Management of bleeding with non-Vitamin K antagonist oral anticoagulants in the era of specific reversal agents

Circulation

Volumn 134, Issue 3, 2016, Pages 248-261

  Ruff, Christian T ^a   Giugliano, Robert P ^a   Antman, Elliott M ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

anticoagulants; atrial fibrillation; hemorrhage; venous thromboembolism

Indexed keywords

ANDEXANET ALFA; ANTICOAGULANT AGENT; ANTIVITAMIN K; APIXABAN; CIRAPARANTAG; DABIGATRAN; EDOXABAN; FRESH FROZEN PLASMA; IDARUCIZUMAB; PROTHROMBIN COMPLEX; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RIVAROXABAN; VITAMIN K GROUP; WARFARIN; ANTITHROMBIN; ARGININE; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; BLOOD CLOTTING FACTOR 7A; HEMOSTATIC AGENT; MONOCLONAL ANTIBODY; PIPERAZINE DERIVATIVE; PROTHROMBIN COMPLEX CONCENTRATES; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; PYRIDONE DERIVATIVE; RECOMBINANT FVIIA; RECOMBINANT PROTEIN; THIAZOLE DERIVATIVE;

ACUTE KIDNEY FAILURE; ANTICOAGULATION; ARTICLE; BLEEDING; BLOOD CLOTTING TEST; HUMAN; MODERATE RENAL IMPAIRMENT; NONHUMAN; PRIORITY JOURNAL; VENOUS THROMBOEMBOLISM; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; HEMORRHAGE; ORAL DRUG ADMINISTRATION; PLASMA;

ADMINISTRATION, ORAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTITHROMBINS; ARGININE; BLOOD COAGULATION FACTORS; DABIGATRAN; FACTOR VIIA; FACTOR XA; FACTOR XA INHIBITORS; HEMORRHAGE; HEMOSTATICS; HUMANS; PIPERAZINES; PLASMA; PYRAZOLES; PYRIDINES; PYRIDONES; RECOMBINANT PROTEINS; RIVAROXABAN; THIAZOLES;

EID: 84979210724     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.116.021831     Document Type: Article

References (85)

1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee, and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: 1139-1151. doi: 10.1056/NEJMoa0905561.
2. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med. 2010; 363: 1875-1876. doi: 10.1056/NEJMc1007378.
3. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365: 883-891. doi: 10.1056/NEJMoa1009638.
4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees, and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365: 981-992. doi: 10.1056/NEJMoa1107039.
5. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369: 2093-2104. doi: 10.1056/NEJMoa1310907.
6. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369: 799-808. doi: 10.1056/NEJMoa1302507.
7. Hokusai-VTE Investigators, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013; 369: 1406-1415.
8. Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, Berkowitz SD, Wells PS; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT, and PE randomized studies. Thromb J. 2013; 11: 21. doi: 10.1186/1477-9560-11-21.
9. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin, and pooled analysis. Circulation. 2014; 129: 764-772. doi: 10.1161/CIRCULATIONAHA. 113.004450.
10. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. 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: 955-962. doi: 10.1016/S0140-6736(13)62343-0.
11. van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness, and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review, and meta-Analysis. J Thromb Haemost. 2014; 12: 320-328. doi: 10.1111/jth.12485.
12. Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, Michalski F, Köhler C, Werth S, Sahin K, Tittl L, Hänsel U, Weiss N. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014; 124: 955-962. doi: 10.1182/blood-2014-03-563577.
13. Beyer-Westendorf J, Ebertz F, Förster K, Gelbricht V, Michalski F, Köhler C, Werth S, Endig H, Pannach S, Tittl L, Sahin K, Daschkow K, Weiss N. Effectiveness, and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost. 2015; 113: 1247-1257. doi: 10.1160/TH14-11-0954.
14. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015; 131: 157-164. doi: 10.1161/CIRCULATIONAHA.114.012061.
15. Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY. Efficacy, and safety of dabigatran etexilate, and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013; 61: 2264-2273. doi: 10.1016/j.jacc.2013.03.020.
16. Larsen TB, Gorst-Rasmussen A, Rasmussen LH, Skjøth F, Rosenzweig M, Lip GY. Bleeding events among new starters, and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med. 2014; 127: 650-656.e5. doi: 10.1016/j.amjmed. 2014.01.031.
17. Hylek EM, Held C, Alexander JH, Lopes RD, De Caterina R, Wojdyla DM, Huber K, Jansky P, Steg PG, Hanna M, Thomas L, Wallentin L, Granger CB. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke, and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol. 2014; 63: 2141-2147. doi: 10.1016/j. jacc.2014.02.549.
18. Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, Brueckmann M, Fraessdorf M, Yusuf S, Schulman S. Management, and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013; 128: 2325-2332. doi: 10.1161/CIRCULATIONAHA.113.002332.
19. Lane DA, Aguinaga L, Blomström-Lundqvist C, Boriani G, Dan GA, Hills MT, Hylek EM, LaHaye SA, Lip GY, Lobban T, Mandrola J, McCabe PJ, Pedersen SS, Pisters R, Stewart S, Wood K, Potpara TS, Gorenek B, Conti JB, Keegan R, Power S, Hendriks J, Ritter P, Calkins H, Violi F, Hurwitz J. Cardiac tachyarrhythmias, and patient values, and preferences for their management: the European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE). Europace. 2015; 17: 1747-1769. doi: 10.1093/europace/euv233.
20. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. Updated European Heart Rhythm Association Practical Guide on the use of nonvitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015; 17: 1467-1507. doi: 10.1093/.europace/euv309.
21. Kovacs RJ, Flaker GC, Saxonhouse SJ, Doherty JU, Birtcher KK, Cuker A, Davidson BL, Giugliano RP, Granger CB, Jaffer AK, Mehta BH, Nutescu E, Williams KA. Practical management of anticoagulation in patients with atrial fibrillation. J Am Coll Cardiol. 2015; 65: 1340-1360. doi: 10.1016/j.jacc.2015.01.049.
22. Weitz JI, Pollack CV Jr. Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants. Thromb Haemost. 2015; 114: 1113-1126. doi: 10.1160/TH15-03-0222.
23. Aronis KN, Hylek EM. Who, when, and how to reverse non-vitamin K oral anticoagulants. J Thromb Thrombolysis. 2016; 41: 253-272. doi: 10.1007/s11239-015-1297-0.
24. Wang X, Mondal S, Wang J, Tirucherai G, Zhang D, Boyd RA, Frost C. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014; 14: 147-154. doi: 10.1007/s40256-013-0055-y.
25. Woo JS, Kapadia N, Phanco SE, Lynch CA. Positive outcome after intentional overdose of dabigatran. J Med Toxicol. 2013; 9: 192-195. doi: 10.1007/s13181-012-0276-5.
26. Sajkov D, Gallus A. Accidental rivaroxaban overdose in a patient with pulmonary embolism: some lessons for managing new oral anticoagulants. Clin Med Insights Case Rep. 2015; 8: 57-59. doi: 10.4137/CCRep.S27992.
27. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa), and hemodialysis to manage massive dabigatran-Associated postcardiac surgery bleeding. Blood. 2012; 119: 2172-2174. doi: 10.1182/.blood-2011-11-393587.
28. Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012; 46: e21. doi: 10.1345/.aph.1R081.
29. Getta B, Muller N, Motum P, Hsu D, Zebeljan D, Rosenfeld D. Intermittent haemodialysis, and continuous veno-venous dialysis are effective in mitigating major bleeding due to dabigatran. Br J Haematol. 2015; 169: 603-604. doi: 10.1111/bjh.13236.
30. Paul S, Hamouda D, Prashar R, Mbaso C, Khan A, Ali A, Shah S, Assaly R. Management of dabigatran-induced bleeding with continuous venovenous hemodialysis. Int J Hematol. 2015; 101: 594-597. doi: 10.1007/s12185-015-1739-7.
31. Parasrampuria DA, Marbury T, Matsushima N, Chen S, Wickremasingha PK, He L, Dishy V, Brown KS. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015; 113: 719-727. doi: 10.1160/TH14-06-0547.
32. Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, Song Y, Pursley J, Boyd RA, Frost C. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016; 56: 628-636. doi: 10.1002/jcph.628.
33. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A. Dabigatran etexilate-A novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays, and reversal of anticoagulant activity. Thromb Haemost. 2010; 103: 1116-1127. doi: 10.1160/TH09-11-0758.
34. Pragst I, Zeitler SH, Doerr B, Kaspereit FJ, Herzog E, Dickneite G, van Ryn J. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost. 2012; 10: 1841-1848. doi: 10.1111/j.1538-7836.2012.04859.x.
35. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM. Evaluation of prothrombin complex concentrate, and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012; 116: 94-102. doi: 10.1097/ALN.0b013e318238c036.
36. Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost. 2012; 10: 1830-1840. doi: 10.1111/j.1538-7836.2012.04863.x.
37. Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, Heitmeier S, Laux V. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats, and primates. Thromb Haemost. 2013; 110: 162-172. doi: 10.1160/TH12-12-0907.
38. Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, Godier A. 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: 4228-4233. doi: 10.1016/j.ijcard.2013.07.152.
39. Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013; 44: 771-778. doi: 10.1161/STROKEAHA.112.675231.
40. Honickel M, Treutler S, van Ryn J, Tillmann S, Rossaint R, Grottke O. Reversal of dabigatran anticoagulation ex vivo: porcine study comparing prothrombin complex concentrates, and idarucizumab. Thromb Haemost. 2015; 113: 728-740. doi: 10.1160/TH14-08-0712.
41. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban, and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124: 1573-1579. doi: 10.1161/CIRCULATIONAHA.111.029017.
42. Levi M, Moore KT, Castillejos CF, Kubitza D, Berkowitz SD, Goldhaber SZ, Raghoebar M, Patel MR, Weitz JI, Levy JH. Comparison of three-factor, and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014; 12: 1428-1436. doi: 10.1111/jth.12599.
43. Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, Lomeli B, Feussner A, Feng W, He L, Grosso MA, Lanz HJ, Antman EM. Edoxaban effects on bleeding following punch biopsy, and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015; 131: 82-90. doi: 10.1161/CIRCULATIONAHA.114.013445.
44. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Crackowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran, and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012; 108: 217-224. doi: 10.1160/TH12-03-0179.
45. Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, Roquer J, Reverter JC, Sanz VV, Molina P, Lopez-Vilchez I, Diaz-Ricart M, Galan AM. 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: e78696. doi: 10.1371/journal.pone.0078696.
46. Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012; 107: 253-259. doi: 10.1160/TH11-09-0668.
47. 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: 989-995. doi: 10.1160/TH13-07-0607.
48. 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: 735-740. doi: 10.1177/1076029613494468.
49. 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: 671-681. doi: 10.1016/j.thromres.2014.01.017.
50. Escolar G, Arellano-Rodrigo E, Lopez-Vilchez I, Molina P, Sanchis J, Reverter JC, Carne X, Cid J, Villalta J, Tassies D, Galan AM, Diaz-Ricart M. 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: 331-338. doi: 10.1253/circj.CJ-14-0909.
51. Halim AB, Samama MM, Mendell J. Ex vivo reversal of the anticoagulant effects of edoxaban. Thromb Res. 2014; 134: 909-913. doi: 10.1016/j.thromres.2014.07.036.
52. Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015; 39: 395-402. doi: 10.1007/.s11239-015-1167-9.
53. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012; 23: 138-143. doi: 10.1097/.MBC.0b013e32834f1b0c.
54. Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013; 11: 1111-1118. doi: 10.1111/jth.12236.
55. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics, and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, singlecentre study. Clin Pharmacokinet. 2010; 49: 259-268. doi: 10.2165/11318170-000000000-00000.
56. Crescenzi G, Landoni G, Biondi-Zoccai G, Pappalardo F, Nuzzi M, Bignami E, Fochi O, Maj G, Calabrò MG, Ranucci M, Zangrillo A. Desmopressin reduces transfusion needs after surgery: a meta-Analysis of randomized clinical trials. Anesthesiology. 2008; 109: 1063-1076. doi: 10.1097/ALN.0b013e31818db18b.
57. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy, and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013; 128: 1234-1243. doi: 10.1161/CIRCULATIONAHA. 113.002283.
58. Baudo F, Collins P, Huth-Kühne A, Lévesque H, Marco P, Nemes L, Pellegrini F, Tengborn L, Knoebl P; EACH2 registry contributors. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood. 2012; 120: 39-46. doi: 10.1182/blood-2012-02-408930.
59. Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-Analysis. Thromb Haemost. 2011; 106: 429-438. doi: 10.1160/TH11-01-0052.
60. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia. 2002; 8: 83-90.
61. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI; Subcommittee on Control of Anticoagulation. When, and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016; 14: 623-627. doi: 10.1111/jth.13227.
62. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A specific antidote for dabigatran: functional, and structural characterization. Blood. 2013; 121: 3554-3562. doi: 10.1182/blood-2012-11-468207.
63. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: the antidote for reversal of dabigatran. Circulation. 2015; 132: 2412-2422. doi: 10.1161/CIRCULATIONAHA.115.019628.
64. Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, Lang B, Ramael S, Reilly P. A randomised study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015; 113: 943-951. doi: 10.1160/TH14-12-1080.
65. Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol. 2012; 52(1 suppl): 54S-62S. doi: 10.1177/0091270011413894.
66. van Ryn J, Litzenburger T, Gan G, Coble K, Schurer J. In vitro characterization, pharmacokinetics, and reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a specific antibody fragment antidote to dabigatran. Blood. 2012; 21: 3418.
67. van Ryn J, Litzenburger T, Waterman A, Canada K, Hauel N, Sarko C, Kroe-Barrett R, Singh S, Park J. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro, and in vivo models. J Am Coll Cardiol. 2011; 57: E1130.
68. Grottke O, Honickel M, van Ryn J, ten Cate H, Spronk H, Rossaint R. Abstract 18544: bloods loss in dabigatran anticoagulated pigs with polytrauma is significantly reduced by early therapy with activated, and non-Activated prothrombin complex concentrates. Circulation. 2014; 130: A18544.
69. Glund S, Stangier J, Schmohl M, Moschetti V, Haazen W, De Smet M, Gansser D, Norris S, Lang B, Reilly P. Idarucizumab, a specific antidote for dabigatran: immediate, complete, and sustained reversal of dabigatran induced anticoagulation in elderly, and renally impaired subjects. Blood. 2014; 124: 344.
70. Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015; 386: 680-690. doi: 10.1016/S0140-6736(15)60732-2.
71. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for dabigatran reversal. N Engl J Med. 2015; 373: 511-520. doi: 10.1056/NEJMoa1502000.
72. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet alfa for the reversal of factor xa inhibitor activity. N Engl J Med. 2015; 373: 2413-2424. doi: 10.1056/.NEJMoa1510991.
73. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U. A specific antidote for reversal of anticoagulation by direct, and indirect inhibitors of coagulation factor Xa. Nat Med. 2013; 19: 446-451. doi: 10.1038/nm.3102.
74. Crowther M, Levy G, Lu G, Leeds J, Lin J, Pratikhya P, Conley P, Connolly S, Curnutte J. a phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Blood. 2014; 124: 4269.
75. Hashizume M, Tan SL, Takano J, Ohsawa K, Hasada I, Hanasaki A, Ito I, Mihara M, Nishida K. Tocilizumab, a humanized anti-IL-6R antibody, as an emerging therapeutic option for rheumatoid arthritis: molecular, and cellular mechanistic insights. Int Rev Immunol. 2015; 34: 265-279. doi: 10.3109/08830185.2014.938325.
76. Zhang LJ, Lu GM. Takayasu's arteritis involving the pulmonary arteries: evaluation by quantitative dual-energy computed tomographic pulmonary angiography. Eur Heart J. 2012; 33: 928. doi: 10.1093/eurheartj/ehr335.
77. Lu G, Deguzman F, Hollenbach S, , et al. Reversal of low molecular weight heparin, and fondaparinux by a recombinant antidote (r-Antidote, PRT064445). Circulation. 2010; 122: 12420.
78. Crowther M, Lu G, Conley P, et al. Reversal of factor Xa inhibitorsinduced anticoagulation in healthy subjects by andexanet alpha. Crit Care Med. 2014; 42: A1469.
79. Crowther M, Mathur V, Kitt M, Lu G, Conley P, Hollenback S, Castillo J, Hutchaleelaha A, Karbarz M, Lin J, Barron L, Russel S, Levy G, Connolly S, Curnutte J. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for Fxa inhibitors. Blood. 2013; 122: 3636.
80. Crowther M, Kitt M, Lorenz T. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct, and indirect factor Xa inhibitors. J Thromb Haemost. 2013; 11: 30.
81. Laulicht B, Bakhru S, Jiang X. Antidote for new oral anticoagulants: mechanism of action, and binding specificity of PER977. J Thromb Haemost. 2013; 11: 75.
82. Laulicht B, Bakhru S, Lee C. Small molecule antidote for anticoagulants. Circulation. 2012; 126: A11395.
83. Bakhru S, Laulicht B, Jiang X. PER977: a synthetic small molecule which reverses over-dosage, and bleeding by new oral anticoagulants. Circulation. 2013; 128: A18809.
84. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, Dishy V, Noveck RJ, Costin JC. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014; 371: 2141-2142. doi: 10.1056/NEJMc1411800.
85. Sarich TC, Seltzer JH, Berkowitz SD, Costin J, Curnutte JT, Gibson CM, Hoffman M, Kaminskas E, Krucoff MW, Levy JH, Mintz PD, Reilly PA, Sager PT, Singer DE, Stockbridge N, Weitz JI, Kowey PR. Novel oral anticoagulants, and reversal agents: considerations for clinical development. Am Heart J. 2015; 169: 751-757. doi: 10.1016/j.ahj.2015.03.010.