Background: Severe injury activates the sympathoadrenal, hemostatic and inflammatory systems, but a maladapted response may contribute to poor outcome. Soluble CD40L is a platelet derived mediator that links inflammation, hemostasis and vascular dysfunction. Objectives: To investigate the association between the sCD40L level and tissue injury, shock, coagulopathy and mortality in trauma patients. Methods: Prospective, observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS) and 30-day mortality were recorded and admission plasma/serum analyzed for sCD40L and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments (hcDNA), Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (PF1.2, TAT-complex, antithrombin, protein C, activated Protein C, sEPCR, TFPI, vWF, fibrinogen, FXIII), fibrinolysis (D-dimer, tPA, PAI-1) and inflammation (IL-6, sC5b-9). We compared patients stratified by median sCD40L level and investigated predictive values of sCD40L for mortality. Results: High circulating sCD40L was associated with enhanced tissue and endothelial damage (ISS, hcDNA, Annexin V, syndecan-1, sTM), shock (pH, SBE), sympathoadrenal activation (adrenaline) and coagulopathy evidenced by reduced thrombin generation (PF1.2), hyperfibrinolysis (D-dimer), increased APTT and inflammation (IL-6) (all p