Characterizing and combatting thromboinflammation in infection and autoimmune disease

Abstract

Coagulation and inflammation are intimately linked processes that protect the body from a wide range of insults. However, dysregulation of this system contributes to morbidity and mortality in infection, autoimmune disease, and countless other disease processes. To successfully intervene on this axis, we need to understand the molecular drivers of thromboinflammation and design biocompatible pharmaceuticals to combat them. Towards that effort, this dissertation first explores the clinical landscape of COVID-19, with specific focus on characterization of the molecular drivers of COVID-19-associated coagulopathy. Through analysis of coagulative profiles and clinical data, fibrinolytic suppression and endothelial injury are identified as primary drivers of thrombosis and respiratory distress in COVID-19. Next, this dissertation describes efforts to reduce the toxicity of the anti-inflammatory scavenging polymer polyamidoamine (PAMAM). We show that the density of cationic surface charges underpins the direct cellular and systemic toxicity of these polymers and present novel PAMAM variants with a mix of cationic and neutral surface groups that resolve the toxicity of the original cationic polymers while retaining their scavenging properties. Together, these data highlight the importance of thromboinflammation in human disease and advance the translational potential of a new class of anti-inflammatory agents.