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Sci Transl Med. 2014 Oct 29;6(260):260ra150. doi: 10.1126/scitranslmed.3009427. Epub 2014 Oct 29.

Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants.

Author information

1
Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
2
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
3
Michael Smith Laboratories, Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
4
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
5
Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
6
Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. jay@pathology.ubc.ca.

Abstract

Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.

PMID:
25355700
DOI:
10.1126/scitranslmed.3009427
[Indexed for MEDLINE]
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