The source of lethal heparin contamination

The mysterious deaths of patients around the world following a routine dosage of the common blood thinner heparin sent researchers on a frantic search to uncover what could make the standard drug so toxic. A researcher at Rensselaer Polytechnic Institute was among a small group of scientists with the expertise and the high-tech equipment necessary to determine the source of the contamination.

Robert J Linhardt, the Ann and John H Broadbent Jr ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer, is part of an international team that recently announced it had uncovered the source of the deadly contamination. On 23 April, the team led by researchers at the Massachusetts Institute of Technology (MIT) described the source in the journal Nature Biotechnology — a complex carbohydrate named oversulfated chondroitin sulfate, which has a structure so similar to heparin it was nearly undetectable to less advanced technology.

“Days after the deaths were first linked to heparin, we had the drugs in our hands from the FDA and our nuclear magnetic resonator (NMR) was set into motion to break down the structure of the drug and determine what could possibly be the source of the contamination,” Linhardt said. “Now that we know the most likely source of the contamination, we are developing much stronger monitoring systems to ensure that this type of contamination is detected before it reaches patients.”

Although extremely close in chemical structure to heparin, the contaminant caused severe allergic reaction in many patients who were receiving routine treatment for kidney dialysis, heart surgery and other common medical issues. The researchers’ extremely detailed structural analysis of the drug, using technology such as the NMR, was able to detect the minute differences between the contaminated drug and a normal dosage of heparin. And while Linhardt and others are developing more sophisticated detection systems, Linhardt is also helping lead the race for a safer, man-made alternative to the traditional biologic heparin. Biological heparin is currently developed by purifying the scrapings of pig and cow intestines.

“This contamination is unfortunately a sign that the way we currently manufacture heparin is simply unsafe,” he said. “Because we rely on animals, we open ourselves up for spreading prions and diseases like mad cow disease through these animals. And because most of the raw material is imported, we often can’t be sure of exactly what we are getting.”

Linhardt is helping lead the global race to develop a synthetic alternative to heparin that could help eliminate the potential for contamination and adverse effects of biologic heparin. His lab developed the first fully synthetic heparin in amounts large enough for human dosage in 2005, and he continues to work to get the product further tested and commercialised.

“A synthetic heparin is built using sugars and enzymes found in the human body,” Linhardt said of his recipe for synthetic heparin. “So instead of taking pig intestines and trying to purify it over and over again to reduce it down to just heparin, we are building heparin from scratch with no foreign material present. This method ensures that we know exactly what is in the drug and have complete control over its ingredients.”