Trauma induces a plethora of biochemical and physiologic changes, including activation of both procoagulant and anticoagulant mechanisms. Several, non-mutually exclusive hypotheses have been proposed as the underlying etiology of TIC, but causative mechanisms are currently unclear. Additionally, the relationship between laboratory-based evidence of TIC, upon which most research efforts are based, and clinically-evident coagulopathic bleeding has not been adequately investigated. TIC, trauma-induced coagulopathy; tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; APC, activated protein C; EGL, endothelial glycocalyx layer. Reproduced from Blood 2016;128(8):1043–9. Used with permission.