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Trigger in heparin deaths confirmed

Contaminant set off allergic-like reactions.

A contaminant found in tainted heparin, the blood-thinner drug that has been linked to dozens of deaths, can trigger severe adverse reactions all by itself, researchers report.

In one study released today, researchers confirm the presence of the chemical, known as oversulphated chondroitin sulphate, in suspect batches of heparin1. Another study found that the compound seems to trigger in pigs the same symptoms that have been seen in patients treated with the contaminated drug2.

Contaminated heparin produces similar adverse reactions in swine. Credit: ANTONIA REEVE / SCIENCE PHOTO LIBRARY

“We show that the contaminated heparin activates two inflammatory pathways, causing severe allergic reactions and low blood pressure,” says bioengineer Ram Sasisekharan of the Massachusetts Institute of Technology in Cambridge, Massachusetts, who led both studies.

The results bolster the findings of the US Food and Drug Administration, which has been investigating the possibility that oversulphated chondroitin sulphate may be responsible for at least 62 deaths in the United States since November. On Monday, the agency announced that tainted heparin had also been distributed to ten other countries. An investigation of heparin supplier Changzhou SPL of Changzhou, China, and associated US distributors is ongoing. Baxter International, which distributed the drug in some of the early cases, recalled all its heparin products at the end of February.

Finding the structure

To investigate the composition of tainted heparin, Sasisekharan and colleagues freeze-dried samples and used nuclear magnetic resonance to analyze their chemical structure. Oversulphated chondroitin sulphate is, like heparin, a complex sugar molecule, and hence it had not been possible to distinguish it before in ordinary safety screening tests.

Heparin is derived from pig intestines. While the contaminant can be made from chemicals derived from animal cartilage, the researchers wrote that it was “highly unlikely” the chemical was produced naturally. Exactly how the chemical entered the heparin manufacturing process is unclear.

The additional structural information should help enhance screening tests for the contaminant, says Sasisekharan.

Adverse effects

In separate work, another team led by Sasisekharan investigated the biological effects of oversulphated chondroitin sulphate. The researchers found that both the tainted heparin and a pure, synthetically-made version of the contaminant trigger enzymes associated with blood clotting. The contaminant also seems to produce two potent substances that can trigger the release of histamines and may account for the allergic reactions reported.

Tests in pigs seemed to confirm this chain of events. Animals that received intravenous treatment with the synthetic contaminant or the tainted heparin showed adverse reactions within minutes. Heart rate increased, and blood pressure and body temperature dropped.

Although the results are suggestive, some caution it may be premature to say for sure that oversulphated chondroitin sulphate is responsible for the heparin deaths. “This certainly doesn’t prove it, but everything is consistent with a scenario whereby this contaminant is responsible,” says chemist Jeremy Berg, director of the National Institute of General Medical Sciences in Bethesda, Maryland.

References

  1. Guerrini, M., et al. Nat. Biotech. 26, doi:10.1038/nbt1407 (2008)

  2. Kishimoto, T.K. et al. New England Journ. Med. 358, doi:10.1056/NEJMoa0803200 (2008).

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Courtland, R. Trigger in heparin deaths confirmed. Nature (2008). https://doi.org/10.1038/news.2008.774

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  • DOI: https://doi.org/10.1038/news.2008.774

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