Researchers unravel heparin death mystery

April 23, 2008
Help for heparin mystery
Top image depicts the chemical structure of chondroitin sulfate, the contaminant found in batches of heparin. Bottom image shows the chemical structure of normal heparin. Graphic courtesy / Ishan Capila, Momenta Pharmaceuticals

An international team of researchers led by MIT has explained how contaminated batches of the blood-thinner heparin were able to slip past traditional safety screens and kill dozens of patients recently in the United States and Germany.

The team, led by Professor Ram Sasisekharan of MIT, identified the chemical structure of the contaminant, known as oversulfated chondroitin sulfate (OSCS). The researchers present their findings and offer new approaches to detecting the contaminant in a report appearing today in the online edition of Nature Biotechnology.

Another team led by Sasisekharan has shown exactly how OSCS can kill-specifically by setting off an allergy-like reaction. The biological effects of the contaminant are outlined in a report also being published online today in the New England Journal of Medicine.

“Sophisticated analytical techniques enabled complete characterization of the contaminant present in heparin. Further, this study also provides the scientific groundwork for critical improvements in screening practices that can now be applied to monitor heparin, thus ensuring patient safety,” said Sasisekharan, senior author of the papers and the Underwood Prescott Professor of Biological Engineering and Health Sciences and Technology at MIT.

Heparin, a blood thinner often used during kidney dialysis or heart surgery, is normally produced from pig intestines. FDA officials say the contaminated heparin came from factories in China that manufacture the drug for Baxter International.

Baxter recalled its heparin in February after dozens of deaths were reported, dating back to November. The tainted heparin has been blamed for 81 U.S. deaths so far, and earlier this week, the FDA announced that contaminated batches were also found in 10 other countries.

The New England Journal of Medicine study offers the first potential link between the contaminant and the reported deaths. The researchers found that the contaminated heparin activates two inflammatory pathways, causing severe allergic reactions and low blood pressure.

“These results provide a potential link between the presence of chemical contaminant in heparin and the clinical symptoms observed in affected patients. Our findings also suggest that a simple bioassay could help protect the global supply chain of heparin, by screening heparin lots for the presence of polysulfated contaminants that may have unintended pharmacological consequences,” said Sasisekharan.

Heparin consists of a long, complex chain of repeating sugar molecules. The contaminant, which is derived from animal cartilage, has a structure very similar to that of heparin and thus cannot be identified with the tests normally used to inspect batches of heparin.

It is unclear whether the contaminant got into the heparin during the manufacturing process, or how and where contamination could have occurred during the process. More investigations are needed to address this issue.

Traditional heparin safety screens test only for contaminants such as protein, lipids or DNA, and thus would not detect the presence of sugar chains that do not belong. Sasisekharan's laboratory has played a key role in developing new technologies for analyzing complex sugars. Using the new technology, the research team was able to detect the presence of the faulty sugars.

“In addition to being vital for public health, identifying the recent impurity in heparin was a chemical triumph,” said Jeremy M. Berg, director of the National Institute of General Medical Science, which supported the work. “The research team accomplished this difficult task by using a unique combination of scientific techniques that might in the future be used to detect other impurities in pharmaceutical materials.”

More than 100 patients have experienced adverse reactions after receiving the tainted heparin. Symptoms include extremely low blood pressure, swelling of the skin and mucus membranes, shortness of breath, and abdominal pain.

The researchers found that the contaminant activates two inflammatory pathways: one that initiates blood clotting and dilation of the blood vessels, and one that produces anaphylactic toxins. The first leads to a dangerous decrease in blood pressure, the second a serious allergic reaction. In blinded laboratory tests, the contaminated heparin activated the biological pathways, while normal heparin did not.

Sasisekharan emphasized the remarkable willingness of dozens of scientists across the globe to work together to rapidly resolve what might otherwise have left people with serious uncertainties about drug safety.

“The generosity and willingness of people to do whatever they could to help solve this problem was unlike anything I'd experienced before. It is extremely satisfying to see how teamwork has resulted in the application of rigorous, peer-reviewed science that helps to keep our medicines safe,” he said.

Sasisekharan expressed his hope that such effective teamwork will extend to other dimensions of public health, in which rigorous team-based science leads not only toward safer drugs, but also toward safer foods and a safer environment.

Source: Massachusetts Institute of Technology

Explore further: US issues guidelines to avoid heparin contamination

Related Stories

US issues guidelines to avoid heparin contamination

February 10, 2012
Four years after US drug-maker Baxter International's blood thinner heparin was contaminated in China, causing dozens of deaths, US regulators on Friday issued draft guidelines for safe production.

Researchers create synthetic version of heparin for use in kidney patients

February 25, 2014
Researchers at Rensselaer Polytechnic Institute and the University of North Carolina at Chapel Hill (UNC) have created a synthetic form of low-molecular-weight heparin that can be reversed in cases of overdose and would be ...

Scientists find safer way to make common blood thinner heparin

April 6, 2016
For the first time, scientists have discovered a way to make the common blood-thinning medication heparin using human cells in the laboratory. The new method could offer a safer alternative to current heparin production methods, ...

Heparin derived from cattle is equivalent to heparin from pigs, study finds

October 5, 2016
As demand for the widely used blood thinning drug heparin continues to grow, experts worry of possible shortages of the essential medication.

Biotech to the rescue

April 28, 2014
MIT professor Ram Sasisekharan's three biotech companies—Momenta Pharmaceuticals, Cerulean Pharma, and Visterra—share a similar goal. "It's about the impact we can have on patient care," says Sasisekharan, the Alfred ...

Blood thinning drug helps in understanding a natural HIV barrier

March 23, 2015
A blood thinning agent is helping researchers at the University of East Anglia understand more about the body's natural barriers to HIV.

Recommended for you

Fabric imbued with optical fibers helps fight skin diseases

February 23, 2018
A team of researchers with Texinov Medical Textiles in France has announced that their PHOS-ISTOS system, called the Fluxmedicare, is on track to be made commercially available later this year. The system consists of a piece ...

Low-calorie diet enhances intestinal regeneration after injury

February 22, 2018
Dramatic calorie restriction, diets reduced by 40 percent of a normal calorie total, have long been known to extend health span, the duration of disease-free aging, in animal studies, and even to extend life span in most ...

Artificial intelligence quickly and accurately diagnoses eye diseases and pneumonia

February 22, 2018
Using artificial intelligence and machine learning techniques, researchers at Shiley Eye Institute at UC San Diego Health and University of California San Diego School of Medicine, with colleagues in China, Germany and Texas, ...

Gut microbes protect against sepsis—mouse study

February 22, 2018
Sepsis occurs when the body's response to the spread of bacteria or toxins to the bloodstream damages tissues and organs. The fight against sepsis could get a helping hand from a surprising source: gut bacteria. Researchers ...

Breakthrough could lead to better drugs to tackle diabetes and obesity

February 22, 2018
Breakthrough research at Monash University has shown how different areas of major diabetes and obesity drug targets can be 'activated', guiding future drug development and better treatment of diseases.

Fertility breakthrough: New research could extend egg health with age

February 22, 2018
Women have been told for years that if they don't have children before their mid-30s, they may not be able to. But a new study from Princeton University's Coleen Murphy has identified a drug that extends egg viability in ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

SDMike
not rated yet Apr 25, 2008
China again. But no punishment of either China or Baxter. Looks like it's up to those nasty trial lawyers to go after Baxter. The Chinese are out of reach and our federal government is far more interested in playing footsy with the ChiComs than protecting Americans. Besides, who would fund Democrats if not the Chinese?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.