The Role of von Willebrand Factor in the Pathogenesis of Deep Vein Thrombosis in Acute Inflammation

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Authors
Choi, Crystal
Keyword
von Willebrand Factor , Deep Vein Thrombosis , Immunothrombosis , Inflammation
Abstract
Venous thromboembolism, comprised of deep vein thrombosis (DVT) and pulmonary embolism, is a thrombotic cardiovascular disease that accounts for a significant portion of the global health burden. Among its risk factors, inflammatory states such as sepsis and more recently, COVID-19, have been correlated with increased DVT risk. Combined with the prevalence of breakthrough VTE incidences despite thromboprophylaxis, inflammation-associated venous thrombosis raises significant clinical concerns for hospitalized patients. Mechanistic insights into the link between these pathologies were consolidated with the introduction of immunothrombosis, whereby the dysregulation of the interplay between the innate immune system and thrombosis could contribute to pathological thrombosis. For example, the uncontrolled release of immune mediators such as cytokines can lead to endothelial dysfunction. This in turn can result in the upregulation of prothrombotic mediators such as von Willebrand factor (VWF), a multimeric hemostatic protein with well-documented roles in hemostasis. Indeed, increased levels of plasma VWF have been reported in inflammatory diseases such as sepsis, while the critical role of VWF in venous thrombogenesis has previously been demonstrated. However, whether VWF plays a role in mediating inflammation-associated venous thrombosis has not been elucidated. Therefore, using the previously established murine inferior vena cava stenosis model of DVT, we aimed to investigate the role of VWF in venous thrombosis concurrent with lipopolysaccharide-induced endotoxemia. We hypothesized that an inflammation-induced increase in plasma VWF levels would enhance DVT development. In our model, we show that endotoxemia does significantly increase thrombosis incidence, concurrently with elevated plasma VWF levels. Using inhibitory antibodies, we further confirm that VWF inhibition produces a protective effect against thrombosis incidence in endotoxemia. Our histological analyses using a mass cytometry imaging approach demonstrate that VWF assumes a distinct localization pattern that coincides with fibrin and markers of neutrophil extracellular traps, recognized to comprise the thrombus scaffolding network. This localization pattern remains relatively stable despite endotoxemia, demonstrating that despite thrombus heterogeneity, the scaffold remains constant. Overall, our findings suggest significant pathogenic implications for the clinical management of inflammation-associated venous thrombosis, which may be of especially high relevance in the current landscape of the COVID-19 pandemic and its associated highly thrombotic coagulopathy.
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