Venous thromboembolism (VTE) remains a major public health crisis which severely impacts several ethnic communities in the US. Furthermore, a 2-way link between VTE and cancer has also been confirmed. In fact, cancer patients constitute 15-20% of all patients diagnosed with VTE. Anticoagulants are the mainstay of VTE treatment. Nevertheless, clinically used anticoagulants are plagued with a number of drawbacks including a life-threatening risk of internal bleeding. New approaches to safely prevent and/or treat VTE are highly clinically significant. Factor Xllla (FXllla) is a transglutaminase procoagulant that is different from all other physiologic procoagulants which are serine proteases. This unique biochemical aspect of FXllla has been under investigation in the context of VTE mechanism. Venous thrombi from FXlll-deficient mice were found to be significantly smaller in size. Various studies also suggested that specific FXllla polymorphism provides a moderate protection against VTE and that heterozygous FXlll-deficient mice do not show signs of excessive bleeding. Therefore, FXllla may serve as a potential therapeutic target for a new VTE treatment, yet with no risk of the deadly bleeding side effect. Very few FXllla inhibitors have been reported thus far, most of which are not selective as they target the active site. I propose to consider sulfated/sulfonated glycosaminoglycan (GAG) mimetics platform to discover and subsequently rationally design FXllla inhibitors. These GAG mimetics are projected to potently and selectively inhibit FXllla through allosteric modulation , a mechanism often exploited by nature to achieve specific regulation. In preliminary studies , I independently discovered that suramin, a sulfonated GAG mimetic and an approved antiparasitic drug, inhibits FXllla with an IC50 value of 85 �M. This proposal specifically aims to use a multidisciplinary approach to establish the principles of effective and selective inhibition of FXllla by suramin and its analogs . The overall goal of research in this area is to 1) enhance our understanding of FXllla role in the coagulation physiology and pathology and 2) investigate an alternative approach to modulate FXllla through allostery so as to pave the way to a transforming potent and safe anticoagulant therapy to prevent and/or treat thrombotic disorders.