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Previous Volume 358:2457-2467 June 5, 2008 Number 23 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Avorn, J. Editorial by Schwartz, L. B. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.

Methods Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.

Results The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.

Conclusions Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.

Source Information

From Momenta Pharmaceuticals (T.K.K., T.G., S.S., J.C.L., G.Z., Z.G.-G., G.S.B., S.R., Z.S., G.V.), the Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research (K.V., Z.S., R.S.L., G.V., R.S.), and the Massachusetts Institute of Technology (M.W., J.F.) — all in Cambridge, MA; Virginia–Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg (S.E., K.P., N.S., T.R.-C.); the Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD (A.A.-H., B.F., L.B., M.N., G.J.D.P., J.W.); and Brigham and Women's Hospital and Harvard Medical School, Boston (K.F.A.).

This article (10.1056/NEJMoa0803200) was published at www.nejm.org on April 23, 2008.

Address reprint requests to Dr. Sasisekharan at the Department of Biological Engineering, Harvard–MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., 16-561, Cambridge, MA 02139, or at rams{at}mit.edu.

Full Text of this Article

Related Letters:

Contaminated Heparin
Greinacher A., Warkentin T. E., Kakkar A. K., Bonnefoi M., Austen F., Woodcock J., Sasisekharan R.
Extract | Full Text | PDF  
N Engl J Med 2008; 359:1291-1293, Sep 18, 2008. Correspondence

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