Heparin: Past, Present, and Future

Abstract

Heparin, the most widely used anticoagulant drug in the world today, remains an animal-derived product with the attendant risks of adulteration and contamination. A contamination crisis in 2007-2008 increased the impetus to provide non-animal-derived sources of heparin, produced under cGMP conditions. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity, while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease. A variety of strategies have been proposed to produce a bioengineered heparin. In this review, we discuss several of these strategies including microbial production, mammalian cell production, and chemoenzymatic modification. We also propose strategies for creating "designer" heparins and heparan-sulfates with various biochemical and physiological properties.

Keywords: Chinese hamster ovary cells; UFH; anti-inflammatory; antitumor; bioengineering; heparan sulfate; heparin; heparin-like molecules; low molecular weight heparin.

Figure 1

Heparin mechanisms within the coagulation cascade. Box A: AT (red) bound with heparin fragments (green) of any length within the unique pentasaccharide sequence can inhibit factor Xa. Box B: AT (red) bound with heparin (green) with chain length >17 disaccharide units can inhibit thrombin (Factor IIa).

Figure 2

Heparin biosynthesis. The glycosaminoglycan-protein linkage region is first formed under the action of glycosyltransferases. The repeating disaccharide units are then elongated by GlcA and GlcNAc transferases. Chain modifications including N-deacetylation and N-sulfonation, O-sulfonations, and epimerization then occur under the actions of the specified enzymes. Monosaccharide symbols in this figure follow the SNFG (Symbol Nomenclature for Glycans) system [15]