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

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A Quantitative and Mechanistic Assessment of Activated Thrombin- Activatable Fibrinolysis Inhibitor and Its Role in Pathological Bleeding and Thrombosis A Quantitative and Mechanistic Assessment of Activated Thrombin- Activatable Fibrinolysis Inhibitor and its Role in Pathological Bleeding and Thrombosis by Jonathan H. Foley A thesis submitted to the Department of Biochemistry In conformity with the requirements for the degree of Doctoral of Philosophy Queen’s University Kingston, Ontario, Canada (September, 2010) Copyright ©Jonathan H. Foley, 2010 Abstract 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 ii 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. iii Co-Authorship Chapter 2: Ms. Paula Kim helped develop the TAFIa assay used in this chapter and Dr. Michael Nesheim offered experimental advice, helped write this chapter and was the primary editor. Chapter 3: Dr. Nesheim offered experimental advice and contributed to the data analysis by developing the mathematical models. He also helped write this chapter and was the primary editor. Paul Cook provided essential materials that allowed us to complete the project. Chapter 4: Dr. Michael Nesheim offered experimental advice, contributed to the data analysis, helped write this chapter and was the primary editor. Chapter 5: Dr. Georges Rivard organized the study and provided clinical samples to be assayed for TAFIa. Dr. Nesheim helped write and edit this chapter. Dr. Kathleen Brummel-Ziedins organized the study, provided clinical samples, contributed to the data analysis, helped write this chapter and was the primary editor. Chapter 6: Dr. Karl-Uwe Petersen provided Solulin and advice pertaining to the use of Solulin. Dr. David Lillicrap provided access to whole blood from the hemophilic dog colony and Dr. Nesheim offered experimental advice, contributed to the data analysis, helped write this chapter and was the primary editor. Chapter 7: Dr. Edwin Bovill provided clinical samples to be assayed for TAFIa. Dr. Nesheim helped write and edit this chapter. Dr. Kathleen Brummel-Ziedins organized the study, provided clinical samples, contributed to the data analysis, helped write this chapter and was the primary editor. iv Acknowledgements The work presented here would not be possible without a lot of help from a lot of people. Mike – You gave me the freedom to explore my own scientific curiosities which has ultimately given me the passion required to pursue a career in the field of coagulation and fibrinolysis. For this I will always be indebted. To my family – You gave me every opportunity to be successful. Your love and support helped me to achieve my potential. Thank you! Kim – What can I say? Without you I would not be here. Your unconditional love and support helped me get through difficult times and your work ethic provided constant motivation by showing me how many things one person can juggle at a time! I would also like to thank my collaborators Dr. Kathleen Brummel-Ziedins, Dr. David Lillicrap, Dr. Georges Rivard, Dr. Anetta Undas, Dr. Dirk Hendriks, Dr. Paul Cook, Dr. Karl-Uwe Petersen and Dr. Benny Sorensen for giving me opportunities to work on many interesting projects. Finally, I wish to thank my labmates, both past and present, for providing a great learning environment. I believe that a person’s training is a reflection of their training environment and I am confident that ours is among the best out there. v Table of Contents Abstract............................................................................................................................................ii Co-Authorship ................................................................................................................................iv Acknowledgements..........................................................................................................................v Table of Contents............................................................................................................................vi List of Figures..................................................................................................................................x List of Abbreviations ....................................................................................................................xiii Chapter 1 Introduction .....................................................................................................................1 Coagulation..................................................................................................................................1 Tissue Factor Pathway .............................................................................................................2 Contact Pathway ......................................................................................................................3 Prothrombinase and Thrombin ................................................................................................3 Fibrinolysis ..................................................................................................................................5 Fibrin(ogen) .............................................................................................................................6 Plasmin(ogen) and plasmin-modified fibrin ............................................................................6 TAFI and TAFIa-modified fibrin.............................................................................................7 Pathology of improperly regulated hemostasis..........................................................................10 Hemophilia A and Factor VIII...............................................................................................10 Current Studies ..........................................................................................................................12 Hypotheses.............................................................................................................................12 Aims/ Objectives....................................................................................................................13 Chapter 2 Thrombin-activatable fibrinolysis inhibitor zymogen does not play a significant role in the attenuation of fibrinolysis ........................................................................................................15 Abstract......................................................................................................................................16 Introduction................................................................................................................................17 Experimental Procedures ...........................................................................................................19 Materials ................................................................................................................................19 Clot Lysis Assays...................................................................................................................20 AAFR Cleavage by TAFI and TAFIa....................................................................................20 Preparation of Samples for Assay of TAFIa..........................................................................21 Effect of TAFI Zymogen on the Assay for TAFIa ................................................................21 Assay of TAFIa......................................................................................................................22
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