Contaminants in Heparin: Review of the Literature, Molecular Profiling, and Clinical Implications

Background: The contaminant isolated from contaminated heparin was oversulfated chondroitin sulfate (OSCS). Other possible contaminants should be evaluated. Methods: Contaminants were isolated from recalled contaminated heparin and were compared to OSCS from animal sources and to heparin by-products synthetically persulfated. Results: A great variability in molecular weight was observed in the isolated contaminants. Dermatan sulfate with high-molecular-weight in addition to OSCS was detected. Oversulfated chondroitin sulfate from different sources as well as heparin by-products produced activation of prekallikrein to kallikrein at variable rates as measured by the generation of kallikrein. All agents produced activation of the complement system. All compounds formed complexes with platelet factor 4 (PF4) and all produced C-14 serotonin release in the heparin-induced thrombocytopenia (HIT) analysis. The agents also exhibited variable anticoagulant responses that were mostly mediated via heparin cofactor II. Conclusion: These results suggest that heparin contaminants represent a heterogeneous group of oversulfated glycosaminoglycans (OSGAGs) which may mediate multiple pathophysiologic responses.