The role of the endothelial glycocalyx in sepsis-induced coagulation

The National Heart, Lung, and Blood Institute awarded Worcester Polytechnic Institute $532,935 on August 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of the endothelial glycocalyx in sepsis-induced coagulopathy.

The research targets sepsis-associated coagulopathy, a condition characterized by uncontrolled thrombosis, large vessel occlusion, and stroke that resists traditional anticoagulation therapies. The project will examine how sepsis damages the endothelial glycocalyx—the protective layer surrounding blood vessel endothelial cells—and how this damage leads to release of von Willebrand factor into the bloodstream, triggering platelet recruitment and blood clotting. Three specific aims structure the work: defining molecular damage to the glycocalyx caused by direct endotoxin infection of endothelial cells and indirect damage from proinflammatory cytokines; determining which glycocalyx molecules cooperate with P-selectin to tether von Willebrand factor to the endothelial membrane; and testing whether glycocalyx regeneration using an existing or modified protocol can reduce symptoms of sepsis-associated coagulopathy in cell culture models. The laboratory will employ in vitro studies using human cells grown in a custom device to model lung vasculature and in vivo mouse models.

The period of performance runs through April 30, 2029. Work is performed in Worcester, Massachusetts. This is a Project Grant, the assistance type used by NIH to support discrete, circumscribed research projects.

Abstract

Sepsis-associated coagulopathy (SAC) is a symptom of sepsis that can cause uncontrolled thrombosis, large vessel occlusion, and stroke. SAC has resistance to traditional anticoagulation therapies, and there is an urgent need to understand how sepsis causes coagulopathy so that new therapies can be developed. IT is known that sepsis causes damage to endothelial cells that line blood vessels and to the protective layer of glycocalyx that surrounds these cells. Further, patients with severe SAC have a high concentration of the pro-coagulation molecule VON willebrand factor (VWF) in their blood. We hypothesize that the endothelial glycocalyx is damaged by direct endotoxin infection of endothelial cells and by the "cytokine storm" of proinflammatory molecules released from other cell types. We further hypothesize that, when the endothelial glycocalyx is damaged, the transmembrane molecule p-selectin is no longer able to tether VWF to the cell membrane, so VWF is released into the bloodstream to recruit platelets and cause blood clots. We will test these hypotheses using three specific aims. In specific aim 1, we will define the molecular damage to the glycocalyx caused by direct endotoxin infection of endothelial cells and indirect damage from proinflammatory cytokines. In specific aim 2, we will determine which molecules within the glycocalyx cooperate with p-selectin to tether VWF to the endothelial membrane. In specific aim 3, we will test whether we can reduce symptoms of SAC in cell culture models by regenerating the glycocalyx using a protocol we have already developed, or by using a modified protocol that incorporates knowledge gained from specific aims 1 and 2. Our laboratory has expertise in studying the endothelial glycocalyx in vitro (human cells grown in a custom-made device to model the lung vasculature) and in vivo (mouse models), and we have recruited collaborators and advisers with expertise in all other disciplines required to fulfill our proposed objectives. At the end of this project, we will have elucidated the role of the endothelial glycocalyx in sepsis-induced vascular pathologies and tested a prophylactic measure to reduce SAC damage to the vascular endothelium. This work is likely to offer a strong scientific framework whereby new therapeutic strategies can be developed for sepsis patients, and IT will have a lasting positive impact by demonstrating the usefulness of new physiologically relevant model systems. These studies will improve our ability to study sepsis in the future and, potentially, also improve our ability to study other diseases with the same clinical presentation as sepsis such as covid-19-associated coaugulation.