Biological Profile of the Hyper/Oversulfated Chondroitin Sulfate Contaminant Isolated from Recalled Heparin

Abstract

An unexpectedly high rate of adverse events and deaths were reported from November 2007 to April 2008 in patients exposed to heparin. Investigations on the quality of heparin revealed an oversulfated chondroitin sulfate (OSCS) contaminant in the heparin. Several reports on the chemical structure and limited biologic actions of OSCS have recently become available. However, no data are available on its anticoagulant and antiprotease effects. Moreover, its interaction with heparin, resulting in the modulation of heparin's anticoagulant activity, is not reported. The isolated contaminant from recalled batches of heparin and several semisynthetic OSCSs were profiled for their in vitro anticoagulant effects. The contaminant and OSCSs both exhibited measurable anticoagulant activity and produced supra-additive effects in the presence of heparin. In addition, in animal models of thrombosis and bleeding, the contaminated heparin produced stronger anticoagulant and bleeding effects than heparin. Thus, in addition to the reported biological actions, the heparin contaminant exerts measurable anticoagulant effects and interacts with heparin to produce supra-additive effects. These studies suggest that the contamination of heparin with OSCS was based on a rational design and prior knowledge of molecular and anticoagulant profiles. These studies also indicate that the OSCS contaminant may itself be heterogeneous and its molecular and biological profiles may vary in different recalled heparins.