Tranexamic acid: is it about time?
Authors: David J Dries
Journal: The Lancet (2017)

For decades, the antifibrinolytic drug tranexamic acid has been used for indications such as dental extractions in patients with haemophilia. Additionally, tranexamic acid has been widely used, although not routinely across the world, to reduce blood loss in surgery. More recently, the potential of tranexamic acid in trauma and post-partum haemorrhage has been of interest.1Pusateri AE Weiskopf RB Bebarta V et al.Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities.Shock. 2013; 39: 121-126Crossref PubMed Scopus (82) Google Scholar In two large, randomised controlled trials, CRASH-22CRASH-2 Trial CollaboratorsEffects 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: 23-32Summary Full Text Full Text PDF PubMed Scopus (2108) Google Scholar and WOMAN,3WOMAN Trial CollaboratorsEffect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.Lancet. 2017; 389: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (719) Google Scholar tranexamic acid reduced mortality from bleeding in patients with these conditions. One caution identified from these large trials is that mortality due to bleeding can be increased if tranexamic acid is given more than 3 h after injury.2CRASH-2 Trial CollaboratorsEffects 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: 23-32Summary Full Text Full Text PDF PubMed Scopus (2108) Google Scholar, 3WOMAN Trial CollaboratorsEffect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.Lancet. 2017; 389: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (719) Google Scholar The extensive data review of the Antifibrinolytic Trials Collaboration, reported in The Lancet, appears to confirm this temporal relationship.4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar Angèle Gayet-Ageron and colleagues4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar did a meta-analysis of individual patient-level data involving more than 40 000 patients from these two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Absence of death from bleeding was the primary measure of treatment benefit. From this dataset, the investigators examined the effect of treatment delay on mortality benefit by use of logistic regression models. Delaying tranexamic acid administration reduced treatment benefit, while immediate treatment improved survival from bleeding by more than 70% (odds ratio 1·72, 95% CI 1·42–2·10; p<0·0001) compared with later treatment. The benefit of tranexamic acid administration decreased by 10% for every 15 min of treatment delay until 3 h after the onset of haemorrhage, when there was no benefit.4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 5The CRASH-2 CollaboratorsThe importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.Lancet. 2011; 377: 1096-1101Summary Full Text Full Text PDF PubMed Scopus (794) Google Scholar Is the benefit seen with tranexamic acid reflected only in the control of bleeding? Effects beyond inhibition of fibrinolysis might be seen with tranexamic acid that are not reflected in coagulation panels.1Pusateri AE Weiskopf RB Bebarta V et al.Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities.Shock. 2013; 39: 121-126Crossref PubMed Scopus (82) Google Scholar Tranexamic acid binds to plasminogen and plasmin and exerts an antifibrinolytic action to reduce blood loss. Plasmin, a target of tranexamic acid, has a role in inflammation, angiogenesis, and wound healing. Tranexamic acid has protective effects on the endothelium and shows beneficial modulation of inflammation and other responses following ischaemia and reperfusion.1Pusateri AE Weiskopf RB Bebarta V et al.Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities.Shock. 2013; 39: 121-126Crossref PubMed Scopus (82) Google Scholar, 6Diebel LN Martin JV Liberati DM Early tranexamic acid administration ameliorates the endotheliopathy of trauma and shock in an in vitro model.J Trauma Acute Care Surg. 2017; 82: 1080-1086Crossref PubMed Scopus (27) Google Scholar However, at times, reduced inflammatory response might be deleterious. This perspective has been suggested by the Glue Grant investigations,7Thompkins RG Genomics of injury: the Glue Grant experience.J Trauma Acute Care Surg. 2015; 78: 671-686Crossref PubMed Scopus (55) Google Scholar which used a dataset obtained from 22 US trauma centres and examined the genomics of injury in a 12-year trial. Where genetic outcome differences were identified, these related to immune response. Adaptive immunity studies revealed suppression of genes involved in antigen presentation (eg, HLA-DR) and interferon-inducible genes. The genetic response pattern associated with best outcomes after injury favoured expression of pro-inflammatory interferon γ. One simple observation of these investigators is that, in appropriate patients, administration of interferon γ to enhance immune response should be considered.7Thompkins RG Genomics of injury: the Glue Grant experience.J Trauma Acute Care Surg. 2015; 78: 671-686Crossref PubMed Scopus (55) Google Scholar Can we create a physiological rationale for the strong signal favouring early administration of tranexamic acid identified by the Antifibrinolytic Trials Collaboration?4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar One potential approach is consideration of patterns of fibrinolysis after injury.8Napolitano LM Prehospital tranexamic acid: what is the current evidence?.Trauma Surg Acute Care Open. 2017; 2: 1-7Crossref Scopus (25) Google Scholar, 9Moore 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: 811-817Crossref PubMed Scopus (0) Google Scholar, 10Meizoso JP Karcutskie CA Ray JJ Namias N Schulman CI Proctor KG Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients.J Am Coll Surg. 2016; 224: 575-582Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 11Moore HB Moore EE Liras IN et al.Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severe injured patients.J Am Coll Surg. 2016; 222: 347-355Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar Patients sustaining injury of various kinds present with appropriate or physiological fibrinolysis, exaggerated or hyperfibrinolysis, or fibrinolysis shutdown. This observation has been made in both adults and children.9Moore 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: 811-817Crossref PubMed Scopus (0) Google Scholar, 10Meizoso JP Karcutskie CA Ray JJ Namias N Schulman CI Proctor KG Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients.J Am Coll Surg. 2016; 224: 575-582Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 12Leeper CM Neal MD McKenna CJ Gaines BA Trending fibrinolytic dysregulation: fibrinolysis shutdown in the days after injury is associated with poor outcome in severely injured children.Ann Surg. 2017; 266: 508-515Crossref PubMed Scopus (41) Google Scholar Fibrinolytic state might be distinguished by rapid thromboelastography within 1 h of injury.9Moore 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: 811-817Crossref PubMed Scopus (0) Google Scholar, 11Moore HB Moore EE Liras IN et al.Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severe injured patients.J Am Coll Surg. 2016; 222: 347-355Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar Patients with substantial bleeding who die early after injury tend to have hyperfibrinolysis where administration of tranexamic acid makes sense, consistent with the data of Gayet-Ageron and colleagues.4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 8Napolitano LM Prehospital tranexamic acid: what is the current evidence?.Trauma Surg Acute Care Open. 2017; 2: 1-7Crossref Scopus (25) Google Scholar, 9Moore 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: 811-817Crossref PubMed Scopus (0) Google Scholar Despite very different patient groups, these observations are supported in both the CRASH-2 and WOMAN trials.2CRASH-2 Trial CollaboratorsEffects 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: 23-32Summary Full Text Full Text PDF PubMed Scopus (2108) Google Scholar, 3WOMAN Trial CollaboratorsEffect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.Lancet. 2017; 389: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (719) Google Scholar Patients with severe brain injury or multi-organ trauma are more likely to present with shutdown of fibrinolysis than with massive bleeding.9Moore 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: 811-817Crossref PubMed Scopus (0) Google Scholar, 11Moore HB Moore EE Liras IN et al.Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severe injured patients.J Am Coll Surg. 2016; 222: 347-355Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar In these patients, administration of tranexamic acid might not be as effective. Thromboelastography is under investigation by the US military and multiple investigative centres.10Meizoso JP Karcutskie CA Ray JJ Namias N Schulman CI Proctor KG Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients.J Am Coll Surg. 2016; 224: 575-582Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 11Moore HB Moore EE Liras IN et al.Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severe injured patients.J Am Coll Surg. 2016; 222: 347-355Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 12Leeper CM Neal MD McKenna CJ Gaines BA Trending fibrinolytic dysregulation: fibrinolysis shutdown in the days after injury is associated with poor outcome in severely injured children.Ann Surg. 2017; 266: 508-515Crossref PubMed Scopus (41) Google Scholar, 13Prat NJ Meyer AD Ingalls NK et al.Rotational thromboelastometry significantly optimizes transfusion practices for damage control resuscitation in combat casualties.J Trauma Acute Care Surg. 2017; 83: 373-380Crossref PubMed Scopus (36) Google Scholar Thus, early administration of tranexamic acid appears to offer the best hope for a good outcome in a bleeding patient with hyperfibrinolysis. The effect of tranexamic acid on inflammation and other pathways in patients without active bleeding is less clear. It is also unclear whether thromboelastography will move out of the research laboratory and become a routine means of assessment for bleeding patients. A multitude of trials can be identified in registries, such as ClinicalTrials.gov from the US National Library of Medicine, reflecting ongoing work with tranexamic acid. At present, the careful study of Gayet-Ageron and coworkers suggests applicability of early administration of this agent in patients with substantial bleeding from multiple causes.4Gayet-Ageron A Prieto-Merino D Ker K et al.for the Antifibrinolytic Trials CollaborationEffect 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. 2017; (published online Nov 7.)http://dx.doi.org/10.1016/S0140-6736(17)32455-8Summary Full Text Full Text PDF PubMed Scopus (189) Google Scholar As data from additional trials with tranexamic acid become available, the spectrum of applications for this agent should become apparent. I declare no competing interests. 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 patientsDeath from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. Full-Text PDF Open Access