To prevent blood clots during procedures such as heart surgery, doctors administer the anticoagulant heparin. In some cases—particularly overdoses—physicians need an “antidote” that binds to heparin and reverses its activity.
A research team led by Jayachandran N. Kizhakkedathu of the University of British Columbia recently designed a reversal agent for heparin (Sci. Transl. Med. 2014, DOI: 10.1126/scitranslmed.3009427). The only compound currently approved to counteract heparin is a cationic protein called protamine sulfate, but it has its drawbacks. The new agent succeeds where protamine sulfate falls short because it neutralizes the activity of all forms of heparin, a mixture of highly sulfated glycosaminoglycans of different lengths.
Protamine effectively neutralizes unfractionated heparin, but it doesn’t work against the more commonly administered low-molecular-weight heparins or the synthetic heparin fragment fondaparinux. “Protamine neutralizes unfractionated heparin by electrostatic binding,” says Kizhakkedathu, an associate professor of chemistry and of pathology and laboratory medicine. “The binding strength is not sufficient at physiological conditions to neutralize low-molecular-weight heparins and fondaparinux.”
To make their reversal agent, Kizhakkedathu and his team synthesized a polyglycerol-based branched scaffold, which they capped with polyethylene glycol to improve biocompatiblity. Then they attached methylated branched amines, which are positively charged and therefore bind to negatively charged heparin.
The researchers made reversal agents with different scaffold sizes and numbers of heparin-binding groups. The best combination consists of a 23,000-dalton scaffold decorated with 20 heparin-binding groups for optimal binding strength and biocompatibility.
The researchers tested the toxicity of the reversal agent in mice and tested its efficacy in mice and rats. The reversal agent neutralized all heparins commonly used by doctors. They plan to test the compound in pigs and nonhuman primates.
Protamine sulfate has also been associated with allergic reactions. “This universal antidote has the potential to eliminate the allergic reactions associated with protamine and to reverse all heparin preparations,” says Jeffrey Weitz, an expert on blood coagulation at McMaster University in Hamilton, Ontario. “The results are important.”