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Multiple inflammatory disease states are marked by disturbances in coagulation. Coagulation is the biological process initiated from activation of two independent enzymatic pathways, which join to a common pathway, to produce the matrix component of blood clots. Tissue factor initiates extrinsic coagulation when damaged endothelial cells interact with circulating blood plasma, while factor XII initiates the contact pathway upon interaction with an anionic surface. Factor XIIa, the activated form, proceeds to activate factor XI and drive intrinsic coagulation. Additionally, factor XIIa activates prekallikrein, driving the inflammatory contact system. High molecular weight kininogen is a cofactor for intrinsic coagulation and the contact system; kininogen facilitates localization factor XI or prekallikrein, respectively, to the same surface as factor XII. Once prekallikrein is activated to kallikrein, it cleaves kininogen to release the inflammatory peptide bradykinin. While inhibition of the extrinsic coagulation pathway may limit the pathological clotting (thrombosis), it increases the risk of bleeding. However, inhibition of factor XII has been demonstrated to prevent thrombosis while not producing the same bleeding risk. We anticipate that genetic deficiency of high molecular weight kininogen would confer protection in animal models of these disease states. Moreover, we believe that cleaved kininogen in plasma from human patients could serve as an indicator of inflammation, or a biomarker for disease severity. First, I recapitulated enzyme linked immunosorbent assays (ELISAs) which detect enzyme:inhibitor complexes from human plasma, as an indicator of contact system activation. These assays are sensitive, and specific, at percentages near that of a typical clinical assay. Second, kininogen-deficient mice examined for disease severity. In an acetaminophen-induced liver injury model, kininogen-deficient mice exhibited significantly less liver injury within the first 24 hours, as indicated by liver histology and circulating biomarkers of hepatotoxicity. Third, human patient plasmas from acute liver failure were analyzed for the circulating concentration of cleaved kininogen. In acute liver failure, while circulating cleaved kininogen was significantly higher than that of normal controls, it did not correlate with increased likelihood of death. Finally, we identified that plasmin, the terminal enzyme in the clot dissolution pathway (fibrinolysis), can cleave kininogen independent of factor XIIa or kallikrein.