Trauma associated haemorrhage accounts for 40% of all injury related mortality. Patients with major bleeding die early, with almost three quarters of mortality among bleeding trauma patients occurring within the first six hours of injury either in the prehospital setting or upon arrival to hospital. Acute Traumatic Coagulopathy (ATC) occurs within minutes after injury, exacerbates bleeding and is associated with worse clinical outcomes including increased mortality after major trauma. Hyperfibrinolysis (HF) is a key component of ATC and can be effectively treated with pharmacological interventions such as the antifibrinolytic drug Tranexamic Acid (TXA). National Institute of Care Excellence (NICE) guidelines recommend TXA in patients who are bleeding, or at risk of bleeding and have Systolic Blood Pressure (SBP) less than 90 mmHg and/or Heart Rate (HR) greater than 110 beats per minute. The NHS currently endorses the use of TXA immediately following injury and has recently modified the Trauma Best Practice Tariff to incentivise TXA administration within one hour of injury, which is typically the responsibility of pre-hospital (PH) care crews. The overall objective of this thesis was to systematically examine the evidence for PH TXA use, evaluate the use of PH TXA in a national trauma system, and finally investigate the effect of TXA both functionally and through biomarker analysis of admission blood samples taken from trauma patients who did or did not receive the drug prior to arrival at hospital. The evidence for PH TXA administration and mortality reduction in trauma haemorrhage was assessed by conducting a systematic review and meta-analysis. Four studies were included in the review and meta-analysis which identified a survival benefit in patients who received PH TXA vs those who did not (No TXA) with a significant reduction in 24-hour mortality; Odds Ratio (OR) 0.60 (95% CI: 0.37 – 0.99; p=0.05). There was no statistical difference for 28 or 30 days mortality OR 0.69 (95% CI: 0.47-1.02; p=0.06), nor the incidence of VTE OR 1.49 (95% CI: 0.90 - 2.46; p=0.12). Real world use of PH TXA and compliance with treatment guidelines was investigated by analysis of data from the UK Trauma Audit & Research Network for patients eligible for TXA treatment, and who were admitted to a Major Trauma Centre in England and Wales. The data was divided into two cohorts: 2013-2015 (n=32,072) and 2017-2019 (n=14,974) to assess temporal changes following introduction of TXA to PH treatment guidelines after publication of the CRASH-2 trial in 2010. PH TXA use increased from eight percent to 27% over the study period (p<0.001). Only three percent of eligible patients who fell <2m received PH TXA vs. 63% in patients with penetrating injuries (p<0.001). Older patients were less likely to receive TXA than younger patients; 20 years old: OR 1.14 (0.84-1.6), 40 years old: OR 0.88 (0.66-1.29), 60 years old: OR 0.68 (0.43-1.08), 80 years old: OR 0.52 (0.30-0.90). There was significant interaction between age and sex with fewer older women receiving PH TXA. In shocked patients, older people eligible for TXA were less likely to be treated: ≥65 years: n=263 (34%) vs <65 years: n=1655 (60%) (p<0.001). The description of the admission functional coagulation and fibrinolytic biomarkers profiles in patients exposed to PH TXA compared to No PH TXA was investigated by a retrospective analysis of a perpetual observational cohort study at a single-major trauma centre. 450 patients were included into the study who were shocked and/or had received a blood transfusion. Patients were divided into three groups PH TXA: 184 patients, No PH TXA: 266 (ED TXA: 53 patients; and no TXA: 213 patients). There were no significant differences in injury variables, age or shock status between PH TXA and no PH TXA patients, other than GCS, PH TXA, GCS<8: 38% vs no PH TXA, GCS<8 (24%) (p<0.001) and marginally higher ISS in PH TXA patients: 30 (IQR: 22 – 43) vs no PH TXA patients 27 (IQR: 17-36) (p<0.001). There was significant difference in the incidence of ATC: PH TXA, INR>1.2: 38% vs no PH TXA, INR >1.2: 21% (p<0.001), and MHP activations: PH TXA, MHP: 82% vs no PH TXA, MHP 49% (p<0.001). 178 (97%) of PH TXA patients received RBC transfusion with a median of 12 units (IQR: 6 – 21), compared to 228 (86%) of no PH TXA patients who on average received RBC 8 units (IQR: 3 – 16) (p= 0.003). Over half of patients who received PH TXA presented with ML Low admission and only one percent of patients had ROTEM defined hyperfibrinolysis (ML>15%). Regardless of TXA treatment all fibrinolytic biomarkers were elevated significantly above normal values. There was no difference between TXA treatment groups for D Dimer, PAP, PAI-1 or Plasminogen. A2-AP level was lower on admission in PH TXA patients with a median of 69 IU/dL (IQR: 50 – 86) compared to No PH TXA with a median of 97 IU/dL (IQR: 80 – 117) (p<0.001). tPA level was higher in PH TXA patients with a median of 24 ng/ml (17 – 39); compared to No PH TXA with a median of 19 (11 – 29) (p= 0.002). Age (β: 0.302; p= 0.002), sex (male) (β: -0.244; p= 0.010), tPA (β: 0.299; p= 0.002), and PAI-1 (β: -0.191; p= 0.041) were independent variables that significantly were associated with admission PAP values. For admission D dimer values, only ISS (β: 0.150; p= 0.043) and AIS head ≥3 (β: -0.192; p= 0.015) were significant independent variables. Admission ML was independently associated with admission t-PA (β: 0.199; p= 0.008) with a strong trend for PH TXA (β: -1.128; p= 0.139) The thesis has shown that PH TXA significantly reduces 24-hour mortality. TXA is safe and does not increase VTE for survivors. On a national level, there is a clear implementation gap between evidence-based guidelines for PH TXA administration, and universal administration for all eligible bleeding patients. It is clear that some specific patient populations are far less likely to not receive this intervention i.e. low energy trauma and older patients than others. Finally, PH TXA alters functional and biomarker profiles of bleeding trauma patients demonstrating significant modulation of fibrinolysis soon after administration.

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