Actions of Heparin Contaminant Revealed
The contaminant in recalled heparin lots appears to trigger hypotension and other adverse reactions by activating the kinin-kallikrein pathway and generating anaphylactoid complement proteins. Testing of the isolated contaminant, oversulfated chondroitin sulfate, and a synthetically generated version on human plasma and in pigs was reported in today’s NEJM.
Among the most intriguing findings was the fact that not all animals treated with the contaminated heparin developed adverse clinical signs; however, all treated animals demonstrated activation of kallikrein. On the basis of this observation, the authors speculate that some patients who received the tainted heparin, such as those undergoing dialysis, may have been more vulnerable to the contaminant’s contact-system-induced hypotensive effects, because of concurrent exposure to the dialysis membrane (which also activates the contact system) or treatment with ACE inhibitors (which block bradykinin degradation).
The authors conclude that a simple in vitro bioassay that assesses kallikrein activity, in addition to more sophisticated analytic tests, will aid the screening of heparin lots for oversulfated chondroitin sulfate and other polysulfated contaminants.*
*Dermatan sulfate, a known heparin impurity, was found in most of the contaminated lots; however, the compound’s presence was not associated with kallikrein activity.