Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.
In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.
And the LMWH is cleared by the liver rather than the kidneys.
The team described their creation of the drug in Nature Chemical Biology.
“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.
Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.
But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.
The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.
That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.
“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.
“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”
LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.
“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.
“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”
LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.
“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”
