Semin Thromb Hemost 2017; 43(2): 213-223
DOI: 10.1055/s-0036-1586226
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Tranexamic Acid for Trauma Resuscitation in the United States of America

Mark Walsh
1   Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Scott Thomas
1   Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana
,
Ernest Moore
3   Department of Surgery, Denver General Hospital, Denver, Colorado
,
Hunter Moore
3   Department of Surgery, Denver General Hospital, Denver, Colorado
,
Andres Piscoya
2   Indiana University School of Medicine, Indianapolis, Indiana
4   Division of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland
,
Daniel Hake
1   Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana
,
Michael Son
1   Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana
,
Tim Pohlman
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Julie Wegner
5   Midwestern University, Glendale, Arizona
,
John Bryant
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Alberto Grassetto
6   Departments of Anesthesia, Emergency, and Critical Care Medicine, Ospedale dell'Angelo di Mestre, Venice, Italy
,
Patrick Davis
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Nathan Nielsen
7   Division of Pulmonary Diseases, Critical Care and Environmental Medicine Tulane School of Medicine, New Orleans, Louisiana
,
Anton Crepinsek
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Jacob T. Shreve
1   Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana
2   Indiana University School of Medicine, Indianapolis, Indiana
,
Francis Castellino
8   W.M. Keck Center for Transgene Research, Notre Dame, Indiana
› Author Affiliations
Further Information

Publication History

Publication Date:
01 December 2016 (online)

Abstract

The utilization of tranexamic acid (TXA) for the management of bleeding trauma patients has been a subject of much debate on both sides of the Atlantic and in Australia. As a result of the large randomized controlled study called the Clinical Randomization of an Antifibrinolytic in Severe Hemorrhage (CRASH-2), there was an initial enthusiasm for the use of TXA to treat bleeding patients. However, the adoption of TXA in the United States was delayed by concerns of “knowledge and evidence gaps” of the CRASH-2 study and because of a lack of mechanistic rationale that would explain the survival benefit noted in the study. Subsequent nonrandomized controlled trials questioned the liberal use of TXA in trauma patients. This narrative review explores the historical as well as clinical and theoretical grounds for the more measured use of TXA in the United States and proposes a clinical and point-of-care guided utilization of TXA, blood components, and adjunctive hemostatic agents in bleeding trauma patients.

 
  • References

  • 1 Shakur H, Roberts I, Bautista R , 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
  • 2 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 (6) 1575-1586
  • 3 Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg 2012; 147 (2) 113-119
  • 4 Swendsen H, Galante J, Utter G , et al. Tranexamic acid use in trauma: effective but not without consequences. J Trauma Treat 2013; 2 (4) DOI: 10.4172/2167-1222.1000179.
  • 5 Valle EJ, Allen CJ, Van Haren RM , et al. Do all trauma patients benefit from tranexamic acid?. J Trauma Acute Care Surg 2014; 76 (6) 1373-1378
  • 6 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 (2) 390-394
  • 7 Cap AP, Baer DG, Orman JA, Aden J, Ryan K, Blackbourne LH. Tranexamic acid for trauma patients: a critical review of the literature. J Trauma 2011; 71 (1, Suppl): S9-S14
  • 8 Henry DA, Carless PA, Moxey AJ , et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 19 (4) CD001886
  • 9 Colman R. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006
  • 10 Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg 2010; 18 (3) 132-138
  • 11 Inaba K. Antifibrinolytics in trauma patients: does it MATTER?. Arch Surg 2012; 147 (2) 119
  • 12 Gruen RL, Jacobs IG, Reade MC ; PATCH-Trauma Study. Trauma and tranexamic acid. Med J Aust 2013; 199 (5) 310-311
  • 13 Brown JB, Neal MD, Guyette FX , et al. Design of the study of tranexamic acid during air medical prehospital transport (STAAMP) trial: addressing the knowledge gaps. Prehosp Emerg Care 2015; 19 (1) 79-86
  • 14 National Trauma Research Institute. Pre-hospital anti-fibrinolytics for traumatic coagulopathy and haemorrhage (the PATCH study). In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US).; 2000. [cited April 26, 2016]. Available at: https://clinicaltrials.gov/ct2/show/NCT02187120 NLM Identifier: NCT02187120
  • 15 Spinella P, Bochicchio G. Tranexamic acid mechanisms and pharmacokinetics in traumatic injury (TAMPITI trial). Washington University. Available at: http://tampiti.wustl.edu/ ; Accessed April 26, 2016
  • 16 University of Tennessee. Tranexamic acid in orthopaedic trauma surgery. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US).; 2000. [cited April 26, 2016]. Available at: https://clinicaltrials.gov/ct2/show/NCT02080494?term=Tennessee+tranexamic+acid+orthopedics&rank=1 NLM Identifier: NCT02080494
  • 17 Pusateri AE, Weiskopf RB, Bebarta V , et al; US DoD Hemorrhage and Resuscitation Research and Development Steering Committee. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock 2013; 39 (2) 121-126
  • 18 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 (6) 811-817 , discussion 817
  • 19 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 (5) 905-909 , discussion 909–911
  • 20 Zufferey PJ, Miquet M, Quenet S , et al; Tranexamic Acid in Hip-Fracture Surgery (THIF) Study. Tranexamic acid in hip fracture surgery: a randomized controlled trial. Br J Anaesth 2010; 104 (1) 23-30
  • 21 United States Army. Tactical combat casualty care guidelines. Available at: http://www.usaisr.amedd.army.mil/pdfs/TCCC_Guidelines_140602.pdf ; Accessed June 2, 2014
  • 22 Holcomb JB, Minei KM, Scerbo ML , et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg 2012; 256 (3) 476-486
  • 23 Tapia NM, Chang A, Norman M , et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg 2013; 74 (2) 378-385 , discussion 385–386
  • 24 Tapia N, Chang A, Norman M , et al. Hyperfibrinolysis on thromboelastogram (TEG) predicts mortality in massively transfused trauma patients. J Am Coll Surg 2012; 215 (3) S52
  • 25 Gonzalez E, Moore E, Moore H , et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg 2016; 263 (6) 1051-1059
  • 26 Kashuk JL, Moore EE, Sawyer M , et al. Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. Ann Surg 2010; 251 (4) 604-614
  • 27 Johansson P, Stissing T, Bochsen L, Otstrowski S. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. SJTREM 2009; 17: 45
  • 28 Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med 2012; 20 (15) 15
  • 29 Görlinger K, Fries D, Dirkmann D, Weber CF, Hanke AA, Schöchl H. Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy. Transfus Med Hemother 2012; 39 (2) 104-113
  • 30 Schöchl H, Maegele M, Voelckel W. Fixed ratio versus goal-directed therapy in trauma. Curr Opin Anaesthesiol 2016; 29 (2) 234-244
  • 31 Spahn DR, Bouillon B, Cerny V , et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17 (2) R76
  • 32 Spahn DR, Cerny V, Coats TJ , et al; Task Force for Advanced Bleeding Care in Trauma. Management of bleeding following major trauma: a European guideline. Crit Care 2007; 11 (1) R17
  • 33 Rossaint R, Bouillon B, Cerny V , et al; Task Force for Advanced Bleeding Care in Trauma. Management of bleeding following major trauma: an updated European guideline. Crit Care 2010; 14 (2) R52
  • 34 Schöchl 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 (2) R55
  • 35 Coleman WP, Benzel D, Cahill DW , et al. A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury. J Spinal Disord 2000; 13 (3) 185-199
  • 36 Schöchl H, Voelckel W, Grassetto A, Schlimp CJ. Practical application of point-of-care coagulation testing to guide treatment decisions in trauma. J Trauma Acute Care Surg 2013; 74 (6) 1587-1598
  • 37 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 (2) 365-370 , discussion 370
  • 38 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 (6) 961-967 , discussion 967
  • 39 Raza I, Davenport R, Rourke C , et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013; 11 (2) 307-314
  • 40 Dobson GP, Letson HL, Sharma R, Sheppard FR, Cap AP. Mechanisms of early trauma-induced coagulopathy: The clot thickens or not?. J Trauma Acute Care Surg 2015; 79 (2) 301-309
  • 41 Campbell JE, Meledeo MA, Cap AP. Comparative response of platelet fV and plasma fV to activated protein C and relevance to a model of acute traumatic coagulopathy. PLoS ONE 2014; 9 (6) e99181
  • 42 Cap A, Hunt BJ. The pathogenesis of traumatic coagulopathy. Anaesthesia 2015; 70 (Suppl. 01) 96-101 , e32–e34
  • 43 Moore HB, Moore EE, Liras IN , et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg 2016; 222 (4) 347-355
  • 44 Schöchl H, Cadamuro J, Seidl S , et al. Hyperfibrinolysis is common in out-of-hospital cardiac arrest: results from a prospective observational thromboelastometry study. Resuscitation 2013; 84 (4) 454-459
  • 45 de Fouw NJ, van Hinsbergh VW, de Jong YF, Haverkate F, Bertina RM. The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb Haemost 1987; 57 (2) 176-182
  • 46 Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating adrenaline levels at admission predict increased mortality after trauma. J Trauma Acute Care Surg 2012; 72 (2) 428-436
  • 47 Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 2011; 254 (2) 194-200
  • 48 Hrafnkelsdottir T, Gudnason T, Wall U, Jern C, Jern S. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost 2004; 2 (11) 1960-1968
  • 49 Hrafnkelsdóttir T, Ottosson P, Gudnason T, Samuelsson O, Jern S. Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension. Hypertension 2004; 44 (3) 300-304
  • 50 Burggraaf J, Schoemaker HC, Kroon JM, Huisman L, Kluft C, Cohen AF. Influence of 1-desamino-8-D-vasopressin on endogenous fibrinolysis, haemodynamics and liver blood flow in healthy subjects. Clin Sci (Lond) 1994; 86 (5) 497-503
  • 51 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007; 13 (6) 680-685
  • 52 Chapman MP, Moore EE, Moore HB , et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 2016; 80 (1) 16-23 , discussion 23–25
  • 53 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 (3) 434-442 , discussion 443–444
  • 54 Kutcher ME, Cripps MW, McCreery RC , et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma Acute Care Surg 2012; 73 (1) 87-93
  • 55 Chakrabarti R, Hocking ED, Fearnley GR. Reaction pattern to three stresses—electroplexy, surgery, and myocardial infarction—of fibrinolysis and plasma fibrinogen. J Clin Pathol 1969; 22 (6) 659-662
  • 56 Griffiths NJ. Factors affecting the fibrinolytic response to surgery. Ann R Coll Surg Engl 1979; 61 (1) 12-16
  • 57 Kluft C, Verheijen JH, Jie AF , et al. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45 (7) 605-610
  • 58 Ostrowski SR, Berg RM, Windeløv NA , et al. Discrepant fibrinolytic response in plasma and whole blood during experimental endotoxemia in healthy volunteers. PLoS ONE 2013; 8 (3) e59368
  • 59 Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost 2015; 13 (Suppl. 01) S82-S91
  • 60 Groth CG, Pechet L, Starzl TE. Coagulation during and after orthotopic transplantation of the human liver. Arch Surg 1969; 98 (1) 31-34
  • 61 Kang YG, Martin DJ, Marquez J , et al. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985; 64 (9) 888-896
  • 62 Fergusson DA, Hébert PC, Mazer CD , et al; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358 (22) 2319-2331
  • 63 Larsen OH, Fenger-Eriksen C, Ingerslev J, Sørensen B. Improved point-of-care identification of hyperfibrinolysis is needed. Thromb Res 2012; 130 (4) 690-691
  • 64 Ramos CR, Moore EE, Manco-Johnson ML, Silliman CC, Chapman MC, Banerjee A. The incidence and magnitude of fibrinolytic activation in trauma patients: a rebuttal. J Thromb Haemost 2013; 11 (7) 1435-1437
  • 65 Mutch N, Booth N. Plasmin-antiplasmin system. In: Gonzalez E, Moore H, Moore E, , eds. Trauma Induced Coagulopathy. 1st ed. Switzerland: Springer International Publishing; 2016: 31-51
  • 66 Schreiber M. Current practice of medicine for severe bleeding. Presented at: Product Development Program for Interventions in Severe Bleeding Due to Trauma or Other Causes; December 9, 2010; Masur Auditorium, Bldg. 10, National Institutes of Health, 8800 Rockville Pike, Bethesda, MD
  • 67 Walsh M, Fritz S, Hake D , et al. Targeted thromboelastographic (TEG) blood component and pharmacologic hemostatic therapy in traumatic and acquired coagulopathy. Curr Drug Targets 2016; 17 (8) 954-970
  • 68 Johansson PI, Stensballe J, Oliveri R, Wade CE, Ostrowski SR, Holcomb JB. How I treat patients with massive hemorrhage. Blood 2014; 124 (20) 3052-3058
  • 69 Dzik WH, Blajchman MA, Fergusson D , et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products—massive transfusion consensus conference 2011: report of the panel. Crit Care 2011; 15 (6) 242
  • 70 Spahn DR. TEG®- or ROTEM®-based individualized goal-directed coagulation algorithms: don't wait—act now!. Crit Care 2014; 18 (6) 637
  • 71 Holcomb JB, Tilley BC, Baraniuk S , et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015; 313 (5) 471-482
  • 72 McCurdy MT, Liew-Spilger A, Walsh M. Mortality and ratio of blood products used in patients with severe trauma. JAMA 2015; 313 (20) 2077-2078
  • 73 Dutton RP. Management of traumatic haemorrhage—the US perspective. Anaesthesia 2015; 70 (Suppl. 01) 108-111
  • 74 Schochl H, Voelckel HW, Schlimp CJ. Management of traumatic haemorrhage—the European perspective. Anaesthesia 2015; 70 (Suppl. 01) 102-107
  • 75 Moore EE, Moore HB, Gonzalez E , et al. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion 2016; 5 (Suppl. 02) S109-S114
  • 76 Roberts I. Fibrinolytic shutdown: fascinating theory but randomized controlled trial data are needed. Transfusion 2016; 56 (Suppl. 02) S115-S118