Download PDF
Semin Thromb Hemost 2017; 43(2): 224-234
DOI: 10.1055/s-0036-1598001
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diagnosis and Treatment of Hyperfibrinolysis in Trauma (A European Perspective)

Lewis S. Gall
1   Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
,
Karim Brohi
1   Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
,
Ross A. Davenport
1   Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
20 February 2017 (online)

    Permissions and Reprints

Abstract

Fibrinolysis activation occurs almost universally after severe trauma. Systemic hyperfibrinolysis is a key component of acute traumatic coagulopathy and associated with poor clinical outcomes, although controversy exists over optimal treatment strategies. The mechanistic drivers and dynamics of fibrinolytic activation in response to injury and trauma resuscitation are currently unclear. Furthermore, therapeutic triggers are compounded by the lack of a sensitive and rapid diagnostic tool, with discrepancy between hyperfibrinolysis diagnosed by viscoelastic hemostatic assays versus biomarkers for fibrinolysis. Rotational thromboelastometry and thromboelastography appear capable of detecting the severest forms of hyperfibrinolysis but are relatively insensitive to moderate, yet clinically significant fibrinolytic activation. Rapid evaluation of the current status of the fibrinolytic system remains a challenge and therefore the decision whether to administer an antifibrinolytic agent should be based on available evidence from clinical trials. In line with current European guidelines, we recommend that all bleeding trauma patients, and in particular, severely injured patients with evidence of hemorrhagic shock, should receive early empiric tranexamic acid. This review explains our current knowledge of the pathophysiological pathways which induce hyperfibrinolysis in trauma hemorrhage, evaluates the available diagnostic modalities, and describes current treatment strategies.

Keywords

trauma - fibrinolysis - hemorrhage - coagulopathy - tranexamic acid
 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev 2015; 29 (1) 17-24
    CrossrefPubMedGoogle Scholar
  • 3 Brohi K, Cohen MJ, Ganter MT , et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008; 64 (5) 1211-1217 , discussion 1217
    CrossrefPubMedGoogle Scholar
  • 4 Davenport RA, Guerreiro M, Frith D , et al. Activated protein C drives the hyperfibrinolysis of acute traumatic coagulopathy. Anesthesiology 2017; 126 (1) 115-127
    CrossrefPubMedGoogle Scholar
  • 5 Kutcher ME, Redick BJ, McCreery RC , et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 2012; 73 (1) 13-19
    CrossrefPubMedGoogle Scholar
  • 6 Hunt BJ, Segal H. Hyperfibrinolysis. J Clin Pathol 1996; 49 (12) 958
    CrossrefPubMedGoogle Scholar
  • 7 Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60 (6, Suppl): S3-S11
    CrossrefPubMedGoogle Scholar
  • 8 Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A, Silliman CC. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion 2016; 56 (Suppl. 02) S110-S114
    CrossrefPubMedGoogle Scholar
  • 9 Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion 2009; 49 (12) 2652-2660
    CrossrefPubMedGoogle Scholar
  • 10 Levin EG, Loskutoff DJ. Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators. J Cell Biol 1982; 94 (3) 631-636
    CrossrefPubMedGoogle Scholar
  • 11 Levin EG, Santell L, Osborn KG. The expression of endothelial tissue plasminogen activator in vivo: a function defined by vessel size and anatomic location. J Cell Sci 1997; 110 (Pt 2): 139-148
    PubMedGoogle Scholar
  • 12 Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol 1994; 144 (5) 855-861
    PubMedGoogle Scholar
  • 13 Huber D, Cramer EM, Kaufmann JE , et al. Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo. Blood 2002; 99 (10) 3637-3645
    CrossrefPubMedGoogle Scholar
  • 14 Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol 1997; 139 (1) 245-256
    CrossrefPubMedGoogle Scholar
  • 15 Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord 2015; 15: 130
    CrossrefPubMedGoogle Scholar
  • 16 Van De Craen B, Declerck PJ, Gils A. The biochemistry, physiology and pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb Res 2012; 130 (4) 576-585
    CrossrefPubMedGoogle Scholar
  • 17 Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D. Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood 1994; 83 (2) 351-356
    CrossrefPubMedGoogle Scholar
  • 18 Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71 (1) 220-225
    CrossrefPubMedGoogle Scholar
  • 19 Booth NA, Simpson AJ, Croll A, Bennett B, MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1988; 70 (3) 327-333
    CrossrefPubMedGoogle Scholar
  • 20 Schleef RR, Sinha M, Loskutoff DJ. Immunoradiometric assay to measure the binding of a specific inhibitor to tissue-type plasminogen activator. J Lab Clin Med 1985; 106 (4) 408-415
    PubMedGoogle Scholar
  • 21 Brogren H, Karlsson L, Andersson M, Wang L, Erlinge D, Jern S. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood 2004; 104 (13) 3943-3948
    CrossrefPubMedGoogle Scholar
  • 22 Brogren H, Wallmark K, Deinum J, Karlsson L, Jern S. Platelets retain high levels of active plasminogen activator inhibitor 1. PLoS One 2011; 6 (11) e26762
    CrossrefPubMedGoogle Scholar
  • 23 Moore HB, Moore EE, Gonzalez E , et al. Hemolysis exacerbates hyperfibrinolysis, whereas platelolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock 2015; 43 (1) 39-46
    CrossrefPubMedGoogle Scholar
  • 24 Levi M, Biemond BJ, van Zonneveld AJ, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85 (1) 305-312
    CrossrefPubMedGoogle Scholar
  • 25 Mosnier LO, Buijtenhuijs P, Marx PF, Meijers JCM, Bouma BN. Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets. Blood 2003; 101 (12) 4844-4846
    CrossrefPubMedGoogle Scholar
  • 26 Mitchell JL, Lionikiene AS, Fraser SR, Whyte CS, Booth NA, Mutch NJ. Functional factor XIII-A is exposed on the stimulated platelet surface. Blood 2014; 124 (26) 3982-3990
    CrossrefPubMedGoogle Scholar
  • 27 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
    CrossrefPubMedGoogle Scholar
  • 28 Holcomb JB, Wade CE, Michalek JE , et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248 (3) 447-458
    PubMedGoogle Scholar
  • 29 Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg 2009; 197 (5) 565-570 , discussion 570
    CrossrefPubMedGoogle Scholar
  • 30 Whyte CS, Mitchell JL, Mutch NJ. Platelet-mediated modulation of fibrinolysis. Semin Thromb Hemost 2017; 43 (2) 115-128
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 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 (7) 1342-1351
    CrossrefPubMedGoogle Scholar
  • 32 Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54 (6) 1127-1130
    CrossrefPubMedGoogle Scholar
  • 33 Floccard B, Rugeri L, Faure A , et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury 2012; 43 (1) 26-32
    CrossrefPubMedGoogle Scholar
  • 34 Davenport R, Khan S. Management of major trauma haemorrhage: treatment priorities and controversies. Br J Haematol 2011; 155 (5) 537-548
    CrossrefPubMedGoogle Scholar
  • 35 Davenport RA, Brohi K. Cause of trauma-induced coagulopathy. Curr Opin Anaesthesiol 2016; 29 (2) 212-219
    CrossrefPubMedGoogle Scholar
  • 36 Boldt J, Papsdorf M, Rothe A, Kumle B, Piper S. Changes of the hemostatic network in critically ill patients--is there a difference between sepsis, trauma, and neurosurgery patients?. Crit Care Med 2000; 28 (2) 445-450
    CrossrefPubMedGoogle Scholar
  • 37 Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma 2005; 58 (3) 475-480 , discussion 480–481
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost 2001; 27 (6) 585-592
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Innes D, Sevitt S. Coagulation and fibrinolysis in injured patients. J Clin Pathol 1964; 17: 1-13
    CrossrefPubMedGoogle Scholar
  • 41 Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet J-F. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway?. Ann Surg 2007; 245 (5) 812-818
    CrossrefPubMedGoogle Scholar
  • 42 Cohen MJ, Call M, Nelson M , et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 2012; 255 (2) 379-385
    CrossrefPubMedGoogle Scholar
  • 43 Cohen MJ, Kutcher M, Redick B , et al; PROMMTT Study Group. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg 2013; 75 (1) (Suppl. 01) S40-S47
    CrossrefPubMedGoogle Scholar
  • 44 Chesebro BB, Rahn P, Carles M , et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 2009; 32 (6) 659-665
    CrossrefPubMedGoogle Scholar
  • 45 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007; 13 (6) 680-685
    CrossrefPubMedGoogle Scholar
  • 46 Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet J-F. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma 2007; 63 (6) 1254-1261 , discussion 1261–1262
    CrossrefPubMedGoogle Scholar
  • 47 Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011; 254 (1) 10-19
    CrossrefPubMedGoogle Scholar
  • 48 Gando S, Wada H, Thachil J ; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost 2013; 11 (5) 826-835
    CrossrefPubMedGoogle Scholar
  • 49 Kooistra T, Schrauwen Y, Arts J, Emeis JJ. Regulation of endothelial cell t-PA synthesis and release. Int J Hematol 1994; 59 (4) 233-255
    PubMedGoogle Scholar
  • 50 Bärtsch P, Haeberli A, Hauser K, Gubser A, Straub PW. Fibrinogenolysis in the absence of fibrin formation in severe hypobaric hypoxia. Aviat Space Environ Med 1988; 59 (5) 428-432
    PubMedGoogle Scholar
  • 51 Hayakawa M, Sawamura A, Gando S , et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery 2011; 149 (2) 221-230
    CrossrefPubMedGoogle Scholar
  • 52 Gando S. Acute coagulopathy of trauma shock and coagulopathy of trauma: a rebuttal. You are now going down the wrong path. J Trauma 2009; 67 (2) 381-383
    CrossrefPubMedGoogle Scholar
  • 53 Viersen VA, Greuters S, Korfage AR , et al. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation 2012; 83 (12) 1451-1455
    CrossrefPubMedGoogle Scholar
  • 54 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
    CrossrefPubMedGoogle Scholar
  • 55 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
    CrossrefPubMedGoogle Scholar
  • 56 von Känel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol 2000; 65 (6) 357-369
    CrossrefPubMedGoogle Scholar
  • 57 Kowalski E, Kopec M, Niewiarowski S. An evaluation of the euglobulin method for the determination of fibrinolysis. J Clin Pathol 1959; 12 (3) 215-218
    CrossrefPubMedGoogle Scholar
  • 58 Boudjeltia KZ, Cauchie P, Remacle C , et al. A new device for measurement of fibrin clot lysis: application to the euglobulin clot lysis time. BMC Biotechnol 2002; 2: 8
    CrossrefPubMedGoogle Scholar
  • 59 Katz J, Lurie A, Becker D, Metz J. The euglobulin lysis time test: an ineffectual monitor of the therapeutic inhibition of fibrinolysis. J Clin Pathol 1970; 23 (6) 529-532
    CrossrefPubMedGoogle Scholar
  • 60 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
    CrossrefPubMedGoogle Scholar
  • 61 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
    CrossrefPubMedGoogle Scholar
  • 62 Ostrowski SR, Sørensen AM, Larsen CF, Johansson PI. Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study. Scand J Trauma Resusc Emerg Med 2011; 19: 64
    CrossrefPubMedGoogle Scholar
  • 63 Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE. Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 2014; 41 (6) 514-521
    CrossrefPubMedGoogle Scholar
  • 64 Lisman T. Decreased plasma fibrinolytic potential as a risk for venous and arterial thrombosis. Semin Thromb Hemost 2016; DOI: 10.1055/s-0036-1585081.
    PubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 Carroll RC, Craft RM, Langdon RJ , et al. Early evaluation of acute traumatic coagulopathy by thrombelastography. Transl Res 2009; 154 (1) 34-39
    CrossrefPubMedGoogle Scholar
  • 67 Jeger V, Zimmermann H, Exadaktylos AK. Can RapidTEG accelerate the search for coagulopathies in the patient with multiple injuries?. J Trauma 2009; 66 (4) 1253-1257
    CrossrefPubMedGoogle Scholar
  • 68 Davenport R, Manson J, De'Ath H , et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011; 39 (12) 2652-2658
    CrossrefPubMedGoogle Scholar
  • 69 Inaba K, Rizoli S, Veigas PV , et al; Viscoelastic Testing in Trauma Consensus Panel. 2014 Consensus conference on viscoelastic test-based transfusion guidelines for early trauma resuscitation: report of the panel. J Trauma Acute Care Surg 2015; 78 (6) 1220-1229
    CrossrefPubMedGoogle Scholar
  • 70 National Institute for Health and Care Excellence (NICE). Major trauma: assessment and initial management. Guideline 39. 2016 . Available at: www.nice.org.uk/guidance/ng39 . Accessed September 11, 2016
    PubMedGoogle Scholar
  • 71 Hunt H, Stanworth S, Curry N , et al. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev 2015; 2 (2) CD010438
    PubMedGoogle Scholar
  • 72 Gonzalez E, Moore EE, Moore HB , 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
    CrossrefPubMedGoogle Scholar
  • 73 TACTIC partners. iTACTIC Trial: Implementing Treatment Algorithms for the Correction of Trauma Induced Coagulopathy. Available at: www.tacticgroup.dk/ . Accessed September 11, 2016
    PubMedGoogle Scholar
  • 74 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
    CrossrefPubMedGoogle Scholar
  • 75 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 (6) 792-797
    CrossrefPubMedGoogle Scholar
  • 76 Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009; 67 (1) 125-131
    CrossrefPubMedGoogle Scholar
  • 77 Theusinger OM, Wanner GA, Emmert MY , et al. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg 2011; 113 (5) 1003-1012
    CrossrefPubMedGoogle Scholar
  • 78 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 (3) 378-387
    CrossrefPubMedGoogle Scholar
  • 79 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
    CrossrefPubMedGoogle Scholar
  • 80 Ives C, Inaba K, Branco BC , et al. Hyperfibrinolysis elicited via thromboelastography predicts mortality in trauma. J Am Coll Surg 2012; 215 (4) 496-502
    CrossrefPubMedGoogle Scholar
  • 81 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
    PubMedGoogle Scholar
  • 82 Dekker SE, Viersen VA, Duvekot A , et al. Lysis onset time as diagnostic rotational thromboelastometry parameter for fast detection of hyperfibrinolysis. Anesthesiology 2014; 121 (1) 89-97
    CrossrefPubMedGoogle Scholar
  • 83 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
    CrossrefPubMedGoogle Scholar
  • 84 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
    CrossrefPubMedGoogle Scholar
  • 85 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
    CrossrefPubMedGoogle Scholar
  • 86 Pommerening MJ, Goodman MD, Farley DL , et al. Early diagnosis of clinically significant hyperfibrinolysis using thrombelastography velocity curves. J Am Coll Surg 2014; 219 (6) 1157-1166
    CrossrefPubMedGoogle Scholar
  • 87 Leebeek FWG, Rijken DC. The fibrinolytic status in liver diseases. Semin Thromb Hemost 2015; 41 (5) 474-480
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Harr JN, Moore EE, Chin TL , et al. Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early. Eur J Trauma Emerg Surg 2015; 41 (1) 49-56
    CrossrefPubMedGoogle Scholar
  • 89 Moore HB, Moore EE, Chapman MP , et al. Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients. J Thromb Haemost 2015; 13 (10) 1878-1887
    CrossrefPubMedGoogle Scholar
  • 90 Lang T, von Depka M. Possibilities and limitations of thrombelastometry/-graphy [in German]. Hamostaseologie 2006; 26 (3) (Suppl. 01) S20-S29
    Article in Thieme ConnectPubMedGoogle Scholar
  • 91 Maegele M, Lefering R, Yucel N , et al; AG Polytrauma of the German Trauma Society (DGU). Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007; 38 (3) 298-304
    CrossrefPubMedGoogle Scholar
  • 92 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
    CrossrefPubMedGoogle Scholar
  • 93 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
    CrossrefPubMedGoogle Scholar
  • 94 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
    CrossrefPubMedGoogle Scholar
  • 95 Moore HB, Moore EE, Morton AP , et al. Shock-induced systemic hyperfibrinolysis is attenuated by plasma-first resuscitation. J Trauma Acute Care Surg 2015; 79 (6) 897-903 , discussion 903–904
    CrossrefPubMedGoogle Scholar
  • 96 Vulliamy P, Gillespie S, Gall L, Brohi K, Davenport RA. Platelet transfusions reduce fibrinolysis but do not restore platelet function during trauma hemorrhage. J Trauma Acute Care Surg 2013; 3: 1 DOI: 10.1186/2110-5820-3-1.
    CrossrefPubMedGoogle Scholar
  • 97 McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs 2012; 72 (5) 585-617
    CrossrefPubMedGoogle Scholar
  • 98 Dubber AH, McNicol GP, Douglas AS, Melander B. Some properties of the antifibrinolytically active isomer of amino-methylcyclohexane carboxylic acid. Lancet 1964; 2 (7373): 1317-1319
    PubMedGoogle Scholar
  • 99 Verstraete M. Haemostatic Drugs: A Critical Appraisal, 1st ed. The Hague: Martinus Nijhoff; 1977: 132
    CrossrefGoogle Scholar
  • 100 Okamoto S, Sato S, Takada Y, Okamoto U. An active stereo-isomer (trans-form) of amcha and its antifibrinolytic (antiplasminic) action in vitro and in vivo. Keio J Med 1964; 13: 177-185
    CrossrefPubMedGoogle Scholar
  • 101 Henry D, Carless P, Moxey AJ , et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011; 3: CD001886
    PubMedGoogle Scholar
  • 102 Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012; 344: e3054
    CrossrefPubMedGoogle Scholar
  • 103 Dewan Y, Komolafe EO, Mejía-Mantilla JH, Perel P, Roberts I, Shakur H ; CRASH-3 Collaborators. 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
    CrossrefPubMedGoogle Scholar
  • 104 Roberts I, Coats T, Edwards P , et al. HALT-IT--tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials 2014; 15: 450
    CrossrefPubMedGoogle Scholar
  • 105 Shakur H, Elbourne D, Gülmezoglu M , et al. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials 2010; 11: 40
    CrossrefPubMedGoogle Scholar
  • 106 Roberts I, Perel P, Prieto-Merino D , et al; CRASH-2 Collaborators. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 2012; 345: e5839
    CrossrefPubMedGoogle Scholar
  • 107 Perel P, Prieto-Merino D, Shakur H, Roberts I. Development and validation of a prognostic model to predict death in patients with traumatic bleeding, and evaluation of the effect of tranexamic acid on mortality according to baseline risk: a secondary analysis of a randomised controlled trial. Health Technol Assess 2013; 17 (24) 1-45 , v–vi
    PubMedGoogle Scholar
  • 108 Ker K, Kiriya J, Perel P, Edwards P, Shakur H, Roberts I. Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial. BMC Emerg Med 2012; 12: 3
    CrossrefPubMedGoogle Scholar
  • 109 Guerriero C, Cairns J, Perel P, Shakur H, Roberts I ; CRASH 2 trial collaborators. Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS One 2011; 6 (5) e18987
    CrossrefPubMedGoogle Scholar
  • 110 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 (10) 1-79
    PubMedGoogle Scholar
  • 111 Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg 2013; 148 (3) 218-225
    CrossrefPubMedGoogle Scholar
  • 112 Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev 2015; 5 (5) CD004896
    PubMedGoogle Scholar
  • 113 Klein AA, Arnold P, Bingham RM , et al. AAGBI guidelines: the use of blood components and their alternatives 2016. Anaesthesia 2016; 71 (7) 829-842
    CrossrefPubMedGoogle Scholar
  • 114 Rossaint R, Bouillon B, Cerny V , et al; STOP Bleeding Campaign. The STOP the Bleeding Campaign. Crit Care 2013; 17 (2) 136
    CrossrefPubMedGoogle Scholar
  • 115 Roberts I, Shakur H, Afolabi A , et al; CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377 (9771): 1096-1101 , 1101.e1–1101.e2
    CrossrefPubMedGoogle Scholar
  • 116 Jimenez JJ, Iribarren JL, Lorente L , et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care 2007; 11 (6) R117
    CrossrefPubMedGoogle Scholar
  • 117 Godier A, Roberts I, Hunt BJ. Tranexamic acid: less bleeding and less thrombosis?. Crit Care 2012; 16 (3) 135
    CrossrefPubMedGoogle Scholar
  • 118 Hijazi N, Abu Fanne R, Abramovitch R , et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood 2015; 125 (16) 2558-2567
    CrossrefPubMedGoogle Scholar
  • 119 Medcalf RL. The traumatic side of fibrinolysis. Blood 2015; 125 (16) 2457-2458
    CrossrefPubMedGoogle Scholar
  • 120 Faught C, Wells P, Fergusson D, Laupacis A. Adverse effects of methods for minimizing perioperative allogeneic transfusion: a critical review of the literature. Transfus Med Rev 1998; 12 (3) 206-225
    CrossrefPubMedGoogle Scholar
  • 121 Zufferey P, Merquiol F, Laporte S , et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery?. Anesthesiology 2006; 105 (5) 1034-1046
    CrossrefPubMedGoogle Scholar
  • 122 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
    CrossrefPubMedGoogle Scholar
  • 123 European Medicines Agency. Press release February 17, 2012 . Available at: www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/02/news_detail_001447.jsp&mid=WC0b01ac058004d5c1 . Accessed September 10, 2016
    PubMedGoogle Scholar
  • 124 Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331 (24) 1601-1606
    CrossrefPubMedGoogle Scholar
  • 125 Selby R, Geerts W, Ofosu FA , et al. Hypercoagulability after trauma: hemostatic changes and relationship to venous thromboembolism. Thromb Res 2009; 124 (3) 281-287
    CrossrefPubMedGoogle Scholar
  • 126 Poeran J, Rasul R, Suzuki S , et al. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ 2014; 349: g4829
    CrossrefPubMedGoogle Scholar