-138.
73. Loeffen R., Kleinegris M.C., Loubele S.T., et al. Preanalytic variables of thrombin generation: towards a standard procedure and validation of the method. JThromb Haemost 2012, 10:2544-2554.
74. 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.
75. Castoldi E., Castoldi E., Rosing J., et al. Thrombin generation tests. Thromb Res 2011, 127:S21-S25.
76. 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. JThromb Haemost 2009, 7:1639-1648.
77. Tripodi A., Martinelli I., Chantarangkul V., et al. The endogenous thrombin potential and the risk of venous thromboembolism. Thromb Res 2007, 121:353-359.
78. 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.
79. 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. JThromb Haemost 2008, 6:1327-1333.
80. 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. JThromb Haemost 2008, 6:1720-1725.
81. 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.
82. 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.
83. ten Cate H. Thrombin generation in clinical conditions. Thromb Res 2012, 129:367-370.
84. 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.
85. 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.
86. Borissoff J.I., Joosen I.A., Versteylen M.O., et al. Accelerated invivo thrombin formation independently predicts the presence and severity of CT angiographic coronary atherosclerosis. JACC Cardiovasc Imaging 2012, 5:1201-1210.
87. Smid M., Dielis A.W., Winkens M., et al. Thrombin generation in patients with a first acute myocardial infarction. JThromb Haemost 2011, 9:450-456.
88. Smid M., Dielis A.W., Spronk H.M., et al. Thrombin generation in the Glasgow Myocardial Infarction Study. PLoS One 2013, 8:e66977.
89. 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.
90. 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. JThromb Haemost 2011, 9:2243-2250.
91. Nair S.C., Dargaud Y., Chitlur M., et al. Tests of global haemostasis and their applications in bleeding disorders. Haemophilia 2010, 16(Suppl 5):85-92.
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.
93. 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.
94. 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.
95. Gerotziafas G.T., Elalamy I., Depasse F., et al. Invitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. JThromb Haemost 2007, 5:886-888.
96. 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.
97. 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.
98. Serebruany V., Sani Y., Lynch D., et al. Effects of dabigatran invitro on thrombin biomarkers by calibrated automated thrombography in patients after ischemic stroke. JThromb Thrombolysis 2012, 33:22-27.
99. 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.
100. 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. JThromb Haemost 2010, 8:1281-1289.
101. 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.
102. Mattsson C., Menschik-Lundin A., Nylander S., et al. Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C invitro. Thromb Res 2001, 104:475-486.