Browsing by Subject "coagulopathy"

Now showing 1 - 2 of 2
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    Characterizing and combatting thromboinflammation in infection and autoimmune disease
    (2021) Olson, Lyra Beatriz

    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.

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    COVID-19: Thrombosis, thromboinflammation, and anticoagulation considerations.
    (International journal of laboratory hematology, 2021-07) Levy, Jerrold H; Iba, Toshiaki; Olson, Lyra B; Corey, Kristen M; Ghadimi, Kamrouz; Connors, Jean M
    Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19-associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.