Contaminated heparin associated with adverse clinical events and activation of the contact system

Takashi Kei Kishimoto, Karthik Viswanathan, Tanmoy Ganguly, Subbiah Elankumaran, Sean Smith, Kevin Pelzer, Jonathan C. Lansing, Nammalwar Sriranganathan, Ganlin Zhao, Zoya Galcheva-Gargova, Ali Al-Hakim, Gregory Scott Bailey, Blair Fraser, Sucharita Roy, Thomas Rogers-Cotrone, Lucinda Buhse, Mark Whary, James Fox, Moheb Nasr, Gerald J. Dal PanZachary Shriver, Robert S. Langer, Ganesh Venkataraman, K. Frank Austen, Janet Woodcock, Ram Sasisekharan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2457-2467
Number of pages11
JournalNew England Journal of Medicine
Volume358
Issue number23
DOIs
StatePublished - Jun 5 2008
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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