Polymorphonuclear leukocytes, specifically neutrophils, are highly dynamic, multi-functional innate immune cells. Neutrophils are among the first cellular responders to bacterial host tissue infection. At sites of inflammation, neutrophils can undergo activation, releasing their nuclear content to form microbicidal neutrophil extracellular traps (NETs). NETs provide a structural framework for pathogen clearance; however, recent studies have demonstrated that NETs may additionally contribute to thrombotic complications, including deep vein thrombosis. The crosstalk and underlying mechanisms in the blood microenvironment that regulate NETs formation and potentiate thrombus formation remain ill-defined. This gap in knowledge has guided my research thus far, driving investigations into how the blood microenvironment influences neutrophil activation, specifically NETosis, and how the thrombogenic potential of NETs is dynamically regulated.