Clinical data has supported the early use of plasma in high ratios of plasma to red cells to patients in hemorrhagic shock. The benefit from plasma seems to extend beyond its hemostatic effects to include protection to the post-shock dysfunctional endothelium. Resuscitation of the endothelium by plasma and one of its major constituents, fibrinogen, involves cell surface stabilization of syndecan-1, a transmembrane proteoglycan and the protein backbone of the endothelial glycocalyx. The pathogenic role of miRNA-19b to the endothelium is explored along with the PAK-1-mediated intracellular pathway that may link syndecan-1 to cytoskeletal protection. Additionally, clinical studies using fibrinogen and cyroprecipitate to aid in hemostasis of the bleeding patient are reviewed and new data to suggest a role for plasma and its byproducts to treat the dysfunctional endothelium associated with nonbleeding diseases is presented.