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A Non-toxic Polymer Therapeutic for Universal Heparin Reversal Activity

Date: 
Thursday, October 19, 2017 -
18:30 to 19:30
Speaker: 
Dr. Manu Thomas Kalathottukaren
Affiliation: 
Centre for Blood Research, Department of Pathology and Laboratory Medicine - UBC
Event Category: 
CBDG - Chemical Biology Discussion Group
Location: 
Chemistry D300

Abstract:

Heparin anticoagulants are widely used for the prophylaxis and treatment of thrombosis. Heparin is also used to prevent blood clotting during surgeries. However, bleeding during heparin therapy is a clinical concern. Protamine, a cationic peptide, the only approved antidote for unfractionated heparin (UFH), exhibit adverse cardiovascular side-effects and is not effective against other heparin variants such as low molecular weight heparins and fondaparinux. To address this issue, we developed a nontoxic, synthetic polymer therapeutic named as Universal Heparin Reversal Agent (UHRA), that can neutralize the anticoagulant activity of all heparin anticoagulants. UHRA molecule is comprised of three principal components: 1) a hyperbranched polyglycerol core that presents 2) a set of methylated tris(2-aminoethyl)amine ligands beneath 3) a brush of methoxy-terminated polyethylene glycol (mPEG) chains emanating from the cationic-ligand-bearing core. Biophysical studies show that mPEG chains in UHRA avert nonspecific interactions with blood proteins and provide selectivity towards heparins. In support of this observation, we show that UHRA does not affect fibrin polymerization or abrogate blood clotting. Using scanning electron microscopy, confocal microscopy and clot lysis assays, we confirm that UHRA does not incorporate into clots, and clots are stable with normal fibrin morphology. Conversely, protamine binds to the fibrin clot, which could explain how protamine instigates clot lysis and increases bleeding after surgery. Studies in mice reveal that UHRA reverses UFH anticoagulant activity without lung injury as observed with protamine. Overall, our results show that UHRA is a superior heparin antidote compared to protamine in terms of efficacy and safety.