Cambridge, MA- More details of the contaminant found in heparin—oversulfated chondroitin sulfate (OSCS)—and the mechanism by which it is believed to bring about adverse events have now been published in two separate papers [1,2].

At a press conference earlier this week, Dr Janet Woodcock (director of the FDA's Center for Drug Evaluation and Research) said: "This solid mechanistic link between OSCS and the type of adverse reactions seen strengthens considerably the hypothesis that this contaminant is responsible," although regulators from China, where the contaminant has been traced to, have said they are not convinced that OSCS is the cause of the adverse events.

The two published papers are written by two teams of scientists, both of which are led by Dr Ram Sasisekharan (Massachusetts Institute of Technology, Cambridge, MA). In one paper, published online April 23, 2008 in Nature Biotechnology, more details of the chemical structure of the oversulfated chondroitin sulfate contaminant are reported, and tests that can be used to detect it are described.

The other paper, published online on the same day in the New England Journal of Medicine (NEJM), describes the mechanism by which OSCS could induce the type of adverse reactions seen with heparin, which have included hypotension, facial swelling, tachycardia, urticaria, and nausea.

The authors of the NEJM paper report that OSCS can directly activate the contact system, and in laboratory studies, it induced generation of C3a and C5a—potent anaphylatoxins derived from complement proteins. In addition, they say that OSCS directly activates the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. They further note that OSCS can induce a profound hypotensive response in pigs, which the authors say provides "a potential biologic link between the contaminant and the anaphylactic reactions seen in affected patients."

They add: "The finding that hypotension did not develop in all animals treated with OSCS-contaminated heparin, even at a relatively high dose, is consistent with the observation that the majority of patients who received contaminated heparin did not experience an adverse event. However, it is important to note that all animals treated with OSCS-contaminated heparin showed evidence of kallikrein activation in vivo, even in the absence of clinical signs."

They also have a possible explanation as to why many of the adverse reactions have been seen in patients on dialysis. They explain that dialysis patients are already at high risk of hypotension because the dialysis membrane can also activate the contact system and that ACE inhibitors, often taken by such patients, inhibit the breakdown of bradykinin. "Exposure to OSCS-contaminated heparin may further increase the risk and could potentially trigger an adverse event," the scientists say.

They add that these findings suggest that a simple in vitro bioassay could help protect the global supply of heparin, by allowing the screening of heparin lots for the presence not only of OSCS but also of other polysulfated contaminants that may have unintended pharmacological consequences.