A Detailed Evaluation of the Structural and Biological Effects of Alkaline O-Desulfation Reactions of Heparin

Abstract

Heparin has enjoyed over 50 years of clinical use as an anticoagulant and antithrombotic drug. During this period many additional and potentially useful pharmacological properties of heparin have been observed in clinical use, preclinical models and in vitro biological assays. More recently it has been postulated that many of these other pharmacological effects are related to non-anticoagulant activities of heparin and heparan sulfate structures. Extensive research efforts over the years have established that the diverse pharmacological activities of heparin and heparan sulfate-like substances are due to both specific and non-specific ionic interactions with proteins and other biological molecules. These interactions are mediated by the physicochemical parameters of the heparin polymer that include, sequence composition, charge distribution, overall charge density and molecular size (degree of polymerization). The well characterized pentasaccharide sequence responsible for the heparin-antithrobin III (ATIII) interaction,¹ and the minimal hexasaccharide sequence responsible for the heparin-bFGF interaction^2,3 are examples of interactions or activities of heparin mediated by specific oligosaccharide sequences. On the other hand, the interaction of heparin with the coagulation cofactor, heparin cofactor II (HCII) is more prototypical of the non-specific interactions of heparin, where the overall charge density and molecular weight of the polymer chain are more critical than the specific sequence and charge distribution.⁴

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