A large dose of a blood thinning drug called heparin is administered during open-heart surgery to prevent clot formation. However, an overdose of heparin causes complications from excessive bleeding. A common countermeasure for this is the compound protamine sulfate, which binds to heparin to reverse its effects.

The problem with protamine, a natural compound that has been used in surgeries for decades, is that when the doses are too large it can turn a foe.  It morphs into an anticoagulant that increases the bleeding issues caused by the heparin, thus having the exact opposite effect than intended.

A Northwestern University research team has found a safer way to keep blood vessels healthy during and after surgery. Guillermo Ameer, professor of biomedical engineering at Northwestern’s McCormick School of Engineering and surgery at the Feinberg School of Medicine, and his team were able to re-fashion this drug to prevent its side effects. They were also able to use it as a template to deliver nitric oxide, which is used to prevent scarring in vascular grafts and stents.

Nitric oxide, a molecule that plays a vital role in many biological processes, is a very protective molecule for vasculature. It is constantly secreted by all the cells inside blood vessels. It prevents cell overgrowth that leads to scarring in the blood vessel and maintains the inside of the vessel healthy.

Other drugs that release nitric oxide do exist, but most become toxic after the gas is expelled. For example, nitrosamine causes cancer in some cases. Ameer’s team was able to convert protamine into a nitric oxide donor without changing its natural structure much. Since protamine is naturally occurring in the body, it does not leave any toxic byproducts. It releases the nitric oxide and reverts back to its natural form. The research team has found that though the nitric oxide converts the protamine into a slightly different molecule, it does not affect its function as a heparin antidote. Also, the modified molecule is capable of slowly releasing nitric oxide, preventing both cellular overgrowth and protamine’s tendency to become a coagulant at higher doses. Hence it becomes a much safer alternative.

As heparin dosing can be complicated, protamine becomes essential in many surgeries. It must be administered only after bleeding issues arise in the operating room, or when normal blood clotting needs to be re-established at the end of surgery. However, it is not extremely ‘pin-point’ as clotting needs to be monitored by surgeons during the surgery.

The research is supported by the American Heart Association. It is presently available online and will be published in the May 2015 issue of Free Radical Biology and Medicine with Robert van Lith, a postdoctoral fellow in Ameer’s lab, as first author of the paper.

The team plans to further their research by mixing the new drug with a hydrogel that can be applied directly to the outside of an injured blood vessel to provide long-lasting prevention of the cell overgrowth that leads to scarring and obstruction of blood flow.

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