A Quantitative and Mechanistic Assessment of Activated Thrombin-Activatable Fibrinolysis Inhibitor and its Role in Pathological Bleeding and Thrombosis

The coagulation and fibrinolytic systems are linked by the thrombin-thrombomodulin complex which regulates each system through activation of protein C and TAFI, respectively. We have used novel assays and techniques to study the enzymology and biochemistry of TAFI and TAFIa, to measure TAFI activation in hemophilia A and protein C deficiency and to determine if enhancing TAFI activation can improve hemostasis in hemophilic plasma and whole blood. We show that TAFIa not TAFI attenuates fibrinolysis in vitro and this is supported by a relatively high catalytic efficiency (16.41μM-1s-1) of plasminogen binding site removal from fibrin degradation products (FDPs) by TAFIa. Since the catalytic efficiency of TAFIa in removing these sites is ~60-fold higher than that for inflammatory mediators such as bradykinin it is likely that FDPs are a physiological substrate of TAFIa. The high catalytic efficiency is primarily a result of a low Km which can be explained by a novel mechanism where TAFIa forms a binary complex with plasminogen and is recruited to the surface of FDPs. The low Km also suggests that TAFIa would effectively cleave lysines from FDPs during the early stages of fibrinolysis (i.e. at low concentrations of FDPs). Since individuals with hemophilia suffer from premature fibrinolysis as a result of insufficient TAFI activation we quantified TAFI activation in whole blood from hemophilic subjects. Both the rate of activation and the area under the TAFI activation time course (termed TAFIa potential) was determined to be reduced in hemophilia A and the TAFIa potential was significantly and inversely correlated with the clinical bleeding iii phenotype. Using a novel therapeutic strategy, we used soluble thrombomodulin to increase TAFI activation which improved the clot lysis time in factor VIII deficient human plasma and hemophilic dog plasma as well as hemophilic dog blood. Finally, we briefly show in a biochemical case study that TAFI activation is enhanced in protein C deficiency and when afflicted individuals are placed on Warfarin anticoagulant therapy, TAFI activation is reduced. Since TAFIa stabilizes blood clots, this suggests that reducing TAFI activation or inhibiting TAFIa may help restore blood flow in vessels with pathological thrombosis.

READING AND RESPONDING: FINDING AND MAKING MEANING IN THE LIFE WRITING OF DIASPORIC IRANIAN JEWISH WOMEN

This project investigates the English-language life writing of diasporic Iranian Jewish women. It examines how these women have differentially imagined their diasporic lives and travels, and how they have in turn been imagined and accepted or rejected by their audiences. In the first chapter, I use “home” as a lens for understanding three distinct life writing texts, showing how the authors write about what it means to have a home and to be at home in contrasting and even contradictory ways. I show how, despite potential hegemonic readings that perpetuate unequal relationships and a normative definition of the ideal home, the texts are open to multiple contestatory readings that create spaces for new formulations and understandings. In the second chapter, I look more closely at the intersections between trauma stories and the life writing of Iranian Jewish women, and I argue that readers use life writing texts about trauma to support an egocentric reconstruction of American democracy and dominance. I also show how a critical frame for understanding trauma can yield interpretations that highlight, rather than ignore, relationships of power and privilege. In the final chapter of the thesis, I present a case study of two online reading groups, and I show that communal reading environments, though they participate in dominant discourses, are also spaces where resistance and subversion can develop.