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Intravenous Haemostatic Adjuncts

  • Jez FabesEmail author
  • Simon Stanworth
Chapter

Abstract

This chapter summarises the evidence base for use of tranexamic acid, prothrombin complex concentrate (PCC), fibrinogen concentrate, cryoprecipitate and recombinant Factor VII a in trauma.

The use of tranexamic acid within 3 hours of trauma has clear outcome benefits at a low cost, and on-going research appears to support a role for this agent in the pre-hospital setting. There is evolving evidence for the use of fibrinogen concentrates and cryoprecipitate, including within initial resuscitation. Further studies are required to determine the role for these agents either instead of, or in conjunction with, plasma. There is limited data to support the use of PCC in the trauma setting at present and care must be taken with potential risks, including the precipitation of disseminated intravascular coagulation. Factor VIIa should be reserved as a salvage intervention where life-threatening bleeding has been unresponsive to all other measures.

The ongoing development of algorithmic and viscoelastic testing-based approaches to the management of trauma-induced coagulopathy will permit targeted administration of these agents with consequent improvements in efficacy and safety. However, further studies are required to assess the cost-effectiveness of these approaches in trauma.

Keywords

Trauma Coagulopathy Fibrinogen rFVIIa Tranexamic acid Transfusion Haemostasis Cryoprecipitate Thromboembolism Procoagulant 

References

  1. 1.
    Fabes J, Barker G, Simons G, Curry N, Brunskill SJ, Doree C, Lin Y, McKechnie S, Stanworth S. Pro‐coagulant haemostatic factors for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2013;(7):CD010649.  https://doi.org/10.1002/14651858.CD010649.
  2. 2.
    Organisation WH. 20th WHO Model List of Essential Medicines. In, 2017.Google Scholar
  3. 3.
    Committee JF. British National Formulary (online). London: BMJ Group and Pharmaceutical Press.. http://www.medicinescomplete.com. [Accessed on 20.2.2018].
  4. 4.
    McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs. 2012;72:585–617.PubMedCrossRefGoogle Scholar
  5. 5.
    Shakur H, Roberts I, Bautista R, 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. 2010;376:23–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358:2319–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73:365–70; discussion 370.PubMedCrossRefGoogle Scholar
  8. 8.
    Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64:1211–7; discussion 1217.PubMedCrossRefGoogle Scholar
  9. 9.
    Raza I, Davenport R, Rourke C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11:307–14.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Davenport RA, Guerreiro M, Frith D, et al. Activated protein C drives the hyperfibrinolysis of acute traumatic coagulopathy. Anesthesiology. 2017;126:115–27.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Roberts I, Prieto-Merino D, Manno D. Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. Crit Care. 2014;18:685.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015:CD004896.Google Scholar
  13. 13.
    Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011:CD001886.Google Scholar
  14. 14.
    Gausden EB, Qudsi R, Boone MD, O’Gara B, Ruzbarsky JJ, Lorich DG. Tranexamic acid in orthopaedic trauma surgery: a meta-analysis. J Orthop Trauma. 2017;31:513–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015;261:390–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Roberts I, Perel P, Prieto-Merino D, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron FX, Roberts I. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet. 2018;391:125–32.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    National Institute for Health and Care Excellence (2016) Major trauma: assessment and initial management (NICE guideline 39). Available at: https://www.nice.org.uk/guidance/ng39 [Accessed 28/07/2018].
  19. 19.
    Moore HB, Moore EE, Huebner BR, et al. Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis. J Surg Res. 2017;220:438–43.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wafaisade A, Lefering R, Bouillon B, Bohmer AB, Gassler M, Ruppert M. Prehospital administration of tranexamic acid in trauma patients. Crit Care. 2016;20:143.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg. 2013;74:1575–86.PubMedCrossRefGoogle Scholar
  22. 22.
    Ausset S, Glassberg E, Nadler R, et al. Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: a critical appraisal of the medical literature and available alternatives. J Trauma Acute Care Surg. 2015;78:S70–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Stein P, Studt JD, Albrecht R, et al. The impact of prehospital tranexamic acid on blood coagulation in trauma patients. Anesth Analg. 2018;126:522–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, Thinkamrop B, Phuenpathom N, Lumbiganon P. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med. 2013;13:20.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Jokar A, Ahmadi K, Salehi T, Sharif-Alhoseini M, Rahimi-Movaghar V. The effect of tranexamic acid in traumatic brain injury: A randomized controlled trial. Chin J Traumatol. 2017;20:49–51.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Fakharian E, Abedzadeh-Kalahroudi M, Atoof F. Effect of tranexamic acid on prevention of hemorrhagic mass growth in patients with traumatic brain injury. World Neurosurg. 2018;109:e748–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Shiraishi A, Kushimoto S, Otomo Y, Matsui H, Hagiwara A, Murata K. Effectiveness of early administration of tranexamic acid in patients with severe trauma. Br J Surg. 2017;104:710–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Maegele M, Nardi G, Schochl H. Hemotherapy algorithm for the management of trauma-induced coagulopathy: the German and European perspective. Curr Opin Anaesthesiol. 2017;30:257–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American college of chest physicians task force. Chest. 2006;129:174–81.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17:1–79.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hamada SR, Gauss T, Pann J, Dunser M, Leone M, Duranteau J. European trauma guideline compliance assessment: the ETRAUSS study. Crit Care. 2015;19:423.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Grassin-Delyle S, Theusinger OM, Albrecht R, et al. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. Anaesthesia. 2018;73(6):719–29.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Royal College of Paediatrics and Child Health. Evidence statement. Major trauma and the use of tranexamic acid in children. [online]. Available at: http://www.rcpch.ac.uk/system/files/protected/page/121112_TXA%20evidence%20statement_final%20v2.pdf.
  35. 35.
    New Helen V, Berryman J, Bolton-Maggs Paula HB, et al. Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol. 2016;175:784–828.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Harvin JA, Peirce CA, Mims MM, et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78:905–9; discussion 909–911.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg. 2012;93:148–54.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77:811–7; discussion 817.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75:961–7; discussion 967.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Meizoso JP, Dudaryk R, Mulder MB, et al. Increased risk of fibrinolysis shutdown among severely injured trauma patients receiving tranexamic acid. J Trauma Acute Care Surg. 2018;84:426–32.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Harr JN, Moore EE, Chin TL, et al. Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early. Eur J Trauma Emerg Surg. 2015;41:49–56.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Inaba K, Rizoli S, Veigas PV, et al. 2014 consensus conference on viscoelastic test-based transfusion guidelines for early trauma resuscitation: report of the panel. J Trauma Acute Care Surg. 2015;78:1220–9.CrossRefGoogle Scholar
  43. 43.
    Neeki MM, Dong F, Toy J, et al. Efficacy and safety of tranexamic acid in prehospital traumatic hemorrhagic shock: outcomes of the Cal-PAT study. West J Emerg Med. 2017;18:673–83.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study) [online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02187120.
  45. 45.
    Dewan Y, Komolafe EO, Mejia-Mantilla JH, Perel P, Roberts I, Shakur H. CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials. 2012;13:87.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Prehospital Tranexamic Acid Use for Traumatic Brain Injury [online]. Available at: https://clinicaltrials.gov/ct2/show/record/NCT01990768.
  47. 47.
    Germans MR, Post R, Coert BA, Rinkel GJ, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials. 2013;14:143.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Flaherty K, Bath PM, Dineen R, et al. Statistical analysis plan for the ‘Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage’ (TICH-2) trial. Trials. 2017;18:607.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Rourke C, Curry N, Khan S, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342–51.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Brohi K, Eaglestone S. Traumatic coagulopathy and massive transfusion: improving outcomes and saving blood. Southampton; 2017.Google Scholar
  51. 51.
    Martini WZ. Fibrinogen metabolic responses to trauma. Scand J Trauma Resusc Emerg Med. 2009;17:2.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Levrat A, Gros A, Rugeri L, et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth. 2008;100:792–7.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Hagemo JS, Stanworth S, Juffermans NP, et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care. 2014;18:R52.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Schlimp CJ, Voelckel W, Inaba K, Maegele M, Ponschab M, Schochl H. Estimation of plasma fibrinogen levels based on hemoglobin, base excess and injury severity score upon emergency room admission. Crit Care. 2013;17:R137.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg. 1995;81:360–5.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Stinger HK, Spinella PC, Perkins JG, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma. 2008;64:S79–85; discussion S85.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: a five-year statewide cohort study. Injury. 2017;48:1074–81.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sorensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008;101:769–73.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Nienaber U, Innerhofer P, Westermann I, et al. The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury. 2011;42:697–701.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Stensballe J, Henriksen HH, Johansson PI. Early haemorrhage control and management of trauma-induced coagulopathy: the importance of goal-directed therapy. Curr Opin Crit Care. 2017;23:503–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Kozek-Langenecker S, Sorensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care. 2011;15:R239.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Chambers LA, Chow SJ, Shaffer LE. Frequency and characteristics of coagulopathy in trauma patients treated with a low- or high-plasma-content massive transfusion protocol. Am J Clin Pathol. 2011;136:364–70.PubMedCrossRefGoogle Scholar
  63. 63.
    Chowdary P, Saayman AG, Paulus U, Findlay GP, Collins PW. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol. 2004;125:69–73.PubMedCrossRefGoogle Scholar
  64. 64.
    Khan S, Brohi K, Chana M, et al. Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage. J Trauma Acute Care Surg. 2014;76:561–7; discussion 567-568.PubMedCrossRefGoogle Scholar
  65. 65.
    Khan S, Davenport R, Raza I, et al. Damage control resuscitation using blood component therapy in standard doses has a limited effect on coagulopathy during trauma hemorrhage. Intensive Care Med. 2015;41:239–47.PubMedCrossRefGoogle Scholar
  66. 66.
    Johnson JL, Moore EE, Kashuk JL, et al. Effect of blood products transfusion on the development of postinjury multiple organ failure. Arch Surg. 2010;145:973–7.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg. 2010;210:957–65.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Wong H, Curry N. Do we need cryoprecipitate in the era of fibrinogen concentrate and other specific factor replacement options? VOXS. 2018;13:23–8.  https://doi.org/10.1111/voxs.12376.CrossRefGoogle Scholar
  69. 69.
    Jensen NH, Stensballe J, Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review. Acta Anaesthesiol Scand. 2016;60:1033–42.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Olaussen A, Fitzgerald MC, Tan GA, Mitra B. Cryoprecipitate administration after trauma. Eur J Emerg Med. 2016;23:269–73.PubMedCrossRefGoogle Scholar
  71. 71.
    Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth. 2014;113:922–34.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Stanworth SJ, Davenport R, Curry N, et al. Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice. Br J Surg. 2016;103:357–65.PubMedCrossRefGoogle Scholar
  73. 73.
    Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115:76–83.PubMedCrossRefGoogle Scholar
  74. 74.
    Nascimento B, Callum J, Tien H, et al. Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. Br J Anaesth. 2016;117:775–82.PubMedCrossRefGoogle Scholar
  75. 75.
    Yamamoto K, Yamaguchi A, Sawano M, et al. Pre-emptive administration of fibrinogen concentrate contributes to improved prognosis in patients with severe trauma. Trauma Surg Acute Care Open. 2016;1:e000037.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Inokuchi K, Sawano M, Yamamoto K, Yamaguchi A, Sugiyama S. Early administration of fibrinogen concentrates improves the short-term outcomes of severe pelvic fracture patients. Acute Med Surg. 2017;4:271–7.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, et al. Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2016;30:1196–204.PubMedCrossRefGoogle Scholar
  78. 78.
    Mengoli C, Franchini M, Marano G, et al. The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis. Blood Transfus. 2017;15:318–24.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Aubron C, Reade MC, Fraser JF, Cooper DJ. Efficacy and safety of fibrinogen concentrate in trauma patients--a systematic review. J Crit Care. 2014;29:471 e411–77.Google Scholar
  80. 80.
    Lunde J, Stensballe J, Wikkelso A, Johansen M, Afshari A. Fibrinogen concentrate for bleeding--a systematic review. Acta Anaesthesiol Scand. 2014;58:1061–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Nardi G, Agostini V, Rondinelli B, et al. Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs. Crit Care. 2015;19:83.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Innerhofer P, Westermann I, Tauber H, et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury. 2013;44:209–16.PubMedCrossRefGoogle Scholar
  83. 83.
    Schlimp CJ, Voelckel W, Inaba K, Maegele M, Schochl H. Impact of fibrinogen concentrate alone or with prothrombin complex concentrate (+/− fresh frozen plasma) on plasma fibrinogen level and fibrin-based clot strength (FIBTEM) in major trauma: a retrospective study. Scand J Trauma Resusc Emerg Med. 2013;21:74.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Fries D, Innerhofer P, Perger P, et al. Coagulation management in trauma-related massive bleeding. - Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI). Anasthesiol Intensivmed Notfallmed Schmerzther. 2010;45:552–61.PubMedCrossRefGoogle Scholar
  85. 85.
    Nardi G, Agostini V, Rondinelli BM, et al. Prevention and treatment of trauma induced coagulopathy (TIC). An intended protocol from the Italian trauma update research group. J Anesthesiol Clin Sci. 2013;2Google Scholar
  86. 86.
    Meyer MA, Ostrowski SR, Windelov NA, Johansson PI. Fibrinogen concentrates for bleeding trauma patients: what is the evidence? Vox Sang. 2011;101:185–90.PubMedCrossRefGoogle Scholar
  87. 87.
    Okerberg CK, Williams LA, Kilgore ML, et al. Cryoprecipitate AHF vs. fibrinogen concentrates for fibrinogen replacement in acquired bleeding patients - an economic evaluation. Vox Sang. 2016;111:292–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Schochl 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.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Schochl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14:R55.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Gorlinger K, Fries D, Dirkmann D, Weber CF, Hanke AA, Schochl H. Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy. Transfusion medicine and hemotherapy : offizielles. Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2012;39:104–13.Google Scholar
  91. 91.
    Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Br J Anaesth. 2010;105:116–21.PubMedCrossRefGoogle Scholar
  92. 92.
    Collins PW, Solomon C, Sutor K, et al. Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Br J Anaesth. 2014;113:585–95.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Schochl H, Cotton B, Inaba K, et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Rizoli SB, Scarpelini S, Callum J, et al. Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma. 2011;71:S427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Mackie IJ, Kitchen S, Machin SJ, Lowe GD, Haematology HaTTFotBCfSi. Guidelines on fibrinogen assays. Br J Haematol. 2003;121:396–404.PubMedCrossRefGoogle Scholar
  96. 96.
    Schochl H, Maegele M, Solomon C, Gorlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med. 2012;20:15.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Harr JN, Moore EE, Ghasabyan A, et al. Functional fibrinogen assay indicates that fibrinogen is critical in correcting abnormal clot strength following trauma. Shock. 2013;39:45–9.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Solomon C, Groner A, Ye J, Pendrak I. Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. Thromb Haemost. 2015;113:759–71.PubMedCrossRefGoogle Scholar
  99. 99.
    Ettinger A, Miklauz MM, Bihm DJ, Maldonado-Codina G, Goodrich RP. Preparation of cryoprecipitate from riboflavin and UV light-treated plasma. Transfus Apher Sci. 2012;46:153–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Steinmetz J, Sorensen AM, Henriksen HH, et al. Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial. Trials. 2016;17:327.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Fibrinogen Concentrate (FGTW) in Trauma Patients, Presumed to Bleed (FI in TIC) [online]. Available at: https://clinicaltrials.gov/ct2/show/study/NCT01475344.
  102. 102.
    Winearls J, Wullschleger M, Wake E, et al. Fibrinogen Early In Severe Trauma studY (FEISTY): study protocol for a randomised controlled trial. Trials. 2017;18:241.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Early cryoprecipitate in major trauma haemorrhage: CRYOSTAT-2 [online]. Available at: http://www.isrctn.com/ISRCTN14998314.
  104. 104.
    Pati S, Potter DR, Baimukanova G, Farrel DH, Holcomb JB, Schreiber MA. Modulating the endotheliopathy of trauma: factor concentrate versus fresh frozen plasma. J Trauma Acute Care Surg. 2016;80:576–84; discussion 584-575.PubMedCrossRefGoogle Scholar
  105. 105.
    Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:2652–60.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Hagemo JS, Christiaans SC, Stanworth SJ, et al. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care. 2015;19:97.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Kashuk JL, Moore EE, Sawyer M, et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252:434–42; discussion 443-434.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Vigue B, Ract C, Tremey B, et al. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med. 2007;33:721–5.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622–31.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Joseph B, Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg. 2014;38:1875–81.PubMedCrossRefGoogle Scholar
  111. 111.
    Joseph B, Pandit V, Khalil M, et al. Use of prothrombin complex concentrate as an adjunct to fresh frozen plasma shortens time to craniotomy in traumatic brain injury patients. Neurosurgery. 2015;76:601–7; discussion 607.PubMedCrossRefGoogle Scholar
  112. 112.
    Younis M, Ray-Zack M, Haddad NN, et al. Prothrombin complex concentrate reversal of coagulopathy in emergency general surgery patients. World J Surg. 2018;42(8):2383–91.PubMedCrossRefGoogle Scholar
  113. 113.
    Joseph B, Khalil M, Harrison C, et al. Assessing the efficacy of prothrombin complex concentrate in multiply injured patients with high-energy pelvic and extremity fractures. J Orthop Trauma. 2016;30:653–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Ponschab M, Voelckel W, Pavelka M, Schlimp CJ, Schochl H. Effect of coagulation factor concentrate administration on ROTEM(R) parameters in major trauma. Scand J Trauma Resusc Emerg Med. 2015;23:84.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Tauber H, Innerhofer P, Breitkopf R, et al. Prevalence and impact of abnormal ROTEM(R) assays in severe blunt trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’. Br J Anaesth. 2011;107:378–87.PubMedCrossRefGoogle Scholar
  116. 116.
    Innerhofer P, Fries D, Mittermayr M, et al. Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial. Lancet Haematol. 2017;4:e258–71.CrossRefGoogle Scholar
  117. 117.
    Schochl H, Schlimp CJ, Maegele M. Tranexamic acid, fibrinogen concentrate, and prothrombin complex concentrate: data to support prehospital use? Shock. 2014;41(Suppl 1):44–6.PubMedCrossRefGoogle Scholar
  118. 118.
    Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates--evaluation of safety and thrombogenicity. Crit Care. 2011;15:201.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Schochl H, Voelckel W, Maegele M, Kirchmair L, Schlimp CJ. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care. 2014;18:R147.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Schochl H, Grottke O, Sutor K, et al. Theoretical modeling of coagulation management with therapeutic plasma or prothrombin complex concentrate. Anesth Analg. 2017;125:1471–4.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106:429–38.PubMedCrossRefGoogle Scholar
  122. 122.
    Grottke O, Braunschweig T, Spronk HM, et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–51.PubMedCrossRefGoogle Scholar
  123. 123.
    Majeed A, Eelde A, Agren A, Schulman S, Holmstrom M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res. 2012;129:146–51.PubMedCrossRefGoogle Scholar
  124. 124.
    Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12:R105.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45:1113–8; discussion 1118-1119.PubMedCrossRefGoogle Scholar
  126. 126.
    Sarode R, Milling TJ Jr, Refaai MA, 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;128:1234–43.PubMedCrossRefGoogle Scholar
  127. 127.
    Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev. 2003;17(Suppl 1):S1–5.PubMedCrossRefGoogle Scholar
  128. 128.
    Lewis NR, Brunker P, Lemire SJ, Kaufman RM. Failure of recombinant factor VIIa to correct the coagulopathy in a case of severe postpartum hemorrhage. Transfusion. 2009;49:689–95.PubMedCrossRefGoogle Scholar
  129. 129.
    Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma. 2003;55:886–91.PubMedCrossRefGoogle Scholar
  130. 130.
    Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69:489–500.PubMedCrossRefGoogle Scholar
  131. 131.
    Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005;59:8–15; discussion 15-18.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Harrison TD, Laskosky J, Jazaeri O, Pasquale MD, Cipolle M. “Low-dose” recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. J Trauma. 2005;59:150–4.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Stein DM, Dutton RP, Kramer ME, Handley C, Scalea TM. Recombinant factor VIIa: decreasing time to intervention in coagulopathic patients with severe traumatic brain injury. J Trauma. 2008;64:620–7; discussion 627-628.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Yao D, Li Y, Wang J, Yu W, Li N, Li J. Effects of recombinant activated factor VIIa on abdominal trauma patients. Blood Coagul Fibrinolysis. 2014;25:33–8.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Berkhof FF, Eikenboom JC. Efficacy of recombinant activated factor VII in patients with massive uncontrolled bleeding: a retrospective observational analysis. Transfusion. 2009;49:570–7.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Nascimento B, Lin Y, Callum J, Reis M, Pinto R, Rizoli S. Recombinant factor VIIa is associated with an improved 24-hour survival without an improvement in inpatient survival in massively transfused civilian trauma patients. Clinics (Sao Paulo). 2011;66:101–6.CrossRefGoogle Scholar
  137. 137.
    Morse BC, Dente CJ, Hodgman EI, et al. The effects of protocolized use of recombinant factor VIIa within a massive transfusion protocol in a civilian level I trauma center. Am Surg. 2011;77:1043–9.PubMedPubMedCentralGoogle Scholar
  138. 138.
    DeLoughery EP, Lenfesty B, DeLoughery TG. A retrospective case control study of recombinant factor VIIa in patients with intracranial haemorrhage caused by trauma. Br J Haematol. 2011;152:667–9.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Stein DM, Dutton RP, Kramer ME, Scalea TM. Reversal of coagulopathy in critically ill patients with traumatic brain injury: recombinant factor VIIa is more cost-effective than plasma. J Trauma. 2009;66:63–72; discussion 73-65.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    McQuay N Jr, Cipolla J, Franges EZ, Thompson GE. The use of recombinant activated factor VIIa in coagulopathic traumatic brain injuries requiring emergent craniotomy: is it beneficial? J Neurosurg. 2009;111:666–71.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Yuan Q, Wu X, Du ZY, et al. Low-dose recombinant factor VIIa for reversing coagulopathy in patients with isolated traumatic brain injury. J Crit Care. 2015;30:116–20.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Perel P, Roberts I, Shakur H, Thinkhamrop B, Phuenpathom N, Yutthakasemsunt S. Haemostatic drugs for traumatic brain injury. Cochrane Database Syst Rev. 2010:CD007877.Google Scholar
  143. 143.
    Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2012:CD005011.Google Scholar
  144. 144.
    Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg. 2008;248:61–8.PubMedCrossRefGoogle Scholar
  145. 145.
    Yank V, Tuohy CV, Logan AC, et al. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011;154:529–40.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Zatta A, McQuilten Z, Kandane-Rathnayake R, et al. The Australian and New Zealand Haemostasis registry: ten years of data on off-licence use of recombinant activated factor VII. Blood Transfus. 2015;13:86–99.PubMedPubMedCentralGoogle Scholar
  147. 147.
    MacLaren R, Weber LA, Brake H, Gardner MA, Tanzi M. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005;45:1434–42.PubMedCrossRefGoogle Scholar
  148. 148.
    Knudson MM, Cohen MJ, Reidy R, et al. Trauma, transfusions, and use of recombinant factor VIIa: a multicenter case registry report of 380 patients from the Western Trauma Association. J Am Coll Surg. 2011;212:87–95.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Mitra B, Cameron PA, Parr MJ, Phillips L. Recombinant factor VIIa in trauma patients with the ‘triad of death’. Injury. 2012;43:1409–14.CrossRefGoogle Scholar
  150. 150.
    Biss TT, Hanley JP. Use of recombinant factor VIIa (rFVIIa) in the management of intractable haemorrhage: a survey of current UK practice. Br J Haematol. 2007;138:126–8.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Payen JF, Berthet M, Genty C, et al. Reduced mortality by meeting guideline criteria before using recombinant activated factor VII in severe trauma patients with massive bleeding. Br J Anaesth. 2016;117:470–6.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Vincent JL, Rossaint R, Riou B, Ozier Y, Zideman D, Spahn DR. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding--a European perspective. Crit Care. 2006;10:R120.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Klitgaard T, Tabanera y Palacios R, Boffard KD, et al. Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding. Crit Care. 2006;10:R104.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Ranucci M, Isgro G, Soro G, Conti D, De Toffol B. Efficacy and safety of recombinant activated factor vii in major surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg. 2008;143:296–304; discussion 304.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Bain J, Lewis D, Bernard A, Hatton K, Reda H, Flynn J. Implementation of an off-label recombinant factor VIIa protocol for patients with critical bleeding at an academic medical center. J Thromb Thrombolysis. 2014;38:447–52.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Willis CD, Cameron PA, Phillips LE. Clinical guidelines and off-license recombinant activated factor VII: content, use, and association with patient outcomes. J Thromb Haemost. 2009;7:2016–22.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Rizoli SB, Boffard KD, Riou B, et al. Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials. Crit Care. 2006;10:R178.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Bucklin MH, Acquisto NM, Nelson C. The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding. Thromb Res. 2014;133:768–71.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–800.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Thomas GO, Dutton RP, Hemlock B, et al. Thromboembolic complications associated with factor VIIa administration. J Trauma. 2007;62:564–9.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of AnaesthesiaThe Royal Free HospitalLondonUK
  2. 2.NHS Blood and Transplant, Oxford University Hospitals NHS Trust, University of OxfordOxfordUK

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