Browsing by Subject "Glycocalyx"

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    Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction
    (MDPI, 2017-03-29) Wodicka, James R.; Chambers, Andrea M.; Sangha, Gurneet S.; Goergen, Craig J.; Panitch, Alyssa; Medicine, School of Medicine
    Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.
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    SHock-INduced Endotheliopathy (SHINE): A mechanistic justification for viscoelastography-guided resuscitation of traumatic and non-traumatic shock
    (Frontiers Media, 2023-02-27) Bunch, Connor M.; Chang, Eric; Moore, Ernest E.; Moore, Hunter B.; Kwaan, Hau C.; Miller, Joseph B.; Al-Fadhl, Mahmoud D.; Thomas, Anthony V.; Zackariya, Nuha; Patel, Shivani S.; Zackariya, Sufyan; Haidar, Saadeddine; Patel, Bhavesh; McCurdy, Michael T.; Thomas, Scott G.; Zimmer, Donald; Fulkerson, Daniel; Kim, Paul Y.; Walsh, Matthew R.; Hake, Daniel; Kedar, Archana; Aboukhaled, Michael; Walsh, Mark M.; Graduate Medical Education, School of Medicine
    Irrespective of the reason for hypoperfusion, hypocoagulable and/or hyperfibrinolytic hemostatic aberrancies afflict up to one-quarter of critically ill patients in shock. Intensivists and traumatologists have embraced the concept of SHock-INduced Endotheliopathy (SHINE) as a foundational derangement in progressive shock wherein sympatho-adrenal activation may cause systemic endothelial injury. The pro-thrombotic endothelium lends to micro-thrombosis, enacting a cycle of worsening perfusion and increasing catecholamines, endothelial injury, de-endothelialization, and multiple organ failure. The hypocoagulable/hyperfibrinolytic hemostatic phenotype is thought to be driven by endothelial release of anti-thrombogenic mediators to the bloodstream and perivascular sympathetic nerve release of tissue plasminogen activator directly into the microvasculature. In the shock state, this hemostatic phenotype may be a counterbalancing, yet maladaptive, attempt to restore blood flow against a systemically pro-thrombotic endothelium and increased blood viscosity. We therefore review endothelial physiology with emphasis on glycocalyx function, unique biomarkers, and coagulofibrinolytic mediators, setting the stage for understanding the pathophysiology and hemostatic phenotypes of SHINE in various etiologies of shock. We propose that the hyperfibrinolytic phenotype is exemplified in progressive shock whether related to trauma-induced coagulopathy, sepsis-induced coagulopathy, or post-cardiac arrest syndrome-associated coagulopathy. Regardless of the initial insult, SHINE appears to be a catecholamine-driven entity which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation. Given the intricate hemochemical makeup and changes during these shock states, macroscopic whole blood tests of coagulative kinetics and clot strength serve as clinically useful and simple means for hemostasis phenotyping. We suggest that viscoelastic hemostatic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most applicable clinical tools for assaying global hemostatic function—including fibrinolysis—to enable dynamic resuscitation with blood products and hemostatic adjuncts for those patients with thrombotic and/or hemorrhagic complications in shock states.