Heterogeneity of Unfractionated Heparins Studied in Connection with Species, Source, and Production Processes

Abstract

The heterogeneity of unfractionated heparins (Hep) can be correlated to the species and organs of origin and to the process of production. Heparins, extracted by different, validated processes from different organs and/or tissues (mucosa, thymus, pancreas, placenta, lung, intestine) or mammals (pig, beef, sheep, man) and other vertebrates (chicken), have been examined by HPLC analysis of heparinase digests. By analysis of disaccharides many observations have been made. Porcine mucosa heparin (pm-Hep) was always found to contain higher amounts of the disaccharides delta UA-GlcNS,6S and delta UA-2S-GlcNS,6S, than did bovine mucosa heparin (bm-Hep), whereas bm-Hep always showed higher amounts of the sequence IdoA(2OSO3)-GlcNSO3 than did pm-Hep. These findings mean that the last step of the biosynthesis, the 6-O-sulfation of glucosamine-N-sulfate (GlcNSO3), is accomplished; in bm-Hep, to a lesser extent than in pm-Hep. The 6-O-sulfated molar fractions of pig mucosa, chicken intestine, beef pancreas, beef placenta, and beef lung heparins were higher than the corresponding molar fractions of beef mucosa and beef thymus Heps. Also the manufacturing processes can partially rearrange the heparin structure. Even 6-O-sulfation enrichment (by chromatographic purification) or base-catalyzed displacement of sulfate groups from IdoA2SO3 occurred. The resulting anticoagulant activity roughly correlated with the percentage of trisulfated disaccharide and the 6-O-sulfated molar fraction. The heparin from human placenta was similar to pm-Hep. The observed species- and organ-dependent structural characteristics support the suggestion by Nader and Dietrich (in Heparin, Chemical and Biological Properties, Lane DA, U Lindahl (Eds). Arnold, London, 1989, p 81) on the antipathogenic role of heparin. The 6-O-sulfation of glucosamine, present in higher amounts in organs that function as barriers against many foreign bodies, like lung, placenta, intestine of chicken and pig, may play an important role in this antipathogenic action of Hep.

Pharmacology of Heparin and Related Drugs

“…This finding was exploited by Choay et al (1983), leading to the development of a chemically synthesized pentasaccharide that is now used clinically as an antithrombotic. Heparin is a true biologic and can be extracted from many animal sources (Bianchini et al, 1997;Nader et al, 2004). The first clinical preparations were extracted from bovine lung in the 1930s and shifted toward porcine mucosa because of the scarcity of bovine lung, as beef was being used as a food source in World War II.…”

Biochemical and functional characterization of glycosaminoglycans released from degranulating rat peritoneal mast cells: Insights into the physiological role of endogenous heparin

“…It is clear from heparin preparations used in medicine that heparin composition varies between species and tissue of origin (46). Heparin from bovine lung differs markedly in the degree of sulphation from porcine intestinal mucosal heparin (22), and both are different from bovine intestinal mucosal heparin (47).…”

Detection of 2-O-Sulfated Iduronate and N-Acetylglucosamine Units in Heparan Sulfate by an Antibody Selected against Acharan Sulfate (IdoA2S-GlcNAc)

“…ϩ/Ϫ HS (kidney section) e ϩϩ HS (kidney section) after NDST treatment Ϫ HS (CHO cells) ϩϩ HS (CHO pgsf17, 2-O-sulfotransferase-deficient) f Ϫ a Heparin form porcine intestinal mucosa and bovine lung contain 3.0% and 0.8% IdoA2S-GlcNAc(6S) units, respectively (33).…”