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La, Chanel

University of British Columbia

Thrombosis is a medical condition in which the formation of clots inside a blood vessel can obstruct the flow of blood through the circulatory system. These clots can occur in either arteries or veins, with severe cases leading to stroke, heart attack, or pulmonary embolism. Thrombosis is thus a major cause of death and disability worldwide. The goal of anticoagulants is to attenuate thrombosis without disrupting hemostasis, the essential physiological process to protect our bodies from excess bleeding. Current anticoagulants carry a significant risk of bleeding (>7% per 100 patient years for anticoagulant treatment of venous thromboembolism). In depth investigations into the biochemistry of hemostasis and thrombosis have identified new polyanionic targets for the development of novel anticoagulants. In this thesis, I present a novel therapeutic design strategy to target key polyanions in coagulation without nonspecific interactions with other blood components. A key advance is the design of a new class of synthetic therapeutics offering switchable protonation states on cationic binding groups (CBGs) which are appended onto a biocompatible polymer scaffold (HPG-mPEG). Careful tuning of the size, charge density and identity of the CBGs enables specific polyanions to be targeted, including polyphosphate (polyP), a valuable target which promotes coagulation without affecting hemostasis. These novel macromolecular polyanion inhibitors demonstrate superior polyP inhibition efficacy in vitro and in mice, are well tolerated and do not cause bleeding at high dosages. The tunability of this novel therapeutic design strategy was demonstrated by targeting heparins (unfractionated heparin (UFH), low molecular weight heparins (LMWH), fondaparinux), polyanions used to treat thrombosis. The only available antidote is protamine sulfate, which only fully reverses the effects of UFH. Here, a new molecule, MPI 2, is shown to successfully reverse the effects of UFH, LMWH and fondaparinux in vitro and ex vivo. In mice, MPI 2 completely reverses the effects of UFH and LMWH and does not cause bleeding at concentrations an order of magnitude higher than the effective dose. These emerging strategies address current unmet medical needs and provide new avenues by which to design polyanion inhibitors, improving anticoagulant therapy by reducing the risk of bleeding.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80528

Chemistry

University of British Columbia

UBCV

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