Heparin contamination -- newest findings

A series of adverse anaphylactic like reactions, mostly in dialysis patients, led to recall of Baxter Pharmaceutical brand Heparin in January, 2008.  Raw material for this heparin was sourced in China and a contaminate was suspected.  Baxter is the source for about half of the heparin used in the United States.  A supply loss of this magnitude is serious considering the ubiquity of heparin use.  Two papers from overlapping groups of investigators have used complex chemical techniques to identify the contaminate (an oversulfated chondroitin sulfate, not found in nature) and have linked this contaminate to direct activation of the kinin-kallikrein pathway in human plasma and the potential production of bradykinin, a potent vasoactive mediator.  This contaminate also generates C3a and C5a which are potent vasoactive mediators.

            Of particular interest is the speed of investigation and publication.  The first notification from the Centers for Disease Control of a potential problem was January 7, 2008.  The Heparin recall is dated January 17 and the research described above was done, the papers written, accepted and available online about 14 weeks later.  Clearly the nearly 29 investigators listed as authors, in roughly 8 laboratories made this work their first priority.

            Considering the nature of the contaminate and the fact that the authors have proposed screening techniques it is unlikely that this particular contaminate will re-occur however certain lesions can be learned.  1) The importance of reporting adverse or unexpected reactions to the FDA Medwatch web site (http://www.fda.gov/medwatch/ ).  The initial reports related to heparin came from the Missouri Department of Health to the FDA.  2) Be alert to unusual responses to medications.  The symptoms that occurred are not typical for heparin (hypotension, generalized sensations of warmth, numbness or tingling in the extremities, shortness of breath, chest tightness, and nausea.  3) Be prepared to treat the unexpected.  Though most patients recovered with cessation of the Heparin there may be as many as 103 deaths.

1)      Guerrini M et al: Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events.  Nature Biotechnology.  April 23, 2008 Advance online publication DOI 10.1038/nbt1407

2)      Kishimoto TK et al: Contaminated heparin associated with adverse clinical events and activation of the contact system.  NEJM April 23, 2008 Published on line DOI 10.1056/NEJMoa0803200

3)      MMWR: Acute allergic-type reactions among patients undergoing hemodialysis – multiple states 2007 – 2008.  MMWR Weekly 2008;57:124-125

            4)   Perrone M: FDA probes deaths from contaminated heparin.  Charleston Gazette. April 9, 2008

David S. Smith, M.D., Ph.D.