Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection. Sepsis patients are at risk of disseminated intravascular coagulation (DIC), a severe blood coagulation disorder. In DIC, inappropriate coagulation leads to the deposition of fibrin in the microvasculature and subsequent organ failure. This consumes platelets and coagulation factors, leaving patients at risk of severe or fatal bleeding. No treatments are approved for DIC in the United States.

In order to test the hypothesis that DIC would be best described by a combination of biomarkers representative of multiple physiological processes, an array of biomarkers, representative of hemostasis, inflammation, infection, endothelial function, and platelet function

were measured in plasma from patients with sepsis and DIC. While biomarkers of hemostasis and inflammation demonstrated strong associations with organ failure, markers of infection response and endothelial function were strongly associated with severity of DIC and mortality. Elevated levels of nuclear proteins were associated with severe DIC and mortality. Furthermore, an algorithm to predict mortality in sepsis patients was developed, incorporating parameters representative of inflammation, infection, endothelial function, and platelet function. Drugs for the treatment of DIC represent an unmet therapeutic need. Therefore, three drugs€”thrombomodulin, antithrombin, and heparin€”were studied for use in DIC. In vitro coagulation testing was performed to determine the relative anticoagulant effects of these drugs.

In a rat model of sepsis-associated DIC, treatment with all three drugs resulted in a significant reduction in circulating nuclear material.

This work included focused analysis of the status of the coagulation system in patients with sepsis-associated DIC and integrated analysis of biomarkers representative of multiple physiological systems. Furthermore, this dissertation provides a mathematical approach to predict mortality in sepsis patients. The results in human samples and animal models identify infection response, particularly extracellular nuclear material, as an important component of the pathophysiology of DIC. The demonstration of the reduction in circulating nuclear material due to treatment with thrombomodulin, antithrombin, and heparin has implications for the future

clinical development of these drugs.

Download

Share

COinS