Cryoprecipitate attenuates the endotheliopathy of trauma in mice subjected to hemorrhagic shock and trauma

Abstract

BACKGROUND: Plasma has been shown to mitigate the endotheliopathy of trauma. 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 transendothelial 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 solution (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 messenger RNA 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 with 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 with LR-treated mice. CONCLUSION: Our data suggest that cryoprecipitate attenuates the endotheliopathy of trauma in HS/T similar to FFP. Further investigation is warranted on active components and their mechanisms of action.

Targeting repair of the vascular endothelium and glycocalyx after traumatic injury with plasma and platelet resuscitation

“…Furthermore, plasma that was deprived of fibrinogen lost its protective effects [108] . In vivo in a mouse model of hemorrhagic shock, cryoprecipitate, which is used to replete fibrinogen in massively bleeding patients, replicated many of the effects of FFP in mitigating pulmonary vascular permeability and inflammation in the lung [94] . Fibrinogen concentrate also preserved pulmonary syndecan-1 mRNA and decreased alveolar protein permeability after hemorrhagic shock in a similar model [109] .…”

“…In addition to mitigating endothelial glycocalyx breakdown, plasma has protective effects on adherens junctions, which are intercellular junctions that control vascular permeability to plasma proteins [91] , [92] , [93] . Plasma but not LR preserves adherens junctions on endothelial cells challenged with vascular endothelial growth factor (VEGF) or thrombin as well as in the pulmonary vasculature in mice after hemorrhagic shock [43] , [94] , [95] . The globally stabilizing effects of plasma resuscitation on the vasculature and organ systems are depicted in Fig.…”

“…It is likely that the combination of multiple factors and peptides in plasma contributes to its vasculoprotective effects in hemorrhagic shock. Interestingly, other products that are derived from plasma, such as four-factor prothrombin complex concentrate (which contains high concentrations of factors II, VII, IX, and X, and proteins C and S) and cryoprecipitate (which contains high concentrations of fibrinogen, von Willebrand factor, factor VIII, factor XIII, and fibronectin) likely contain many of these same proteins and have also been shown to mitigate the EOT and lung injury in mouse models of hemorrhagic shock and trauma [94] , [103] .…”

Clinical Benefits of Early Concurrent use of Cryoprecipitate and Plasma Compared with Plasma only in Bleeding Trauma Patients: Analysis of the Trauma Quality Improvement Program Database

“…The immunomodulatory effects of plasma also might have affected patient outcomes. Plasma and cryoprecipitate made from plasma contain various important proteins such as endothelial glycocalyx, bronectin, and platelet microparticles, in addition to clotting factors, which have important biologic functions and are said to regulate vascular permeability [35,36]. Although the concentrations of these immunomodulatory proteins in cryoprecipitate have not been well-studied, potential differences in the amount of administered plasma proteins between cryoprecipitate and FFP could be a possible explanation for the observed differences in the outcomes.…”

The Pathophysiology and Management of Hemorrhagic Shock in the Polytrauma Patient

“…Other coagulation factors enriched in cryo include von Willebrand factor, FVIII, and FXIII, and these plausibly contribute to hemostatic resuscitation. Recent in vitro and in vivo data suggest that cryo potentially attenuates the endotheliopathy induced by hemorrhagic shock [ 164 ].…”