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The roles of fibrinolysis in regulating coagulation factor XIII

University of British Columbia

Coagulation factor XIII (FXIII) is a protransglutaminase enzyme that is activated at the end of the coagulation cascade. Activated FXIII (FXIIIa) stabilizes the blood clot from premature lysis by covalently crosslinking fibrin molecules to itself and to other anti-fibrinolytic proteins. Although the role of FXIIIa as an antifibrinolytic protein has been well characterized, the role of fibrinolysis in regulating FXIII and FXIIIa has not been characterized. FXIIIa lies in close proximity to fibrin during the hemostatic processes; therefore, the effect of plasmin on FXIIIa activity was examined. This thesis shows that plasmin preferentially cleaves the active enzyme FXIIIa, but not the zymogen FXIII. The primary cleavage site identified by mass spectrometry was between K468-Q469. Inactivation of FXIIIa occurred during clot lysis, but not during clot formation. These results indicate FXIIIa activity can be modulated by fibrinolytic enzymes, and suggest that changes in fibrinolytic activity may influence cross-linking of blood proteins. Thrombosis patients who are treated with thrombolytic therapy receive high doses of fibrinolytic enzymes. Since FXIIIa is inactivated by plasmin, the stability of FXIII and FXIIIa during thrombolytic therapy was examined using purified proteins and blood collected from nine DVT patients undergoing CDT. During CDT, FXIII levels were decreased by more than 40% in 5 of 9 patients and FXIIIa levels were decreased by more than 85% in 2 patients when it was activated. FXIII and FXIIIa can decrease during CDT in some patients, warranting further research into the role of FXIIIa in bleeding from thrombolysis. Amyloid beta (Aβ) peptide inhibits fibrinolysis and can form complexes with FXIIIa. Although Aβ can be crosslinked by tissue transglutaminase, the ability of FXIIIa to crosslink Aβ has not been demonstrated. The thesis shows that FXIIIa covalently crosslinked Aβ40 into dimers and oligomers, as well as to fibrin, and to blood clots under flow in vitro. Aβ40 also increased the stiffness of platelet-rich plasma clots in the presence of FXIIIa. These results suggest that crosslinking of Aβ40 by FXIIIa may contribute to the formation of vascular deposits in cerebral amyloid angiopathy.

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2019-02-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/68407

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/