SUMMARY The long-term goal of our research is to develop effective anticoagulants that do not cause bleeding complications to be safely used for a wider range of patients suffering from venous thromboembolism (VTE). This project aims at developing effective and safer anticoagulants by targeting human factor XIIIa (FXIIIa). All available anticoagulants are associated with a significant risk of bleeding. Current anticoagulants inhibit directly or indirectly thrombin and/or factor Xa. This is the reason why they are clinically effective, but it is also the reason why they cause bleeding. The central hypothesis is that inhibiting FXIIIa will result in effective protection against VTE without causing significant bleeding. In contrast to all other clotting factors which are serine proteases, FXIIIa is a transglutaminase that catalyzes the last step in the coagulation process. This unique biochemical aspect of FXIIIa has been under investigation in the context of VTE. In vitro experiments showed that treating normal human blood with an experimental transglutaminase inhibitor increases RBC extrusion from contracting clots and reduces clot size. Various studies also suggested that a certain FXIIIa polymorphism provides significant protection against VTE and that heterozygous FXIII-deficient mice do not show signs of excessive bleeding. Thus, FXIIIa may serve as a potential therapeutic target to develop a new effective treatment for VTE that does not significantly increase the bleeding risk. Despite this promise, very few FXIIIa inhibitors have been developed, all of which lack substantial selectivity as they can also inhibit other transglutaminases by blocking their active sites. Thus, I have proposed sulfonated non-saccharide glycos- aminoglycan mimetics as a platform to develop FXIIIa inhibitors. The sulfonated molecules are to inhibit FXIIIa potently and selectively through allosteric modulation. In preliminary studies, I discovered two sulfonated molecules that inhibit F