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Novel mediators of platelet-mediated hemostasis

University of British Columbia

Platelets are small, discoid, anucleate blood cells that circulate in the blood. The primary role of platelets is to mediate various aspects of hemostasis, but platelets are also key mediators in inflammation, host defense, and tumor growth and metastasis. In hemostasis, platelets work in concert with the endothelium and blood coagulation enzymes to sense and respond to injury and hemostatic challenges. Platelets elicit their functions through activation of a plethora of surface receptors and release of a vast array of granule contents. However, there are substantial gaps in knowledge with various abundant platelet contents with regards to their roles and interactions in hemostasis. This thesis examines the contribution of short-chain polyphosphate (PolyP) on clotting, inactivation of coagulation factor XIII (FXIII) by plasmin, cross-linking of amyloid beta (Aβ) by FXIII, regulation of amyloid precursor protein (APP) processing by FXIII activity, and the contribution of APP to hemostasis. Short-chain polyP is released from platelets upon platelet activation, but it is not clear if it contributes to thrombosis. In this thesis, the ability of localized polyP, as particles or on surfaces, to clot flowing blood plasma was examined using a microfluidic device. Localized polyP of all lengths was more effective at triggering clotting than when solubilized in solution or as nanoparticles. In particular, surface localized short-chain polyP, previously not considered as a hemostatic agent, was able to clot flowing blood plasma at sub-micromolar concentrations at shear rates typical of large veins or valves, where thrombosis usually occurs. These results indicate that platelet-length short-chain polyP can modulate thrombosis when localized onto surfaces. Transglutaminase FXIII circulates in plasma (bound to fibrinogen) and in platelets, and is critical for various hemostatic and platelet functions. However, the mechanism by which FXIII becomes inactivated is unknown. This thesis examined the potential role of the fibrinolytic system in the inactivation of FXIII. Plasmin preferentially cleaves and degrades the active enzyme, FXIIIa, but not the zymogen, FXIII.

Text

2020-08-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75404

Biochemistry and Molecular Biology

University of British Columbia

UBCV

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