The role of von Willebrand factor in the pathogenesis of immunothrombosis
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Pathologic immunothrombosis is the formation of arterial, venous or microvascular thrombi in response to dysregulated activation of the immune system. Inflammatory diseases such as sepsis and obesity are associated with a hypercoagulable state that significantly increases the risk of thrombosis. Von Willebrand factor (VWF) is a hemostatic glycoprotein that mediates platelet aggregation at the site of vessel injury and carriers the coagulation cofactor, factor VIII, in circulation. The plasma concentration and procoagulant function of VWF are influenced by inflammation and elevated VWF levels are an established risk factor for thrombosis. The mechanisms by which inflammation interacts with VWF and other procoagulant effectors to promote thrombosis are incompletely understood. In this thesis I describe VWF as both an effector of inflammation and a potentiator of immunothrombotic disease. We first showed that extracellular histones are potent inducers of endothelial cell VWF and mediate subsequent platelet capture in vitro. We also characterized the relationship between VWF levels and inflammatory mediators in murine and human models of acute and chronic inflammatory disease. We next used a mouse model of deep-vein thrombosis to assess the underlying prothrombotic phenotype associated with stabilin-2 deficiency, a scavenger receptor that was recently associated with increased risk of unprovoked venous thromboembolism. Deficiency of stabilin-2 produced a hypercoagulable state that was independent of VWF levels and was significantly associated with increased venous thrombogenicity. Finally, we used a mouse model of diet-induced obesity to study the role of VWF in a complex, thrombo-inflammatory disease. We demonstrated that VWF is critical for obesity-mediated immunothrombosis and is integral to both thrombus initiation and propagation. These findings add to the growing rationale for targeting VWF-specific interactions in the context of immunothrombotic disease.