BACKGROUND: No FDA-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS: Data were extracted from a placebo-controlled clinical trial in which patients ≥15 years old with TBI (Glascow Coma Scale 3-12) and systolic blood pressure ≥90 mmHg were randomized prehospital to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1g TXA infusion (Bolus Maintenance [BM]); or 2g TXA bolus/placebo infusion (Bolus Only [BO]). TEG was performed and coagulation measures including prothrombin time (PT), activated partial thromboplastin time (aPTT), international ratio (INR), fibrinogen, D-dimer, plasmin anti-plasmin (PAP), thrombin anti-thrombin (TAT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were quantified at admission and six hours later. RESULTS: Of 966 patients receiving study drug, 700 had labs drawn at admission and six hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p>0.05). No differences between PT, aPTT, INR, fibrinogen, TAT, tPA, and PAI-1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at six hours (p<0.001). Concentrations of PAP were less in TXA treatment groups than placebo on admission (p<0.001) and six hours (p=0.02). No differences in D-dimer and PAP were observed between BM and BO. CONCLUSION: While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared to placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and six hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE: III; Diagnostic.