Patients with traumatic brain injury (TBI) and associated intracranial hemorrhage have high morbidity and mortality. Hematoma expansion after TBI occurs in part due to trauma coagulopathy related to hyperfibrinolysis,1 which occurs through various mechanisms that promote the activation of plasminogen to plasmin and subsequent fibrin degradation. These include the endothelial release of tissue plasminogen activator and activation of protein C.2
Tranexamic acid (TXA) is an inhibitor of fibrinolysis, a synthetic lysine analogue that blocks the activation of plasminogen to plasmin. Intravenous TXA has been shown in two randomized trials (>40,000 patients) to reduce death due to bleeding in scenarios driven by hyperfibrinolysis: postpartum hemorrhage (WOMAN3) and extracranial bleeding after trauma (CRASH-24). A patient-level meta-analysis of these trials demonstrated that the relative survival benefit of TXA decreased by 10 percent for each 15 minutes of treatment delay, with no benefit after three hours from injury or bleeding onset.5 There was no increase in the risk of seizures or thrombosis with TXA in either study.
The CRASH-3 study investigators examined the efficacy and safety of TXA in TBI. In this large multicenter randomized controlled trial, patients with TBI and reduced Glasgow Coma Scale (GCS of ≤12) or intracranial hemorrhage on computed tomography scan were randomized to receive TXA (1 g IV over 10 min., then 1 g infused over 8 hours) or placebo. Patients were initially enrolled within eight hours of injury. However, when the above data on early TXA administration were made available, the protocol was amended to enroll patients within three hours of injury such that 9,202 of the 12,737 total patients were included in the final analysis. The primary outcome was head-injury-related death within 28 days of injury in patients randomized within three hours. Safety outcomes included seizures and thrombotic events.
Among patients treated within three hours of TBI, the primary outcome occurred in 18.5 percent of the TXA group versus 19.8 percent with placebo (RR, 0.94; 95% CI, 0.86-1.02), which did not reach statistical significance. In a prespecified sensitivity analysis excluding patients with GCS lower than 3 or bilateral unreactive pupils, the results were 12.5 percent with TXA versus 14.0 percent with placebo (RR, 0.89; 95% CI, 0.89-1.00). However, the effects of TXA differed depending on the severity of head injury. In patients with mild to moderate TBI (GCS, 9-15), the primary outcome occurred significantly less frequently with TXA (5.8%) compared with placebo (7.5%; RR, 0.78; 95% CI, 0.64-0.95); there was no significant difference in severe TBI (GCS, 3-8).
In a regression analysis including all 12,737 participants, early (<3 hours) versus late (>3 hours) TXA administration did not significantly impact on survival at 28 days. However, early treatment with TXA was more effective than later treatment for reducing the primary outcome in patients with mild to moderate TBI (p=0.005), but not in severe TBI (p=0.73). There was no difference in the risk of adverse events including seizures and thrombotic complications.
Strengths of this trial included its large and international sample, prespecified sensitivity analysis, and relatively complete follow-up. Limitations included its wide confidence intervals despite large sample size, potential underestimates of thrombotic complications with a lack of screening diagnostic studies, and protocol changes affecting enrolment.
Although the benefit of TXA was not shown in the overall study population, there are important lessons to be taken from this trial. First, TXA reduces bleeding-related death in patients with mild to moderate TBI. Meanwhile, those with severe TBI have a poorer overall prognosis such that TXA is unlikely to improve outcomes. Second, it is important to act fast as the benefits of TXA in mild to moderate TBI are most pronounced if given within three hours, mirroring what was seen in postpartum hemorrhage and trauma-related extracranial bleeding. Finally, TXA used at low-moderate doses does not appreciably increase the risk of thrombosis or seizures. This is consistent with a substantial body of randomized evidence reflecting the safety of TXA and suggests it should be used as frontline therapy in addition to other hemostatic measures.
I look forward to future studies examining the use of laboratory measures of fibrinolysis to appropriately target antifibrinolytic therapies. Currently available viscoelastic techniques (such as TEG and ROTEM) appear to lack sufficient sensitivity for non-severe fibrinolytic defects, and there is an opportunity for the development of novel markers of fibrinolysis to guide therapy.6 Other priorities include examining the optimal dosing of TXA in bleeding patients, the role of pre-hospital TXA administration, and quality improvement initiatives for the expedient provision of TXA in trauma care.
Gall LS, Davenport TA. Fibrinolysis and antifibrinolytic treatment in the trauma patient. Curr Opin Anaesthesiol. 2018;31:227-233.
Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680-685.
WOMAN Trial Collaborators. Effect 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;389:2105-2116.
CRASH-2 trial collaborators, Shakur H, Roberts I, 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.
Gayet-Ageron A, Prieto-Merino D, Ker K, et al. 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;391:125-132.
Faraoni D, Levy JH. Tranexamic acid for acute hemorrhage: When is enough evidence enough?. Anesth Analg. 2019;129:1459-1461.
Conflict of Interests
Dr. Tseng indicated no relevant conflicts of interest.
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