Injury-induced endotheliopathy: What you need to know

Abstract

The endotheliopathy of trauma involves a complex interplay between the glycocalyx, von Willebrand factor, and platelets that leads to abnormalities in coagulation, inflammation, and endothelial cell (EC) function. The current review presents a synopsis of EC function under homeostatic conditions, the structure and function of the endothelial glycocalyx; mechanisms of EC injury and activation after trauma; pathological consequences of the EoT at the cellular level; and clinical implications of the EoT. Recent evidence is presented that links the EoT to extracellular vesicles and hyperadhesive ultralarge von Willebrand factor multimers through their roles in coagulopathy. Lastly, potential therapeutics to mitigate the EoT are discussed. Most research to date has focused on blood products, primarily plasma, and its contribution to restoring postinjury EC dysfunction. Additional therapeutic adjuvants that target the glycocalyx, ultralarge von Willebrand factor, low ADAMTS-13, and pathologic extracellular vesicles are reviewed. Much of the pathobiology of EoT is known, but a better mechanistic understanding can help guide therapeutics to further repair the EoT and improve patient outcomes.

Figure 1.. Endothelial mechanisms that regulate coagulation, inflammation, and vascular barrier integrity.

Endothelial cells control activation of the coagulation system by balancing both pro- and anticoagulant and fibrinolytic processes. Key anticoagulant mechanisms include 1) expression of heparan sulfates which are bound to a syndecan core and bind antithrombin (AT) to inhibit thrombin (IIa); 2) expression of thrombomodulin (TM) and endothelial protein C receptor (EPCR), which cooperatively generate activated protein C (aPC); and 3) expression of tissue factor pathway inhibitor (TFPI), which suppresses thrombin generation through inhibition of the tissue factor (TF):factor VIIa (FVIIa) complex. Endothelial cells can potently activate the coagulation system through secretion of von Willebrand Factor (vWF), which tethers platelets to the subendothelium and expresses TF. Clot dissolution is regulated through expression of pro-fibrinolytic enzymes tissue and urokinase plasminogen activators (tPA and uPA, respectively) and antifibrinolytic plasminogen activator inhibitor type 1 (PAI-1). Endothelial cells prevent adhesion and activation of circulating platelets and immune cells through secretion of nitric oxide (NO) and prostacyclin (PGI₂). They can also selectively mediate cellular adhesion through expression of selectins and intracellular or vascular adhesion molecules (ICAM-1 and VCAM-1, respectively). Endothelial barrier function is regulated by the transcellular pathway through calveolae and the paracellular pathway through expression of gap, adherens, and tight junctional proteins. (Image created with BioRender.com.)

Figure 2.. Endothelial glycocalyx structure and function during healthy and post-injury states.

Under healthy conditions, the endothelial glycocalyx is composed of proteoglycans (syndecans) and glycoproteins (CD44 and glypican) that are interconnected by an array of glycosaminoglycans (GAG), including heparan sulfate, hyaluronan, and chondroitin sulfate. When intact, the glycocalyx functionally suppresses production of thrombin (IIa) from prothrombin (II), prevents platelet and leukocyte adhesion to the endothelial surface, and regulates molecular transport and transduction of shear stress signals. However, following major injury and hemorrhagic shock, syndecan and GAGs are enzymatically cleaved from the cell surface by sheddases resulting in release of these fragments into circulation. Loss of the endothelial glycocalyx layer contributes to coagulation at the cell surface, loss of vascular barrier integrity, and leukocyte adhesion and transmigration. (Image created with BioRender.com.)