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Review article: Biomedical intelligence

Vol. 148 No. 1112 (2018)

How I manage patients with anticoagulation-associated bleeding or urgent surgery

  • Thomas C. Sauter
  • Balthasar Eberle
  • Walter A. Wuillemin
  • Thomas Thiele
  • Anne Angelillo-Scherrer
  • Aristomenis K. Exadaktylos
  • Gabor Erdoes
  • Adam Cuker
  • Michael Nagler
Cite this as:
Swiss Med Wkly. 2018;148:w14598
Published
14.03.2018

Summary

Antithrombotic treatment puts patients at risk of major bleeding. Fast and adequate response to anticoagulant-associated bleeding may not only stop the bleeding but prevent severe complications. However, practical treatment algorithms to guide physicians in emergency situations are lacking. Important principles that arise from management of bleeding in general are (a) implementation of an in-house algorithm, (b) rapid identification and treatment of the bleeding source, (c) adequate fluid resuscitation, (d) consideration of the application of tranexamic acid and (e) appropriate coagulation testing. We present an algorithm for anticoagulant-associated bleeding and urgent surgery, derived from available data and recommendations, and implemented at our institution. Decisions regarding reversal agents or postponing surgery are based on two questions: the occurrence of a life-threatening bleed or urgent indication for surgery, and the presence of a relevant drug level. Immediate application of reversal agents is suggested if the clinical situation is urgent and laboratory test results are delayed or unavailable. A relevant anticoagulant drug level is required in all other cases. We discuss appropriate laboratory assays for all commonly available anticoagulants, report respective target ranges or expected values, discuss time intervals before surgery, and present critical cut-off values to be used as decision criteria. Specific and unspecific reversal agents for all anticoagulants including the direct oral anticoagulants will be presented. We aim to provide practical guidance for physicians in emergency situations. In addition, we summarise and discuss available experimental and clinical data as well as recommendations provided by scientific societies, authorities and manufacturers.

References

  1. Enriquez A, Lip GY, Baranchuk A. Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants. Europace. 2016;18(7):955–64. doi:.https://doi.org/10.1093/europace/euv030
  2. Wilson D, Seiffge DJ, Traenka C, Basir G, Purrucker JC, Rizos T, et al.; And the CROMIS-2 collaborators. Outcome of intracerebral hemorrhage associated with different oral anticoagulants. Neurology. 2017;88(18):1693–700. doi:.https://doi.org/10.1212/WNL.0000000000003886
  3. Schols AM, Schreuder FH, van Raak EP, Schreuder TH, Rooyer FA, van Oostenbrugge RJ, et al. Incidence of oral anticoagulant-associated intracerebral hemorrhage in the Netherlands. Stroke. 2014;45(1):268–70. doi:.https://doi.org/10.1161/STROKEAHA.113.003003
  4. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20(1):100. doi:.https://doi.org/10.1186/s13054-016-1265-x
  5. Cothren CC, Moore EE, Hedegaard HB, Meng K. Epidemiology of urban trauma deaths: a comprehensive reassessment 10 years later. World J Surg. 2007;31(7):1507–11. doi:.https://doi.org/10.1007/s00268-007-9087-2
  6. Frontera JA, Lewin JJ, 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6–46. doi:.https://doi.org/10.1007/s12028-015-0222-x
  7. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Suppl):e44S–88S. doi:.https://doi.org/10.1378/chest.11-2292
  8. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Suppl):e24S–43S. doi:.. Corrected in: Chest. 2013;144(2):721.https://doi.org/10.1378/chest.11-2291
  9. Sauter TC, Amylidi AL, Ricklin ME, Lehmann B, Exadaktylos AK. Direct new oral anticoagulants in the emergency department: Experience in everyday clinical practice at a Swiss university hospital. Eur J Intern Med. 2016;29:e13–5. doi:.https://doi.org/10.1016/j.ejim.2015.12.009
  10. Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015;39(3):395–402. doi:.https://doi.org/10.1007/s11239-015-1167-9
  11. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30(6):270–382. doi:.https://doi.org/10.1097/EJA.0b013e32835f4d5b
  12. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, et al.; STOP Bleeding Campaign. The STOP the Bleeding Campaign. Crit Care. 2013;17(2):136. doi:.https://doi.org/10.1186/cc12579
  13. ATLS Subcommittee; American College of Surgeons’ Committee on Trauma; International ATLS working group. Advanced trauma life support (ATLS®): the ninth edition. J Trauma Acute Care Surg. 2013;74(5):1363–6.
  14. Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM, Young PP. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. J Trauma. 2009;66(1):41–8, discussion 48–9. doi:.https://doi.org/10.1097/TA.0b013e31819313bb
  15. Johnson JE, Mosher BD, Morrison CA, Schneider PD, Stevens P, Kepros JP. A disciplined approach to implementation of evidence-based practices decreases ICU and hospital length of stay in traumatically injured patients. J Surg Res. 2010;163(2):327–30. doi:.https://doi.org/10.1016/j.jss.2010.03.074
  16. Ruchholtz S, Waydhas C, Lewan U, Piepenbrink K, Stolke D, Debatin J, et al. A multidisciplinary quality management system for the early treatment of severely injured patients: implementation and results in two trauma centers. Intensive Care Med. 2002;28(10):1395–404. doi:.https://doi.org/10.1007/s00134-002-1446-8
  17. Huber-Wagner S, Mand C, Ruchholtz S, Kühne CA, Holzapfel K, Kanz KG, et al.; TraumaRegister DGU. Effect of the localisation of the CT scanner during trauma resuscitation on survival -- a retrospective, multicentre study. Injury. 2014;45(Suppl 3):S76–82. doi:.https://doi.org/10.1016/j.injury.2014.08.022
  18. Martin M, Oh J, Currier H, Tai N, Beekley A, Eckert M, et al. An analysis of in-hospital deaths at a modern combat support hospital. J Trauma. 2009;66(4, Suppl):S51–60, discussion S60–1. doi:.https://doi.org/10.1097/TA.0b013e31819d86ad
  19. Smith W, Williams A, Agudelo J, Shannon M, Morgan S, Stahel P, et al. Early predictors of mortality in hemodynamically unstable pelvis fractures. J Orthop Trauma. 2007;21(1):31–7. doi:.https://doi.org/10.1097/BOT.0b013e31802ea951
  20. Rixen D, Steinhausen E, Dahmen J, Bouillon B. S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung [S3 guideline on treatment of polytrauma/severe injuries. Initial surgical phase: significance--possibilities--difficulties?]. Unfallchirurg. 2012;115(1):22–9. Article in German. doi:.https://doi.org/10.1007/s00113-011-2104-9
  21. Berry C, Ley EJ, Bukur M, Malinoski D, Margulies DR, Mirocha J, et al. Redefining hypotension in traumatic brain injury. Injury. 2012;43(11):1833–7. doi:.https://doi.org/10.1016/j.injury.2011.08.014
  22. Haut ER, Kalish BT, Cotton BA, Efron DT, Haider AH, Stevens KA, et al. Prehospital intravenous fluid administration is associated with higher mortality in trauma patients: a National Trauma Data Bank analysis. Ann Surg. 2011;253(2):371–7. doi:.https://doi.org/10.1097/SLA.0b013e318207c24f
  23. Morrison CA, Carrick MM, Norman MA, Scott BG, Welsh FJ, Tsai P, et al. Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma. 2011;70(3):652–63. doi:.https://doi.org/10.1097/TA.0b013e31820e77ea
  24. Wang CH, Hsieh WH, Chou HC, Huang YS, Shen JH, Yeo YH, et al. Liberal versus restricted fluid resuscitation strategies in trauma patients: a systematic review and meta-analysis of randomized controlled trials and observational studies*. Crit Care Med. 2014;42(4):954–61. doi:.https://doi.org/10.1097/CCM.0000000000000050
  25. Kwan I, Bunn F, Roberts I ; WHO Pre-Hospital Trauma Care Steering Committee. Timing and volume of fluid administration for patients with bleeding. Cochrane Database Syst Rev. 2003;(3):CD002245.
  26. Schreiber MA, Meier EN, Tisherman SA, Kerby JD, Newgard CD, Brasel K, et al.; ROC Investigators. A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial. J Trauma Acute Care Surg. 2015;78(4):687–95, discussion 695–7. doi:.https://doi.org/10.1097/TA.0000000000000600
  27. Brown JB, Cohen MJ, Minei JP, Maier RV, West MA, Billiar TR, et al.; Inflammation and the Host Response to Injury Investigators. Goal-directed resuscitation in the prehospital setting: a propensity-adjusted analysis. J Trauma Acute Care Surg. 2013;74(5):1207–12, discussion 1212–4.
  28. Dick F, Erdoes G, Opfermann P, Eberle B, Schmidli J, von Allmen RS. Delayed volume resuscitation during initial management of ruptured abdominal aortic aneurysm. J Vasc Surg. 2013;57(4):943–50. doi:.https://doi.org/10.1016/j.jvs.2012.09.072
  29. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011;(3):CD001886.
  30. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al., CRASH-2 trial collaborators. 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. 2010;376(9734):23–32. doi:.https://doi.org/10.1016/S0140-6736(10)60835-5
  31. Clavé A, Fazilleau F, Dumser D, Lacroix J. Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: A case-control study in 70 patients. Orthop Traumatol Surg Res. 2012;98(5):484–90. doi:.https://doi.org/10.1016/j.otsr.2011.12.005
  32. Myles PS, Smith JA, Painter T. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2017;376(19):1893.
  33. Levi M. Management of bleeding in patients treated with direct oral anticoagulants. Crit Care. 2016;20(1):249. doi:.https://doi.org/10.1186/s13054-016-1413-3
  34. Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology (Am Soc Hematol Educ Program). 2015;2015(1):117–24. doi:.https://doi.org/10.1182/asheducation-2015.1.117
  35. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127–30. doi:.https://doi.org/10.1097/01.TA.0000069184.82147.06
  36. Pollack CV, Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017;377(5):431–41. doi:.https://doi.org/10.1056/NEJMoa1707278
  37. 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(3):623–7. doi:.https://doi.org/10.1111/jth.13227
  38. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Suppl):e326S–50S. doi:.https://doi.org/10.1378/chest.11-2298
  39. Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost. 2016;14(5):875–85. doi:.https://doi.org/10.1111/jth.13305
  40. Suryanarayan D, Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res. 2014;133(Suppl 2):S158–66. doi:.https://doi.org/10.1016/S0049-3848(14)50026-6
  41. Nagler M, Angelillo-Scherrer A, Méan M, Limacher A, Abbal C, Righini M, et al. Long-term clinical outcomes of patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists: a prospective, multicenter cohort study of elderly patients with venous thromboembolism. J Thromb Haemost. 2017;15(11):2165–75. doi:.https://doi.org/10.1111/jth.13810
  42. Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost. 2015;113(5):931–42. doi:.https://doi.org/10.1160/TH14-11-0982
  43. Sarode R, Milling TJ, Jr, Refaai MA, Mangione A, Schneider A, Durn BL, et al. 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(11):1234–43.
  44. Goldstein JN, Refaai MA, Milling TJ, Jr, Lewis B, Goldberg-Alberts R, Hug BA, 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, non-inferiority, randomised trial. Lancet. 2015;385(9982):2077–87. doi:.https://doi.org/10.1016/S0140-6736(14)61685-8
  45. Sridharan M, Wysokinski WE, Pruthi R, Oyen L, Freeman WD, Rabinstein AA, et al. Periprocedural warfarin reversal with prothrombin complex concentrate. Thromb Res. 2016;139:160–5. doi:.https://doi.org/10.1016/j.thromres.2015.11.024
  46. Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood. 2014;123(8):1152–8. doi:.https://doi.org/10.1182/blood-2013-09-529784
  47. Pollack CV, Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511–20. doi:.https://doi.org/10.1056/NEJMoa1502000
  48. Sauter TC, Blum S, Nagler M, Schlittler FL, Ricklin ME, Exadaktylos AK. Reversal of Dabigatran Using Idarucizumab in a Septic Patient with Impaired Kidney Function in Real-Life Practice. Case Rep Emerg Med. 2016;2016:1393057. doi:.https://doi.org/10.1155/2016/1393057
  49. Ruff CT, Giugliano RP, Antman EM. Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation. 2016;134(3):248–61. doi:.https://doi.org/10.1161/CIRCULATIONAHA.116.021831
  50. Marlu R, Hodaj E, Paris A, Albaladejo P, 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(2):217–24. doi:.https://doi.org/10.1160/TH12-03-0179
  51. 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(2):253–9. doi:.https://doi.org/10.1160/TH11-09-0668
  52. Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168(4):4228–33. doi:.https://doi.org/10.1016/j.ijcard.2013.07.152
  53. Perzborn E, Gruber A, Tinel H, Marzec UM, Buetehorn U, Buchmueller A, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110(1):162–72. doi:.https://doi.org/10.1160/TH12-12-0907
  54. 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(14):1573–9. doi:.https://doi.org/10.1161/CIRCULATIONAHA.111.029017
  55. Barco S, Whitney Cheung Y, Coppens M, Hutten BA, Meijers JC, Middeldorp S. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol. 2016;172(2):255–61. doi:.https://doi.org/10.1111/bjh.13821
  56. Faust AC, Woodard S, Koehl JL, Mees W, Steinke D, Denetclaw TH. Managing Subdural Bleeding Associated With Rivaroxaban: A Series of 3 Cases. J Pharm Pract. 2016;29(3):257–62. doi:.https://doi.org/10.1177/0897190015627116
  57. Durie R, Kohute M, Fernandez C, Knight M. Prothrombin complex concentrate for the management of severe traumatic bleeding in a patient anticoagulated with apixaban. J Clin Pharm Ther. 2016;41(1):92–3. doi:.https://doi.org/10.1111/jcpt.12339
  58. Denetclaw TH, Tam J, Arias V, Kim R, Martin C. Case Report: Apixaban-Associated Gluteal Artery Extravasation Reversed With PCC3 Without FFP. J Pharm Pract. 2016;29(4):427–30. doi:.https://doi.org/10.1177/0897190015613231
  59. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener H-C, Hacke W, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary. Eur Heart J. 2017;38(27):2137–49. doi:.https://doi.org/10.1093/eurheartj/ehw058
  60. Lu G, Hollenbach SJ, Baker DC, Tan S, Hutchaleelaha A, Curnutte JT, et al. Preclinical safety and efficacy of andexanet alfa in animal models. J Thromb Haemost. 2017;15(9):1747–56. doi:.https://doi.org/10.1111/jth.13768
  61. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413–24. doi:.https://doi.org/10.1056/NEJMoa1510991
  62. Connolly SJ, Milling TJ, Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al.; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131–41. doi:.https://doi.org/10.1056/NEJMoa1607887
  63. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–51. doi:.https://doi.org/10.1038/nm.3102
  64. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2. doi:.https://doi.org/10.1056/NEJMc1411800
  65. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238–45. doi:.https://doi.org/10.1160/TH16-03-0224
  66. Studt JD, Alberio L, Angelillo-Scherrer A, Asmis LM, Fontana P, Korte W, et al. Accuracy and consistency of anti-Xa activity measurement for determination of rivaroxaban plasma levels. J Thromb Haemost. 2017;15(8):1576–83. doi:.https://doi.org/10.1111/jth.13747
  67. Nagler M, Wuillemin W. Labordiagnostik neuer Antikoagulantien - Einfluss auf Hämostaseparameter und Monitoring [Laboratory diagnostic with regard to new anticoagulants - monitoring and influence on coagulation tests]. Ther Umsch. Article in German. 2012;69(11):650–6. doi:.https://doi.org/10.1024/0040-5930/a000343
  68. Cuker A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis. 2016;41(2):241–7. doi:.https://doi.org/10.1007/s11239-015-1282-7
  69. Gatt A, Chen D, Pruthi RK, Kamath PS, Leise MD, Ashrani AA, et al. From vitamin K antagonists to liver international normalized ratio: a historical journey and critical perspective. Semin Thromb Hemost. 2014;40(8):845–51. doi:.https://doi.org/10.1055/s-0034-1395160
  70. Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJ, Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med. 1995;333(1):11–7. doi:.https://doi.org/10.1056/NEJM199507063330103
  71. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972;287(7):324–7. doi:.https://doi.org/10.1056/NEJM197208172870703
  72. Greaves M ; Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Limitations of the laboratory monitoring of heparin therapy. Scientific and Standardization Committee Communications: on behalf of the Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2002;87(1):163–4.
  73. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Suppl):e419S–96S. doi:.https://doi.org/10.1378/chest.11-2301
  74. Olson JD, Arkin CF, Brandt JT, Cunningham MT, Giles A, Koepke JA, et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122(9):782–98.
  75. Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res. 1976;8(3):413–6. doi:.https://doi.org/10.1016/0049-3848(76)90034-7
  76. Levine MN, Hirsh J, Gent M, Turpie AG, Cruickshank M, Weitz J, et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med. 1994;154(1):49–56. doi:.https://doi.org/10.1001/archinte.1994.00420010073009
  77. Nagler M, Angelillo-Scherrer A. Thromboembolien und Thrombophilie in der Schwangerschaft. Ther Umsch. 2016;73(7):377–83. doi:.https://doi.org/10.1024/0040-5930/a000807
  78. Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, 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(8):1493–502. doi:.https://doi.org/10.1111/jth.12308
  79. Fontana P, Alberio L, Angelillo-Scherrer A, Asmis LM, Korte W, Mendez A, et al. Impact of rivaroxaban on point-of-care assays. Thromb Res. 2017;153:65–70. doi:.https://doi.org/10.1016/j.thromres.2017.03.019
  80. Asmis LM, Alberio L, Angelillo-Scherrer A, Korte W, Mendez A, Reber G, et al. Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res. 2012;129(4):492–8. doi:.https://doi.org/10.1016/j.thromres.2011.06.031
  81. Samama MM, Contant G, Spiro TE, Perzborn E, Guinet C, Gourmelin Y, et al.; Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial Laboratories. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107(2):379–87. doi:.https://doi.org/10.1160/TH11-06-0391
  82. Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Köhler C, Werth S, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J. 2014;35(28):1888–96. doi:.https://doi.org/10.1093/eurheartj/eht557
  83. Nagler M, Erne P, Babst R, Korte W, Wuillemin WA. Periinterventionelles Management der Antikoagulation und Antiaggregation. Swiss Med Forum. 2011;11(23-24):407–12. doi:https://doi.emh.ch/10.4414/smf.2011.07539