Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2021.03.007
Brazilian Journal of Anesthesiology
Narrative Review

Clinical protocols for oral anticoagulant reversal during high risk of bleeding for emergency surgical and nonsurgical settings: a narrative review

Protocolos clínicos para reversão de anticoagulante oral durante alto risco de sangramento para ambientes cirúrgicos e não cirúrgicos de emergência: uma revisão narrativa

Carlos Galhardo Jr., Luiz Henrique Ide Yamauchi, Hugo Dantas, João Carlos de Campos Guerra

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Abstract

Background and objectives
Oral anticoagulants prevent thromboembolic events but expose patients to a significant risk of bleeding due to the treatment itself, after trauma or during surgery. Any physician working in the emergency department or involved in the perioperative care of a patient should be aware of the best reversal approach according to the type of drug and the patient’s clinical condition. This paper presents a concise review and proposes clinical protocols for the reversal of oral anticoagulants in emergency settings, such as bleeding or surgery.

Contents
The authors searched for relevant studies in PubMed, LILACS, and the Cochrane Library database and identified 82 articles published up to September 2020 to generate a review and algorithms as clinical protocols for practical use. Hemodynamic status and the implementation of general supportive measures should be the first approach under emergency conditions. The drug type, dose, time of last intake, and laboratory evaluations of anticoagulant activity and renal function provide an estimation of drug clearance and should be taken into consideration. The reversal agents for vitamin K antagonists are 4-factor prothrombin complex concentrate and vitamin K, followed by fresh frozen plasma as a second-line treatment. Direct oral anticoagulants have specific reversal agents, such as andexanet alfa and idarucizumab, but are not widely available. Another possibility in this situation, but with less evidence, is prothrombin complex concentrates.

Conclusion
The present algorithms propose a tool to help health care providers in the best decision making for patients under emergency conditions.

Keywords

Reversal of oral anticoagulants,  Warfarin,  Non-vitamin K antagonists,  Direct oral anticoagulants,  Prothrombin complex concentrates,  Idarucizumab,  Andexanet alfa

Resumo

Justificativa e objetivos: Os anticoagulantes orais previnem eventos tromboembólicos, mas expõem os pacientes a um risco significativo de sangramento devido ao próprio tratamento, após trauma ou durante cirurgia. Qualquer médico que trabalhe no departamento de emergência ou envolvido no cuidado perioperatório de um paciente deve estar ciente da melhor abordagem de reversão de acordo com o tipo de medicamento e a condição clínica do paciente. Este artigo apresenta uma revisão concisa e propõe protocolos clínicos para a reversão de anticoagulantes orais em ambientes de emergência, como sangramento ou cirurgia. Conteúdo: Os autores buscaram estudos relevantes no PubMed, LILACS e na base de dados da Biblioteca Cochrane e identificaram 82 artigos publicados até setembro de 2020 para gerar uma revisão e algoritmos como protocolos clínicos para uso prático. O estado hemodinâmico e a implementação de medidas gerais de suporte devem ser a primeira abordagem em condições de emergência. O tipo de medicamento, a dose, o tempo da última ingestão e as avaliações laboratoriais da atividade anticoagulante e da função renal fornecem uma estimativa da depuração do medicamento e devem ser levados em consideração. Os agentes de reversão para os antagonistas da vitamina K são o concentrado do complexo de protrombina de 4 fatores e a vitamina K, seguidos por plasma fresco congelado como tratamento de segunda linha. Os anticoagulantes orais diretos têm agentes de reversão específicos, como andexanet alfa e idarucizumabe, mas não estão amplamente disponíveis. Outra possibilidade nessa situação, mas com menos evidências, são os concentrados de complexo de protrombina. Conclusão: Os algoritmos presentes propõem uma ferramenta para ajudar os profissionais de saúde na melhor tomada de decisão para pacientes em condições de emergência.

Palavras-chave

Reversão de anticoagulantes orais; Varfarina; Antagonistas nãovitamina K; Anticoagulantes orais diretos; Concentrados de complexo de protrombina; Idarucizumab; Andexanet alfa.

References

1 R. Tadros, S. Shakib Warfarin indications, risks and drug interactions Aus Fam Phys., 39 (2010), pp. 476-479

2 Y. Falck-Ytter, C.W. Francis, N.A. Johanson, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest., 141 (2012), pp. e278S-e325S

3 J. Huhtakangas, S. Tetri, S. Juvels, et al. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study Stroke., 42 (2011), pp. 2431-2435

4 J.G. Kelly, K. OʼMalley Clinical Pharmacokinetics of Oral Anticoagulants Clin Pharmacokinet., 4 (1979), pp. 1-15

5 R.A. O’Reilly Vitamin K and other oral anticoagulant drugs Annu Rev Med., 27 (1976), pp. 245-261

6 C. Cameron, D. Coyle, T. Richter, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation BMJ Open., 4 (2014), pp. e004301-e004312

7 M. Jun, L.M. Lix, M. Durand, et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicenter, population based, observational study BMJ., 359 (2017), p. j4323

8 K. Senoo, Y. Kondo, K. Miyazawa, et al. Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: A meta-analysis J Cardiol., 69 (2017), pp. 763-768

9 P. Sardar, S. Chatterjee, C.J. Lavie, et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials Int J Cardiol., 179 (2015), pp. 279-287

10 W. Mueck, A.W. Lensing, G. Agnelli, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention Clin Pharmacokinet., 50 (2011), pp. 675-686

11 N. Raghavan, C.E. Frost, Z. Yu, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans Drug Metab Dispos., 37 (2009), pp. 74-81

12 K. Ogata, J. Mendell-Harary, M. Tachibana, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers J Clin Pharmacol., 50 (2010), pp. 743-753

13 J. Stangier, K. Rathgen, H. Stahle, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects Br J Clin Pharmacol., 64 (2007), pp. 292-303

14 J. Burn, M. Pirmohamed Direct oral anticoagulants versus warfarin: is new always better than the old? Open Heart., 5 (2018), Article e000712

15 J.L. Thigpen, N.A. Limdi Reversal of oral anticoagulation Pharmacotherapy., 33 (2013), pp. 1199-1213

16 M. Almegren Reversal of direct oral anticoagulants Vasc Health Risk Manag., 13 (2017), pp. 287-292

17 A.M. Schols, F.H. Schreuder, E.P. van Raak, et al. Incidence of oral anticoagulant-associated intracerebral hemorrhage in the Netherlands Stroke., 45 (2014), pp. 268-270

18 S.A. Kustos, P.S. Fasinu Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update Medicines (Basel)., 6 (2019), p. E103

19 W. Mueck, D. Kubitza, M. Becka Coadministration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects Br J Clin Pharmacol., 76 (2013), pp. 455-466

20 S.H. Chang, I.J. Chou, Y.H. Yeh, et al. Association between use of nonvitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation JAMA., 318 (2017), pp. 1250-1259

21 A. Zullo, C. Hassan, F. Radaelli Gastrointestinal endoscopy in patients on anticoagulant therapy and antiplatelet agents Ann Gastroenterol., 30 (2017), pp. 7-14

22 J.A. Frontera, J.J. Lewin 3rd, A.A. Rabinstein, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine Crit Care Med., 44 (2016), pp. 2251-2257

23 S. Kaatz, C.E. Mahan, A. Nakhle, et al. Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants Curr Cardiol Rep., 19 (2017), pp. 124-134

24 K. McIlmoyle, H. Tran Perioperative management of oral anticoagulation BJA Education., 18 (2018), pp. 259-264

25 J.D. Douketis, A.C. Spyropoulos, J. Duncan, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant JAMA Intern Med., 179 (2019), pp. 1469-1478

26 Y. Xu, S. Schulman, D. Dowlatshahi, et al. Bleeding Effected by Direct Oral Anticoagulants (BLED-AC) Study Group. Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study Chest., 152 (2017), pp. 81-91

27 CRASH-2 trial collaborators, H. Shakur, I. Roberts, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial Lancet., 376 (2010), pp. 23-32

28 I. Pabinger, D. Fries, H. Schöchl, et al. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis Wien Klin Wochenschr., 129 (2017), pp. 303-316

29 J. Ansell, J. Hirsh, E. Hylek, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest., 133 (2008), pp. 160S-198S

30 J.N. Goldstein, M.A. Refaai, T.J. Milling Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, noninferiority, randomised trial Lancet., 385 (9982) (2015), pp. 2077-2087

31 W.S. Dzik Reversal of drug-induced anticoagulation: old solutions and new problems Transfusion., 52 (2012), pp. 45S-55S

32 M. Bhatia, G. Talawadekar, S. Parihar, et al. An audit of the role of vitamin K in the reversal of International Normalised Ratio (INR) in patients undergoing surgery for hip fracture Ann R Coll Surg Engl., 92 (2010), pp. 473-476

33 K.L. Burbury, A. Milner, B. Snooks, et al. Short-term warfarin reversal for elective surgery using low-dose intravenous vitamin K: safe, reliable and convenient Br J Haematol., 154 (2011), pp. 626-634

34 E. Pautas, I. Peyron, S. Bouhadiba, et al. Reversal of over anticoagulation in very elderly hospitalized patients with an INR above 5.0: 24-hour INR response after vitamin K administration Am J Med., 124 (2011), pp. 527-533

35 C. Chai-Adisaksopha, C. Hillis, D.M. Siegal, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis Thromb Haemost., 116 (2016), pp. 879-890

36 T.A. Allison, P.J. Lin, J.A. Gass, et al. Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients J Intensive Care Med., 35 (2020), pp. 903-908

37 D. Kerebel, L.M. Joly, D. Honnart, et al. A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal Crit Care., 17 (2013), p. R4

38 F. Dentali, C. Marchesi, M. Giorgi Pierfranceschi, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists A meta-analysis. Thromb Haemost., 106 (2011), pp. 429-438

39 T.J. Milling Jr, M.A. Refaai, J.N. Goldstein, et al. Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies Ann Emerg Med., 67 (2016), pp. 96-105.e5

40 T. Steiner, S. Poli, M. Griebe, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial Lancet Neurol., 15 (2016), pp. 566-573

41 N. Chausson, D. Soumah, M. Aghasaryan, et al. Reversal of Vitamin K Antagonist Therapy Before Thrombolysis for Acute Ischemic Stroke Stroke, 49 (2018), pp. 2526-2528

42 J. Rimsans, A. Levesque, E. Lyons, et al. Four-factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices J Thromb Thrombolysis., 46 (2018), pp. 180-185

43 J. Mačiukaitienė, D. Bilskienė, A. Tamašauskas, et al. Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Bleeding in Neurosurgical Patients: A Single-Center Experience Medicina., 54 (2018), pp. 22-31

44 L. Mattisson, L.J. Lapidus, A. Enocson Is fast reversal and early surgery (within 24 h) in patients on warfarin medication with trochanteric hip fractures safe? A case-control study BMC Musculoskelet Disord., 19 (2018), pp. 203-210

45 A. Hedges, J.C. Coons, M. Saul, et al. Clinical effectiveness and safety outcomes associated with prothrombin complex concentrates J Thromb Thrombolysis., 42 (2015), pp. 1-5

46 R. Scott, B. Kersten, J. Basior, et al. Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage J Emerg Med., 54 (2018), pp. 861-866

47 G. Astrup, P. Sarangarm, A. Burnett Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis J Thromb Thrombolysis., 45 (2018), pp. 300-305

48 T. Holt, S. Taylor, P. Abraham, et al. Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding Int J Crit Illn Inj Sci., 8 (2018), pp. 36-40

49 S.A. Voils, M.C. Holder, S. Premraj, et al. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal Thromb Res., 136 (2015), pp. 595-598

50 C. Carothers, A. Giancarelli, J. Ibrahim, et al. Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage J Surg Res., 223 (2018), pp. 183-187

51 A.S. Rowe, P.S. Mahbubani, M.H. Bucklin, et al. Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage Pharmacotherapy., 36 (2016), pp. 1132-1137

52 H.A. Tran, S.D. Chunilal, P.L. Harper, et al. Australasian Society of Thrombosis and Haemostasis (ASTH). An update of consensus guidelines for warfarin reversal Med J Aust., 198 (2013), pp. 198-199

53 D.R. Spahn, B. Bouillon, V. Cerny, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition Crit Care., 23 (2019), p. 98

54 J.C. Hemphill, S.M. Greenberg, C.S. Anderson, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association Stroke., 46 (2015), pp. 2032-2060

55 R. Demeyere, S. Gillardin, J. Arnout, et al. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study Vox Sang., 99 (2010), pp. 251-260

56 S. Choi, M. Casias, D. Tompkins, et al. Blood, blood components, plasma, and plasma products Side Effects of Drugs Annual., 41 (2019), pp. 373-386

57 C.H. Woo, N. Patel, C. Conel, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII and prothrombin complex concentrate World Neurosurg., 81 (2014), pp. 110-115

58 S.A. Chapman, E.D. Irwin, N.M. Abou-Karam, et al. Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal World J Emerg Surg., 9 (2014), pp. 27-34

59 R. Sarode, K. Matevosyan, R. Bhagat, et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage J Neurosurg., 116 (2012), pp. 491-497

60 C.A. Barton, M. Hom, N.B. Johnson, et al. Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa Am J Surg., 215 (2018), pp. 775-779

61 S.L. Mehringer, Z. Klick, J. Bain, et al. Activated Factor 7 Versus 4-Factor Prothrombin Complex Concentrate for Critical Bleeding Post-Cardiac Surgery Ann Pharmacother., 52 (2018), pp. 533-537

62 V. Yank, C.V. Tuohy, A.C. Logan, et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications Ann Intern Med., 154 (2011), pp. 529-540

63 D. Matino, M. Makris, K. Dwan, et al. Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors Cochrane Database Syst Rev. (2015), Article CD004449

64 K.A. OConnell, J.J. Wood, R.P. Wise, et al. Thromboembolic Adverse Events After Use of Recombinant Human Coagulation Factor VIIa JAMA, 295 (2006), pp. 293-298

65 T. Exner, M. Ahuja, L. Ellwood Effect of an activated charcoal product (DOAC Stop™) intended for extracting DOACs on various other APTT-prolonging anticoagulants Clin Chem Lab Med., 57 (2019), pp. 690-696

66 A. Cuker, D.M. Siegal, M.A. Crowther, et al. Laboratory measurement of the anticoagulant activity of the nonvitamin K oral anticoagulants J Am Coll Cardiol., 64 (2014), pp. 1128-1139

67 S.E. Conway, A.Y. Hwang, C.D. Ponte, et al. Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know Pharmacotherapy., 37 (2017), pp. 236-248

68 D.M. Siegal, J.T. Curnutte, S.J. Connolly, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity N Engl J Med., 373 (2015), pp. 2413-2424

69 S.J. Connolly, M. Crowther, J.W. Eikelboom, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors N Engl J Med., 380 (2019), pp. 1326-1335

70 G.F. Tomaselli, K.W. Mahaffey, A. Cuker, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee J Am Coll Cardiol., 76 (2020), pp. 594-622

71 A. Cuker, A. Burnett, D. Triller, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum Am J Hematol., 94 (2019), pp. 697-709

72 E.S. Eerenberg, P.W. Kamphuisen, M.K. Sijpkens, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects Circulation., 124 (2011), pp. 1573-1579

73 L.T. da Luz, M. Marchand, B. Nascimento, et al. Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis Transfusion., 57 (2017), pp. 1834-1846

74 S. Piran, C. Gabriel, S. Schulman Prothrombin complex concentrate for reversal of direct factor Xa inhibitors prior to emergency surgery or invasive procedure: a retrospective study J Thromb Thrombolysis., 45 (2018), pp. 486-495

75 A. Majeed, A. Ågren, M. Holmström, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrate: a cohort study Blood., 130 (2017), pp. 1706-1712

76 S. Schulman, P.L. Gross, B. Ritchie, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study Thromb Haemost., 118 (2018), pp. 842-851

77 M. Sheikh-Taha Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate Intern Emerg Med., 14 (2019), pp. 265-269

78 S.K. Harrison, J.S. Garrett, K.N. Kohman, et al. Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate BUMC Proc, 31 (2018), pp. 153-156

79 J. Tao, E.N. Bukanova, S. Akhtar Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors J Intensive Care., 6 (2018), pp. 34-40

80 R. Grandhi, W.C. Newman, X. Zhang, et al. Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors World Neurosurg., 84 (2015), pp. 1956-1961

81 D. Dybdahl, G. Walliser, M. Chance Spalding, et al. Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage Am J Emerg Med., 37 (2019), pp. 1907-1911

82 S. Piran, R. Khatib, S. Schulman, et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis Blood Adv., 3 (2019), pp. 158-167

83 S. Senger, D. Keiner, P. Hendrix, et al. New target-specific oral anticoagulants and intracranial bleeding: management and outcome in a single-center case series World Neurosurg., 88 (2016), pp. 132-139

84 L. Green, J. Tan, S. Antoniou, et al. Haematological management of major bleeding associated with direct oral anticoagulants - UK experience Br J Haematol., 185 (2019), pp. 514-522

85 A. Maurice-Szamburski, T. Graillon, N. Bruder Favorable outcome after a subdural hematoma treated with FEIBA in a 77-year-old patient treated by rivaroxaban J Neurosurg Anesthesiol., 26 (2014), p. 183

86 J.M. Engelbart, A. Zepeski, C. Galet, et al. Safety and effectiveness of Factor Eight Inhibitor Bypassing Activity for direct oral anticoagulant-related hemorrhage reversal Am J Emerg Med., 37 (2019), pp. 214-219

87 W.E. Dager, A.J. Roberts, D.K. Nishijima Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants Thromb Res., 173 (2019), pp. 71-76

88 N.H. Schultz, R. Lundblad, P.A. Holme Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series J Med Case Rep., 12 (2018), p. 138

89 J.R. Dibu, J.M. Weimer, C. Ahrens, et al. The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage Neurocrit Care., 24 (2016), pp. 413-420

90 J. Van Ryn, J. Stangier, S. Haertter, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity Thromb Haemost., 103 (2010), pp. 1116-1127

91 J. Stangier, K. Rathgen, H. Stähle, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-center study Clin Pharmacokinet., 49 (2010), pp. 259-268

92 D. Khadzhynov, F. Wagner, S. Formella, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-center study in patients with end-stage renal disease Thromb Haemost., 109 (2013), pp. 596-605

93 C.V. Pollack Jr, P.A. Reilly, J. van Ryn, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis N Engl J Med., 377 (2017), pp. 431-441

94 S. Schulman, B. Ritchie, J.K. Goy, et al. Activated prothrombin complex concentrate for dabigatran associated bleeding Br J Haematol., 164 (2014), pp. 308-310

95 S. Schulman, B. Ritchie, S. Nahirniak, et al. Reversal of dabigatran associated major bleeding with activated prothrombin concentrate: a prospective cohort study Thromb Res., 152 (2017), pp. 44-48

96 W.E. Dager, R.C. Gosselin, A.J. Roberts Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity Crit Care Med., 41 (2013), pp. e42-e46

97 L.E. Dumkow, J.R. Voss, M. Peters, et al. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma Am J Health Syst Pharm., 69 (2012), pp. 1646-1650

98 A. Lillo-Le Louët, M. Wolf, L. Soufir, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation Thromb Haemost., 108 (2012), pp. 583-585
 

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