Grant: Master's Award: Canada Graduate Scholarships

Thrombosis (pathological blood clot formation) is the most frequent cause of mortality worldwide. Von Willebrand factor (VWF) is a protein in the blood that helps blood clot formation by binding platelets (the primary cellular component of clots) to each other and to the blood vessel wall. High VWF levels in the blood increases the risk of thrombosis and is associated with diseases such as stroke. Inflammation is part of the immune response mounted against a harmful stimulus and it has been shown that inflammation increases VWF levels in the blood. However, the specific mechanism for this increase remains unclear. A class of white blood cells known as neutrophils participate in the inflammatory response and can release web-like structures in response to indicators of cell death and infections. These structures are called neutrophil extracellular traps (NETs) and consist of a meshwork of DNA and proteins that act like a net to localize the stimulus. NET generation (NETosis) has been shown to trap platelets and activate clot formation. We propose that components of NETs may stimulate VWF release during inflammation and may modify the ability of VWF to bind platelets. We have previously shown that in aging, characterized by a state of chronic inflammation, DNA and VWF levels were tightly correlated indicating a possible interaction between their regulating systems. The purpose of our research is: (1) to determine the role of VWF and NETosis in acute inflammation by using models of systemic infection; (2) to investigate the influence of NET components on VWF release and/or synthesis; (3) to characterize the interaction between NETs and VWF and how this interaction influences VWF’s ability to bind to platelets. These studies are important because they will help us to better understand how the immune and clotting systems crosslink with respect to VWF. This research may help improve treatment strategies for patients with inflammatory and/or thrombotic disorders by identifying targets that perpetuate these pathologies.