The temporal response and mechanism of action of tranexamic acid in endothelial glycocalyx degradation.

Background: The endothelial glycocalyx (GCX) plays an important role in vascular barrier function. Damage to the GCX occurs due to a variety of causes including hypoxia, ischemia-reperfusion, stress related sympathoadrenal activation, and inflammation. Tranexamic acid (TXA) may prevent GCX degradation. The therapeutic window for TXA administration and the mechanism of action has been under review. Membrane-anchored proteases (sheddases) are key components in endothelial cell biology including the regulation of vascular permeability. The effect of TXA administration on stress related GCX damage and the role of sheddases in this process was studied in a cell-based model. Methods: Confluent human umbilical vein endothelial cells (HUVEC) were exposed to hydrogen peroxide and/or epinephrine (EPI) to stimulate post-shock reperfusion. TXA was added at various times after H2O2 and/or EPI exposure. GCX degradation was indexed by syndecan-1 and hyaluronic acid release. Activation of endothelial sheddases was indexed by ADAM-17 and MMP-9 activity in culture supernatants. Results: Exposure of HUVEC to either/both epinephrine and H2O2 resulted in a cellular stress and glycocalyx disruption demonstrated by increased levels of syndecan-1 shedding, hyaluronic acid release, TNF-[alpha] release. Shedding of these glycocalyx components was associated with increased activity of both ADAM-17 and MMP. Disruption of the glycocalyx was further demonstrated via fluorescent imaging, which demonstrated disruption following exposure to either/both H2O2 and epinephrine. Early administration of either TXA or doxycycline resulted in preservation of the glycocalyx. Late administration of TXA had no effect while doxycycline had some residual protective effect. Conclusion: TXA as a serine protease inhibitor prevented GCX degradation via inhibition of endothelial sheddase activation. This effect was not apparent when TXA was administered >60 minutes after "simulated" reperfusion. Our study supports the clinical practice of early TXA administration in the severely injured patient. Level of Evidence: Not applicable (C) 2017 Lippincott Williams & Wilkins, Inc.

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