Heparin has been in the spotlight recently. The U.S. Food and Drug Administration (FDA) began receiving reports of allergic reactions to heparin in January 2008. The extent and significance of the problem have become increasingly clear over the subsequent months, and it has been the topic of much news and debate.
The FDA has received reports of 131 deaths among individuals exposed to heparin between January 2007 and April 13, 2008. Of these, 81 deaths were thought to be linked to heparin use, given the reported clinical syndromes of allergic reactions/hypotension. Hundreds of cases of non-fatal allergic reactions have also been reported in the United States and in 10 other countries worldwide. Following the initial reports of adverse outcomes, Baxter Healthcare Corporation, the supplier of the majority of heparin in the United States, recalled all heparin formulations in February. Covidien and B. Braun, other companies that supply heparin in the United States, subsequently issued heparin recalls in March. More recently, Medtronic (makers of heparin-coated medical devices) and Atrium Medical Corporation (makers of heparin-coated drainage catheters) have also issued product recalls.
Heparin is prepared from porcine intestinal mucous membranes. The active ingredient of heparin manufactured by many companies is produced in China, where the initial steps of procuring the active ingredient occurs at unregulated "workshops," often run as family operations before being sold to larger manufacturing plants via "consolidators." Contamination of heparin with over-sulfated chondroitin sulfate (OSCS) at some early point in this manufacturing "pipeline" has been identified as the cause of the allergic phenomena. While chondroitin sulfate is also a glycosaminoglycan, it does not occur naturally in the over-sulfated form that is structurally similar to heparin.
A group of researchers led by Dr. Ram Sasisekharan at the Massachusetts Institute of Technology investigated the link between OSCS and the reported allergic reactions. Heparin lots were procured from the FDA (13 associated with adverse events, 16 without) and analyzed for the presence of OSCS in a blinded fashion. All 13 heparin lots associated with adverse events showed evidence of contamination with OSCS ranging from 2 percent to 27 percent of the total glycosaminoglycan content. The contaminated heparin samples also demonstrated the ability to activate the kinin contact system (kallikrein activation) while natural chondroitin sulfate A did not. Additionally, contaminated heparin induced the production of complement C5a, which was dependent on activation of the contact system via factor XII activation. These findings were confirmed in a pig model by infusion of both contaminated and control heparin, as well as synthetic OSCS. While the animal studies showed induction of kallikrein with contaminated heparins, it did not always result in clinical manifestations, suggesting a possible role for presence of additional risk factors and variations in regulatory mechanisms. These findings may also explain why certain subsets of patients, such as those receiving hemodialysis, may be more susceptible to adverse outcomes. The results of these studies were recently published in the New England Journal of Medicine,1 and the authors should be commended for their contributions.
Investigations into the source of this contamination have revealed many irregularities in the manufacturing "pipeline." It appears that the contamination of heparin was intentional, as OSCS does not occur naturally. The lack of regulation of overseas manufacturing plants, as well as the FDA itself, has come under significant criticism. It is apparent that current budget restrictions significantly limit the capabilities of this organization to inspect foreign manufacturing plants (>500) every two years — the norm within the United States. This issue has received considerable attention within the House and the Senate in the last few months, and whether this will result in implementation of useful steps to prevent such tragedies from occurring again remains to be seen.
