Cryoprecipitate Attenuates the Endotheliopathy of Trauma in Mice Subjected to Hemorrhagic Shock and Trauma.

BACKGROUND Plasma has been shown to mitigate the endotheliopathy of trauma (EOT). Protection of the endothelium may be due in part to fibrinogen and other plasma-derived proteins found in cryoprecipitate, however the exact mechanisms remain unknown. Clinical trials are underway investigating early cryoprecipitate administration in trauma. In this study, we hypothesize that cryoprecipitate will inhibit endothelial cell (EC) permeability in vitro and will replicate the ability of plasma to attenuate pulmonary vascular permeability and inflammation induced by hemorrhagic shock and trauma (HS/T) in mice. METHODS In vitro, barrier permeability of ECs subjected to thrombin challenge was measured by trans-endothelial electrical resistance. In vivo, using an established mouse model of HS/T, we compared pulmonary vascular permeability among mice resuscitated with 1) lactated Ringer's (LR), 2) fresh frozen plasma (FFP), or 3) cryoprecipitate. Lung tissue from the mice in all groups was analyzed for markers of vascular integrity, inflammation, and inflammatory gene expression via NanoString mRNA quantification. RESULTS Cryoprecipitate attenuates EC permeability and EC junctional compromise induced by thrombin in vitro in a dose-dependent fashion. In vivo, resuscitation of HS/T mice with either FFP or cryoprecipitate attenuates pulmonary vascular permeability (sham: 297±155, LR: 848±331, FFP: 379±275, cryoprecipitate: 405±207; p<0.01 sham vs. LR, p<0.01 LR vs. FFP, and p<0.05 LR vs. cryoprecipitate). Lungs from cryoprecipitate- and FFP-treated mice demonstrate decreased lung injury, decreased infiltration of neutrophils and activation of macrophages, and preserved pericyte-endothelial interaction compared to LR-treated mice. Gene analysis of lung tissue from cryoprecipitate- and FFP-treated mice demonstrates decreased inflammatory gene expression, in particular IL-1β and NLRP3, compared to LR-treated mice. CONCLUSION Our data suggest that cryoprecipitate attenuates the EOT in HS/T similar to FFP. Further investigation is warranted on active components and their mechanisms of action.