- TAFI: from activation to (self-)destruction
- Award date
- 2 February 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The formation and breakdown of a blood clot is tightly balanced and regulated by many factors. Abnormal clot formation or clot breakdown can lead to thrombosis or bleeding. One of the regulators to maintain this delicate balance is Thrombin-activatable Fibrinolysis Inhibitor (TAFI). TAFI delays fibrinolysis by down-regulating the formation of plasmin, the enzyme that dissolves the clot. This makes TAFI an interesting target for the treatment of both thrombosis and bleeding. Increasing TAFI activation or activity will protect a blood clot and may therefore be beneficial against bleeding. On the other hand, inhibiting TAFI activation or activity will enhance the breakdown of a clot and may therefore be beneficial against thrombosis. Knowledge of TAFI-structure and -function is essential for designing strategies to modulate TAFI. Therefore, the aim of this thesis was to increase our understanding of the TAFI structure and function.
In this thesis we elucidated the three-dimensional crystal structure of TAFI with atomic resolution. This structure provided new insights in the mechanism of the inactivation of activated TAFI (TAFIa). We also studied the activation process of TAFI and found several TAFI-derived peptides that can inhibit TAFI activation. Additionally we identified an amino acid in TAFI (Arg12) that plays an important role in thrombin/thrombomodulin-mediated TAFI activation. Finally, we observed that several poly-anionic molecules can function as cofactor for thrombin- and plasmin-mediated TAFI activation. This suggests that there are many cofactors in the vasculature that promote TAFI activation.
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