Early tranexamic acid administration ameliorates the endotheliopathy of trauma and shock in an in vitro model

BACKGROUND: Systemic vascular endothelial injury is a consequence of trauma (T)/hemorrhagic shock (HS) which results in disturbances of coagulation, inflammation, and endothelial barrier integrity. The effect of T/HS on the endothelium (endotheliopathy of trauma [EoT]) is of intense research interest and may lead to EoT-directed therapies. Administration of tranexamic acid (TXA) in trauma patients is associated with a survival benefit and fewer complications if given early after injury. Mechanisms for this protective effect include the antifibrinolytic and anti-inflammatory effects of TXA. We hypothesized that "early" administration of TXAwould abrogate vascular endothelial cell activation and injury after T/HS. This was studied in vitro. METHODS: Confluent human umbilical vein endothelial cells were exposed to hydrogen peroxide and/or epinephrine to stimulate post-T/HS oxidant exposure and/or sympathoadrenal activation. TXAwas added 15 minutes, 60 minutes, or 120 minutes after H₂O₂ and/or epinephrine challenge. Endothelial cell injury was indexed by cell monolayer permeability, intracellular adhesion molecule expression, soluble thrombomodulin, syndecan release (marker for glycocalyx injury), tissue type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and angiopoietin-2/angiopoietin-1 ratio (APO-2/APO-1). RESULTS: Endothelial activation and injury as indexed by permeability, ICAM expression, soluble thrombomodulin were increased by H₂O₂ and/or epinephrine exposure. Biomarkers of endothelial coagulation profile (tPA/PAI-1) demonstrated a profibrinolytic profile (increased tPA and tPA/PAI-1 ratio) after challenge by H₂O₂ and/or epinephrine. Vascular "leakiness" as indexed by APO-2/APO-1 ratio was also evident. The most profound effects were noted with H₂O₂/epinephrine exposure. TXA administration within 60 minutes of H2O2/epinephrine challenge abolished the adverse effects noted on the endothelial-glycocalyx "double barrier." TXA administration after 60 minutes was not protective. CONCLUSION: Antifibrinolytic and other protective effects of TXA administration on endothelial injury are time-dependent. This study supports the concept that the clinical efficacy of TXA administration requires "early administration.