Kishimoto TK et al. (2008) Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358: 2457–2467

In January 2008, clusters of acute hypersensitivity reactions, characterized by hypotension and tachycardia, were reported in patients undergoing dialysis in the US. Investigations revealed that these reactions were caused by contaminated heparin samples, leading to two recalls of the drug. The contaminant was identified as an unusual oversulfated form of chondroitin sulfate (OSCS), but no biological link between OSCS and the adverse clinical events had been established. Kishimoto et al. have now determined that OSCS leads to the observed adverse events via activation of kallikrein, which can stimulate production of the vasoactive mediator bradykinin.

The authors showed that OSCS-contaminated heparin samples induced kallikrein amidolytic activity in human plasma at clinically relevant concentrations of heparin. Purified and synthetic OSCS also caused kallikrein activation, whereas uncontaminated heparin had no effect on the kallikrein system. Furthermore, contaminated heparin induced generation of the complement protein fragments C3a and C5a, which are potent anaphylatoxins. Experiments conducted using factor-XII-depleted plasma suggest that OSCS generates these fragments by a pathway that is dependent on kallikrein activation through factor XII.

In in vivo studies, two out of six pigs that were injected with contaminated heparin samples displayed hypotension. Importantly, rapid induction of kallikrein activity was observed in all six pigs, even when no changes in blood pressure occurred.

The authors conclude that an in vitro assay for kallikrein amidolytic activity can enable easy screening for OSCS and could help to protect the global heparin supply from further contamination.