Article abstract
Nature Biotechnology 26, 669 - 675 (2008)
Published online: 23 April 2008 | doi:10.1038/nbt1407
Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events
Marco Guerrini1,7, Daniela Beccati2,7, Zachary Shriver2,3,7, Annamaria Naggi1, Karthik Viswanathan3, Antonella Bisio1, Ishan Capila2, Jonathan C Lansing2, Sara Guglieri1, Blair Fraser4, Ali Al-Hakim4, Nur Sibel Gunay2, Zhenqing Zhang5, Luke Robinson3, Lucinda Buhse4, Moheb Nasr4, Janet Woodcock4, Robert Langer3,6, Ganesh Venkataraman2,3, Robert J Linhardt5, Benito Casu1, Giangiacomo Torri1 & Ram Sasisekharan3
Abstract
Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side effects indicative of an allergic-type reaction. To identify potential causes for this sudden rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high-resolution analytical techniques. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked 
1
3 to a -N-acetylgalactosamine. The disaccharide unit has an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here.
- Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni," Città Studi, via Giuseppe, Colombo 81, 20133 Milan, Italy.
- Momenta Pharmaceuticals, Inc., 675 West Kendall Street, Cambridge, Massachusetts 02142, USA.
- Department of Biological Engineering, Harvard-MIT Division of Health Sciences & Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, Massachusetts 02139, USA.
- Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, Maryland 20993-0002, USA.
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, Massachusetts 02139, USA.
- These authors contributed equally to this work.
Correspondence to: Ram Sasisekharan3 e-mail: rams@mit.edu
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