Abstract The overall vision is to achieve a detailed understanding of mechanisms that regulate the blood clotting system, with a special goal of identifying the aspects of the clotting machinery that function differentially in hemostasis versus thrombosis. The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism (immunothrombosis) gone awry. In this view, hemostasis following vascular injury is driven by the prompt exposure of blood to preexisting, natural procoagulants such as tissue factor and collagen that are ubiquitous throughout the body and that induce rapid formation of hemostatic plugs. On the other hand, immunothrombosis is likely triggered and/or greatly enhanced by the elaboration of damage- associated molecular patterns (DAMPs) and pathogen-associate molecular patterns (PAMPs). An important concept is that many of these PAMPs and DAMPs that drive immunothrombosis are potential therapeutic targets with little or no involvement in normal hemostasis. In order to achieve this vision, we need to have a much better mechanistic understanding of what regulates blood clotting reactions, and in particular we need to identify and understand the DAMPs that drive thrombosis and coagulopathies. Work initiated in our laboratory in the mid-2000s was the first to identify inorganic polyphosphate (polyP) as a DAMP and PAMP with potent prothrombotic and proinflammatory effects, a finding which opened up a new area of investigation in the field of hemostasis and thrombosis. The proposed work in this grant will focus on three general areas within the general conceptual framework outlined above: elucidating mechanisms by which procoagulant anionic polymers such as polyP and nucleic acids regulate blood clotting, inflammation and fibrosis; identifying key structural details that control the function of the tissue factor/factor VIIa complex; and achieving a detailed understanding of how phospholipid bilayers regulate blood clotting reactions. These studies will build on our prior success in this area and will further advance the field.