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The pathogenesis of <jats:styled-content style=\"fixed-case\">TIC<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">TIC<\/jats:styled-content> as well as produce insights into its pathophysiology. 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