Next Generation Universal Reversal Agents for Safe and Effective Heparin Reversal

OVERVIEW

• Improvement over existing technologies: Safely reverses multiple heparin types, including low molecular weight heparins, with reduced off-target toxicity and bleeding complications.
• Real-world applications: Reversing anticoagulant effects in hospital settings, cardiovascular surgery, emergency medicine, and dialysis procedures.

MODALITY

Polymer therapeutic / Intravenous formulation. Cationic binding groups attached to a hyperbranched polyglycerol-polyethylene glycol (HPG-mPEG) polymer scaffold.

INDICATION

Prevention and treatment of bleeding complications associated with heparin anticoagulant therapy, including unfractionated heparin, low molecular weight heparins (LMWH), and fondaparinux.

PUBLICATIONS

Kalathottukaren, M. T., Abraham, L., Kapopara, P. R., Lai, B. F. L., Shenoi, R. A., Rosell, F. I., Conway, E. M., Pryzdial, E. L. G., Morrissey, J. H., Haynes, C. A., & Kizhakkedathu, J. N. (2017). Alteration of blood clotting and lung damage by protamine are avoided using the heparin and polyphosphate inhibitor UHRA. Blood, 129(10), 1368–1379. https://doi.org/10.1182/blood-2016-10-747915

Shenoi, R. A., Kalathottukaren, M. T., Travers, R. J., Lai, B. F. L., Creagh, A. L., Lange, D., Yu, K., Weinhart, M., Chew, B. H., Du, C., Brooks, D. E., Carter, C. J., Morrissey, J. H., Haynes, C. A., & Kizhakkedathu, J. N. (2014). Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Science Translational Medicine, 6(260), 260ra150. https://doi.org/10.1126/scitranslmed.3009427

INTELLECTUAL PROPERTY

BACKGROUND

Thrombosis is a serious medical condition where blood clots obstruct blood flow within blood vessels, affecting 1 to 2 people per 1,000 and remaining a leading cause of disability. Treating and preventing thrombosis relies heavily on anticoagulant medications, primarily heparins such as unfractionated heparin, low molecular weight heparins, and fondaparinux. However, heparin therapy carries significant risks of severe bleeding and non-bleeding complications. Managing these adverse events requires rapid reversal of the anticoagulant effect. Currently, protamine sulfate is the only available antidote, but its clinical utility is limited to unfractionated heparin and it fails to reverse low molecular weight heparins or fondaparinux. Furthermore, protamine sulfate carries inherent risks of severe adverse effects, including allergic reactions, anaphylaxis, low blood pressure, and paradoxical bleeding. Consequently, an urgent clinical need exists for a safer, broader-spectrum antidote capable of effectively reversing diverse heparin formulations without causing intrinsic toxicity or adverse side effects.

INNOVATION

This technology provides a library of macromolecular heparin reversal agents designed as universal antidotes to counteract unfractionated heparin, low molecular weight heparins, and fondaparinux. The novel agents feature customized cationic binding groups appended to a biocompatible hyperbranched polyglycerol-polyethylene glycol polymer scaffold. By engineering the protonation behavior and density of these ligands, the molecule utilizes charge-switching mechanism that keeps positive charges largely inactive during standard blood circulation, minimizing non-specific interactions and off-target toxicity. Upon encountering polyanionic heparin, the charges switch on to selectively bind and neutralize the anticoagulant. In vitro assays and in vivo rodent studies demonstrate rapid, dose-dependent, and quantitative reversal of heparin activity without inducing adverse bleeding or altered clot times, even at high doses. The technology offers high-impact clinical utility across surgery centers, emergency care, and dialysis units, providing predictable and safe heparin reversal with an improved therapeutic window.