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Oversulfated chondroitin sulfate is not the sole contaminant in heparin

Nature Biotechnology volume 28, pages 203–207 (2010)Cite this article

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To the Editor:

Contaminated heparin was associated with at least 149 deaths in 2007 and 2008, according to the information published at the US Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ucm112669.htm). Sasisekharan and his colleagues1,2,3 have analyzed 6 lots of heparin associated with the contamination event and 28 lots of heparin produced by a heparin manufacturer from 2004 to 2007 (ref. 2). Using NMR analysis, they report that the contaminants in heparin include an impurity, specifically dermatan sulfate, and a contaminant, oversulfated chondroitin sulfate (OSCS) that is presumed to be derived from animal cartilage1. Work in our laboratory analyzing the same 28 heparin samples reveals the presence of other contaminants in heparin—some oversulfated and some undersulfated—all of which, like dermatan sulfate and OSCS, are found in, or can be made from, heparin by-product (a highly variable waste product comprising heparan sulfate, dermatan sulfate and chondroitin sulfate generated during heparin purification from crude heparin). With the exception of dermatan sulfate and OSCS, which can be definitively detected by NMR, our results suggest these additional contaminants cannot be distinguished from heparin in samples because of their similar NMR profiles2 and similar rates of migration under capillary electrophoresis and anion exchange high-performance liquid chromatography (HPLC). Taken together, our findings suggest the need for further work to unambiguously identify and characterize additional contaminants present in different batches of heparin.

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Figure 1: Galactosamine-containing GAGs in heparin.
Figure 2: Proton chemical shifts of oversulfated heparan sulfate were eliminated in the presence of heparin.

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Acknowledgements

The authors would like to thank H. Ye and J. Reepmeyer of the FDA for purification of heparin contaminants and capillary electrophoresis analysis of heparin samples. The authors would like to thank A. d'Avignon of Washington University for the analysis of samples by NMR. The authors also thank J. Esko, E. Conrad, S. Kornfeld, J. Baenziger and D. Tollefsen for their suggestions, comments and critiques of the manuscript. L.Z. thanks E. Unanue, S. Santoro, J. Ladenson and N. Brown for their support in establishing a GAG structure/function laboratory at Washington University. L.Z. thanks J. Metz for critical reading of the original manuscript. This work is supported in part by US National Institutes of Health grant R01GM069968 to L.Z. and a St. Louis Children's Discovery Institute Research Fund to L.Z.

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  1. Jing Pan, Yi Qian and Xiaodong Zhou: These authors contributed equally to this work.

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  1. The Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Jing Pan, Yi Qian, Xiaodong Zhou, Andrew Pazandak, Sarah B Frazier, Peter Weiser, Hong Lu & Lijuan Zhang

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  1. Jing Pan
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Pan, J., Qian, Y., Zhou, X. et al. Oversulfated chondroitin sulfate is not the sole contaminant in heparin. Nat Biotechnol 28, 203–207 (2010). https://doi.org/10.1038/nbt0310-203

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