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Liposomal-encapsulated enzymes can be delivered to and modify platelet function ex vivo

University of British Columbia

Platelets are small, anucleate blood cells that are important mediators of many physiological and pathological processes. These include hemostasis, thrombosis, wound healing, inflammation, immunity, and malignancy. There are currently several uses for platelet therapy in the clinic, such as to increase platelet counts for the prevention of spontaneous bleeding, and to stop uncontrolled bleeding during trauma and surgery. Although platelet transfusions are an efficacious component in preventing and stopping bleeding in most cases, they are still insufficient to stop the most severe cases of surgical and traumatic bleeding. Traumatic bleeding is further complicated by trauma-induced coagulopathy, which often presents with platelet dysfunction and is not corrected by transfusions of normal platelets. Strategies to enhance the endogenous function of platelets to increase the efficacy of platelet transfusions has not been rigorously explored, especially during active bleeding in trauma-induced coagulopathy. When activated by specific stimuli, platelets locally secrete a variety of biologically active molecules in order to contribute to many physiological and pathophysiological processes. For example, platelets can recognize areas of vascular damage and respond by locally adhering, aggregating, and activating to initiate primary hemostasis. Platelets also release procoagulant molecules and mediate the formation of active coagulation factor complexes to ultimately form an insoluble fibrin clot and seal the wound. Taken together, developing strategies to modify the endogenous function of platelets may be a first step towards a platform system that could target many diseases. Moreover, strategies to load platelets with biomolecules could allow for the local delivery of therapeutics to disease sites using endogenous platelet machinery. This provides significant motivation to test our overarching hypothesis, that the endogenous function of platelets can be modified ex vivo through the delivery of liposome-encapsulated enzymes. The objectives of this thesis were to: i) develop a platform approach to deliver biomolecules to platelets, ii) engineer anucleate platelets to transcribe RNA, and iii) increase the coagulability of transfusable platelets. The results shown here demonstrate proof-of-concept that endogenous platelet function can be extended through the delivery of lipid-encapsulated enzymes, and provides new approaches to potentially enhancing current platelet transfusions.

Text

2018-07-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66411

Biochemistry and Molecular Biology

University of British Columbia

UBCV

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