Researchers unravel heparin death mystery

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

Related stories:

Chemists move closer toward developing safer, fully-synthetic form of heparin
Chemists are reporting a major advance toward developing a safer, fully-synthetic version of heparin, the widely used blood thinner now produced from pig intestines. The U. S. Food and Drug Administration last spring linked contaminated batches of the animal-based product, imported from China, to more than 80 deaths and hundreds of allergic reactions among patients exposed to the drug for kidney dialysis and other conditions.
Researchers study prevention of blood clots in cancer patients
As more individuals with cancer are being treated as outpatients, the University of Rochester Medical Center is working on an emerging problem: how to prevent the life-threatening blood clots that can accompany some newer cancer drugs.
Belt and braces approach may prevent deep vein thromboses
Combining short periods of leg compression with medications such as heparin is more effective at preventing blood clots in high-risk patients than using either preventative measure alone. A team of Cochrane Researchers believe that this 'belt and braces' approach can significantly decrease a patient's risk of deep vein thrombosis (DVT).
Boosting survival of insulin-cell transplants for Type 1 Diabetes
Researchers in Japan are reporting a discovery that could improve the effectiveness and expand the use of transplants of insulin-producing cells to treat diabetes. Their study is scheduled for the July 16 issue of ACS' Bioconjugate Chemistry. Insulin-dependent, or Type 1, diabetes affects about 800,000 people in the United States.
New blood clot guidelines for pregnant women
Blood clot recommendations highlight challenges for pediatric and pre-surgery populations
New evidence-based guidelines address the prevention and management of thrombosis in key patient populations and reinforce recommendations related to the routine use of preventive therapies. Published as a supplement in the June issue of CHEST, the peer-reviewed journal of the American College of Chest Physicians (ACCP), Antithrombotic and Thrombolytic Therapy: ACCP Evidence-Based Clinical Practice Guidelines, Eighth Edition was developed by an international panel of 90 experts and includes more than 700 of the most comprehensive recommendations related to the prevention, treatment, and long-term management of thrombotic disorders. The guidelines include chapters on the challenges in preventing and treating thrombosis in pregnant women and children, and on managing peri- and postoperative patients, while also reinforcing previous guidelines related to the routine use of preventive therapies, including aspirin.
US Pharmacopeia announces revised heparin monographs and reference standards
Standards updated in response to public health threat associated with blood-thinning drug's adulteration with over-sulfated chondroitin
The U.S. Pharmacopeial (USP) Convention announces that revised monographs for heparin sodium and heparin calcium in the United States Pharmacopeia (USP) are now available and official on the USP Web site. The revised monographs are accompanied by two new and two updated official USP Reference Standards. These public standards allow any party—and particularly the Food and Drug Administration (FDA) and manufacturers—to test heparin sodium and calcium drug substances to assure their quality. All drug manufacturers who market heparin in the United States are required to meet these newly revised standards. The heparin monographs were updated in the interest of public health following the deaths of more than 200 people earlier this year. These deaths are suspected to have resulted from the adulteration of the blood thinner with over-sulfated chondroitin, which is derived from the chemical chondroitin and used in dietary supplements.
Fewer than 1 in 5 patients receive treatment to prevent life-threatening blood clots
Fewer than 1 in 5 patients received post-discharge therapy to prevent life-threatening blood clots — venous thrombosis — after hip- or knee-replacement surgery, report Rahme and colleagues in a retrospective cohort study. Venous thrombosis is one of the leading causes of death among hospital patients. However, elderly patients have a 70% lower chance of dying within 3 months if they take an anticoagulant drug to prevent blood clots.
Landmark study reveals superiority of bivalirudin in heart attack patients at 30 days
The Cardiovascular Research Foundation (CRF) announced today that the New England Journal of Medicine published results of the HORIZONS AMI trial which showed the use of the anticoagulant bivalirudin following angioplasty in heart attack patients reduced net adverse clinical events by 24 percent compared to the standard treatment, as well as reduced the risk of overall mortality by 33 percent and cardiac mortality by 38 percent.

News discussion:

Medicine & Health news