Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock.

Shibani Pati,Rosemary A Kozar,Zhanglong Peng,Byron Miyazawa,Daniel R Potter,Katherine Wataha,Raghavan Raju

doi:10.1371/journal.pone.0192363

Abstract

In severe trauma and hemorrhage the early and empiric use of fresh frozen plasma (FFP) is associated with decreased morbidity and mortality. However, utilization of FFP comes with the significant burden of shipping and storage of frozen blood products. Dried or lyophilized plasma (LP) can be stored at room temperature, transported easily, reconstituted rapidly with ready availability in remote and austere environments. We have previously demonstrated that FFP mitigates the endothelial injury that ensues after hemorrhagic shock (HS). In the current study, we sought to determine whether LP has similar properties to FFP in its ability to modulate endothelial dysfunction in vitro and in vivo. Single donor LP was compared to single donor FFP using the following measures of endothelial cell (EC) function in vitro: permeability and transendothelial monolayer resistance; adherens junction preservation; and leukocyte-EC adhesion. In vivo, using a model of murine HS, LP and FFP were compared in measures of HS- induced pulmonary vascular inflammation and edema. Both in vitro and in vivo in all measures of EC function, LP demonstrated similar effects to FFP. Both FFP and LP similarly reduced EC permeability, increased transendothelial resistance, decreased leukocyte-EC binding and persevered adherens junctions. In vivo, LP and FFP both comparably reduced pulmonary injury, inflammation and vascular leak. Both FFP and LP have similar potent protective effects on the vascular endothelium in vitro and in lung function in vivo following hemorrhagic shock. These data support the further development of LP as an effective plasma product for human use after trauma and hemorrhagic shock.

Highlights

It is estimated there are over 5 million deaths per year due to traumatic injury, many of which occur from uncontrolled bleeding. [1] Hemorrhage remains the number one cause of early trauma deaths and the primary cause of potentially preventable deaths in both military and civilian settings
Which include the early, and empiric use of plasma in a balanced ratio with packed red cells have reduced early mortality. [2,3,4,5,6,7,8] This decrease in mortality is thought to be more than just a reduction in bleeding related deaths and is hypothesized to involve the protective effects of plasma to an injured and impaired endothelium, termed the “endotheliopathy of trauma (EoT).” [9,10] Clinically this is manifested as a pro-inflammatory state with vessel hyperpermability and tissue edema, all of which can result in organ failures and late deaths
fresh frozen plasma (FFP) and lyophilized plasma (LP) preserve EC adherens junctions on activated endothelial cells To further understand at the molecular level the effects of LP and FFP on endothelial junctional stability, we investigated the adherens junctions

Summary

Introduction

It is estimated there are over 5 million deaths per year due to traumatic injury, many of which occur from uncontrolled bleeding. [1] Hemorrhage remains the number one cause of early trauma deaths and the primary cause of potentially preventable deaths in both military and civilian settings. LP attenuates vascular permeability, inflammation and lung injury in HS which include the early, and empiric use of plasma in a balanced ratio with packed red cells have reduced early mortality. Over the past few years pre-clinical and clinical studies have suggested that the mechanism may not be solely related to hemostasis, and due in part to its ability to globally promote systemic vascular stability, defined by decreased endothelial cell (EC) permeability, decreased inflammation in the lungs and systemically as well as improved hemodynamic stabilization following hemorrhagic shock. [19,20,21,22,23,24,25] Plasma and plasma products have been shown to decrease endothelial cell permeability, inflammation, and lung injury both in vitro and in vivo and may contribute to improved outcomes [10,11,12,13,14,15,16,17,18] Restoration of the glycocalyx may improve outcomes after trauma and hemorrhagic shock by attenuating leukocyte-EC adhesion, platelet adhesion, and inflammatory cytokine binding by establishing a physical barrier between the blood and EC barrier. [19,20,21,22,23,24,25] Plasma and plasma products have been shown to decrease endothelial cell permeability, inflammation, and lung injury both in vitro and in vivo and may contribute to improved outcomes [10,11,12,13,14,15,16,17,18]

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