The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model

Abstract

BACKGROUND: Improved outcomes with early tranexamic acid (TXA) following trauma hemorrhagic shock (T/HS) may be related to its antifibrinolytic, as well as anti-inflammatory properties. Previous in vitro studies have shown that early TXA administration protects against T/HS endothelial barrier dysfunction and associated glycocalyx degradation. An intact endothelial glycocalyx may protect against subsequent neutrophil mediated tissue injury. We postulated that early TXA administration would mitigate against glycocalyx damage and resultant neutrophil adherence and transmigration through the endothelial barrier. This was studied in vitro using a microfluidic flow platform. METHODS:Human umbilical vein endothelial cell monolayers were subjected to control or shock conditions (hypoxia + epinephrine) followed by administration of TXA 90 minutes or 180 minutes later. RESULTS:"Early" TXA administration protected against glycocalyx degradation, biomarkers of increased permeability and the development of a fibrinolytic phenotype. This was associated with decreased neutrophil endothelial adherence and transmigration. There were no differences in low versus high TXA concentrations. The protective effects were only significant with "early" TXA administration. CONCLUSION: There was a concentration and temporal effect of TXA administration on endothelial glycocalyx degradation. This was associated with "vascular leakiness" as indexed by the relative ratio of Ang-2/1 and polymorphonuclear neutrophil transmigration. Tranexamic acid if administered in patients with T/HS should be administered "early"; this includes in the prehospital setting.

Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial

“…Advancements in trauma care increasingly recognize the importance of targeting the dynamic and complex nature of this host response to injury 4,34,35 . In in vitro and animal models of trauma, TXA has been shown to reduce glycocalyx degradation 20 and protect the endothelium 7,21 . Prehospital interventions impact the host response to injury and may specifically mitigate dysregulated endothelial and inflammatory processes 4,32 …”

“…In vitro and animal experiments have shown that TXA reduces syndecan-1 shedding 18 and protects the endothelial glycocalyx 19,20 . Importantly, these results may be sensitive to the dose and timing of TXA administration 15,21 . Tranexamic acid has also been shown to have beneficial effects on vascular permeability, inflammation, and glycocalyx degradation beyond antifibronolysis, highlighting several gaps in our mechanistic understanding of this drug 7 …”

Effect of tranexamic acid on endothelial von Willebrand factor/ADAMTS-13 response to in vitro shock conditions

“…Our earlier studies demonstrate that TXA at physiologically relevant concentrations reduce MMP and other cell related metalloproteinases in our in vitro microfluidic studies. 2 von Willebrand factor multimers secreted from activated endothelial cells may enter the circulation or remain anchored to the endothelial surface. P-selectin and dvβ3 integrins had been proposed as attachment points for vWF factors on the surface of the endothelium.…”

“…We have previously shown that tranexamic acid (TXA) protected the endothelial glycocalyx layer from degradation using a microfluidic model of the microcirculation subjected to hypoxia-reoxygenation (HR) and catecholamine excess. 2 We hypothesized that TXA administration following shock conditions would impact the vWF-ADAMTS-13 axis by protecting the glycocalyx from degradation. This was studied in an endothelial microfluidic flow study.…”

“…Endotheliopathy of trauma is caused by hypoperfusion and catecholamine excess, oxidative stress and subsequent inflammatory mediator production. 2 The endothelial glycocalyx layer is critical for endothelial barrier homeostasis. 3 These functions include a role in hemostasis, white blood cell adhesion and regulation of vascular permeability.…”