Abstract
Abstract 4322The main contaminant in heparin and low molecular weight heparins reported during the heparin crisis (2007–8) was characterized to be oversulfated chondroitin sulfate (OSCS). However, several other sulfated glycosaminoglycans have also been reported to be present. Dermatan sulfate, heparan sulfate and chondroitin sulfate represent heparin byproducts and are invariably present in different proportions in heparin preparations. Hypersulfated derivatives of these are also found as contaminants. The chondroitin sulfate obtained from mammalian tissues and cartilage can be hypersulfated using simple chemical sulfonation techniques such as the chlorosulfonic acid to produce varying degrees of sulfation. The molecular profile of OSCS can be optimized utilizing various depolymerization methods to mimic the required molecular profile of heparin. Moreover, mixing of the molecular mass optimized OSCS to heparin exhibit the anticoagulant potencies in the pharmacopeial assays that are indistinguishable by the methods used prior to 2007. Initial studies carried out to obtain OSCS from bovine, porcine, squid and shark cartilage resulted in the generation of an almost perfect polymer mixture whose molecular profile was similar to heparin (14–16 Kda). The mixing of some of these OSCS preparation to heparin also showed either additive or synergistic effects in the anticoagulant assays. However, the OSCS preparations were resistant to heparinase digestion and some of the other chemical digestion processes. Several other heparinoids such as the galactans, sulfaminoheparosans and sulfated dextrans can also be used to contaminate heparins. Based on these observations, the development of OSCS contaminant was a result of a careful optimization of the molecular profile of non heparin GAG derived oversulfated derivatives and the knowledge of their biologic effects. Despite the implementation of sophisticated analytical techniques such as NMR and mass spectrometry along with the modified biochemical assays for heparin characterization, the heparin molecule renders it to additional approaches for adulteration utilizing chemically and biologically rational approaches. Disclosures:No relevant conflicts of interest to declare.
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