Tranexamic acid: is it about time?

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. In two large, randomised controlled trials, CRASH-2 and WOMAN, 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. The extensive data review of the Antifibrinolytic Trials Collaboration, reported in The Lancet, appears to confirm this temporal relationship. Angèle Gayet-Ageron and colleagues did a metaanalysis 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. 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. 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. However, at times, reduced inflammatory response might be deleterious. This perspective has been suggested by the Glue Grant investigations, 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. Can we create a physiological rationale for the strong signal favouring early administration of tranexamic acid identified by the Antifibrinolytic Trials Collaboration? One potential approach is consideration of patterns of fibrinolysis after injury. 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. Fibrinolytic state might be distinguished by rapid thromboelastography within 1 h of injury. 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. Despite very different patient groups, these observations are supported in both the CRASH-2 Published Online November 7, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)32806-4