Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Harry Ischiropoulos

Abstract

Deep vein thrombosis (DVT) and pulmonary embolism (PE) together comprise the disease state of venous thromboembolism (VTE). Thrombi in the veins of the lower extremities (DVT) can embolize, resulting in complete or partial occlusion of circulation through the pulmonary vasculature (PE). Despite a common etiology between DVT and PE, the cause of embolization remains mostly unknown. Research indicates that fibrin clot structure and functional properties are altered in VTE compared to healthy controls. Whether these properties differ between DVT and PE subjects remains to be determined, and may underscore possible mechanisms of embolization. Inflammation and oxidant production are involved in the pathogenesis of VTE. However, biomarkers documenting these pathways in humans are lacking. Elevated levels of nitrated fibrinogen have been documented during inflammatory and oxidative challenges and may serve as a functional biomarker in VTE. Differences in fibrin clot structure and functional properties between DVT and PE, as well as the role of nitrated fibrinogen as a biomarker of VTE were evaluated in the plasma of subjects presenting with symptoms of VTE to the emergency department at the Hospital of the University of Pennsylvania. Plasma fibrin clots derived from PE subjects showed increased establishment of viscoelastic properties and faster lysis time compared with DVT. The rate and extent of factor XIIIa crosslinking of fibrin were similar between DVT and PE. Clots from PE subjects showed decreased fiber density and no differences in fiber bundling. Together these data suggests that fibrin fibers are formed faster in PE subjects, possibly resulting in earlier lysis, which may lead to instability and embolization. Nitrated fibrinogen levels were elevated in VTE positive compared to VTE negative subjects, with no differences in fibrinogen concentration. Subjects in the highest quartile of nitrated fibrinogen had an increased risk of VTE compared with the lowest quartile. This risk persisted after univariate adjustment for advanced age, active cancer, and recent surgery, but not after multivariate adjustment for all variables. Thus, nitrated fibrinogen is an oxidative risk marker in VTE, providing a novel mechanistic link between oxidant production, inflammation, and VTE.

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