Title: Mechanism of action of Tranexamic Acid in isolated traumatic brain injury
Funder: Department of Health and Social Care

Abstract: Background: The CRASH-3 trial is an HTA/MRC funded multi-centre RCT of the effects of early administration of tranexamic acid (TXA) in traumatic brain injury (TBI). The trial has already enrolled over 3,000/10,000 subjects. Rationale for the mechanistic study: The CRASH-3 trial hypothesis is that TXA reduces death and disability by inhibiting fibrinolysis, thereby reducing intracranial bleeding. TXA crosses the blood brain barrier and its action is to block the lysine binding sites on plasminogen, thus inhibiting its binding to fibrin and its consequent break-down into fibrin degradation products. In addition to its role in fibrinolysis, the plasminogen-plasmin system has diverse non-fibrinolytic effects in the CNS, including on neuronal sprouting, neuro-plasticity, microglial activation, blood brain barrier permeability, excitotoxic injury and extracellular matrix-related neuronal death. We cannot assume that giving TXA will only affect intracranial bleeding: it could affect patient outcome though other important biological mechanisms mediated by neuroinflammation. TXA and neuroinflammation: The injured brain elicits a vigorous inflammatory response characterised by activation of glial cells, microglia and astrocytes and leucocyte infiltration. There is significant cross-talk between cyto/chemokines and plasminogen (which is widely expressed in the brain), with cytokines and plasmin creating a vicious cycle of tissue injury and increased neuroinflammation. By inhibiting plasminogen binding, TXA could have major anti-inflammatory effects in the CNS. Hypothesis: TXA has neuroprotective effects after TBI by reducing neuroinflammation. Study design: It is relatively straightforward to measure neuroinflammation after TBI by performing cerebral microdialysis (MD). This is a standard neuromonitoring technique in use in the three CRASH-3 substudy participating centres. MD allows the hourly sampling of brain extracellular fluid for metabolites of interest, including cytokines and markers of neural injury (glycerol, S100B, Glial Fibrillary Acidic Protein and Metalloproteinases), excitotoxicity (Glutamate) and metabolic dysfunction (lactate/pyruvate ratio). The daily levels and 5-day time course of brain cytokines will be compared between placebo and verum arms of CRASH-3 patients. Daily plasma cyto/chemokine measurements will simultaneously assess the systemic inflammatory response. An additional CT brain scan will be performed at 48-72h as part of routine clinical care to assess the antifibrinolytic effect of TXA with automated intracranial blood load measurements. Justification and importance: Inclusion in the current CRASH-3 trial is restricted to patients who have a moderate to severe TBI (measured by the Glasgow Coma Scale) or have evidence of intracranial bleeding on the initial CT scan. However, over 90% of TBI patients do not fit these criteria, yet suffer a high disability burden (ranging from 10% to 48% at 1 year in one study) due to a range of physical, cognitive, behavioural and emotional symptoms. If the neuroprotective mechanisms of TXA extended beyond its antifibrinolytic effects, potentially, a vastly larger proportion of the 1.4 million TBI patients treated every year in the UK alone, who do not have demonstrable intracranial bleeding on the scan, would benefit from this drug.

Lay abstract: Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. It disproportionately affects young people and low to middle-income countries, where it represents one of the main causes of loss of earning and destitution for millions of families. In the UK, TBI affects 1.4 million people a year, of whom a significant proportion will suffer long-term cognitive, physical, emotional and behavioural morbidity. Rationale: A head injury can damage the brain in many different ways, e.g. by bruising or tearing brain tissue or causing a blood vessel inside the brain to burst. This is called ‘intracranial bleeding’ and can cause pressure on the brain and damage brain tissue. The CRASH-3 trial is studying a drug, Tranexamic acid (TXA) that can potentially stem the intracranial bleeding by helping the blood clot better. TXA is safe and inexpensive, and has already been shown by the CRASH-2 trial to improve survival in major trauma not involving the head. CRASH-2 was similar to CRASH-3, except that it looked at all forms of trauma, whereas CRASH-3 specifically focuses on TBI. TXA works by preventing blood clots from breaking down after a bleed, but it is also known to have anti-inflammatory properties and other effects that can directly stop brain cells from dying. These other beneficial effects are seen even when there is no bleeding. CRASH-3 has already recruited 6,000 patients out of a target of 10,000 and its Data Monitoring Committee (responsible for monitoring the study, independent of the researchers) has looked at the data gathered so far (to which the researchers have no access to avoid biasing the study) and has specifically recommended that the researchers should investigate the way TXA might work, known as a ‘mechanistic’ study. For this reason, we will recruit 60 patients with a view to investigating the effects of TXA on brain inflammation and cell damage. Brain inflammation starts very soon after a brain injury and lingers for weeks, months and even years. Continuing inflammation of the brain is thought to be responsible for some of the long-term effects of TBI including early ageing of the brain, mental health consequences (e.g. depression or anxiety) and possibly epilepsy. Methods: To investigate the way TXA works on brain tissue we will measure certain chemicals released by the brain when it is injured. These chemicals can be used to measure the level of inflammation and damage of the brain, much in the same way certain blood tests can measure the health of the liver or kidneys. Except that brain inflammation cannot be measured with blood tests. Instead, we will need to perform a special technique called cerebral microdialysis (MD). MD involves inserting a very thin tube into the skull to sample chemicals released by the brain. This will happen while the patient is sedated in the Intensive Care. MD is an established procedure and is in routine use in the centres participating in this study. This will allow us to detect any differences in the way damaged brain tissue responds between patients randomised to receive either TXA or placebo. We will also look at the amount of blood on these patients' head CT (computed tomography) scans so that we can account for the effect of TXA on bleeding when we perform our analysis. Study objectives and importance: The insights provided by this project will generate new knowledge on the way the drug TXA works that can potentially allow the drug to be tested in a much wider group of TBI patients. This study has also been deemed 'essential' by our Patient Public Involvement (PPI) Group for Trauma.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS;NEUROLOGICAL