Survival after severe traumatic shock can be complicated by a number of pathophysiologic processes that ensue after the initial trauma. One of these is trauma-induced coagulopathy (TIC) whose onset may occur before initial fluid resuscitation. The pathogenesis of TIC has not yet been fully elaborated, but evolving evidence appears to link severe tissue hypoxia and damage to the endothelium as key factors, which evolve into measurable structural and biochemical changes of the endothelium resulting in a coagulopathic state. This paper will provide a general review of these linkages and identify knowledge gaps as well as suggest new approaches and areas of investigation, which may both limit the development of TIC as well as produce insights into its pathophysiology. A better understanding of these issues will be necessary in order to advance the practice of remote damage control resuscitation.