Characterization of Unfractionated Heparin: Comparison of Materials from the last 50 Years

Summary

Physicochemical and anticoagulant characteristics of 27 samples from recent batches of commercially produced unfractionated heparin have been determined as part of the process of establishment of the 5^th International Standard Unfractionated Heparin. They have been compared with current heparin standards (European Pharmacopoeia, United States Pharmacopoeia, Chinese), with the 4^th International Standard Unfractionated Heparin, and with the three predecessor International Standards. The results indicate that the 4^th International Standard Unfractionated Heparin, established in 1982, has significantly lower molecular weight and specific activity than recently produced heparin; this is also true of all preceding International Standard Heparins and of the United States Pharmacopoeial standard. The composition of commercial unfractionated heparin may therefore have changed over time; reasons for this are discussed.

Key words

Unfractionated heparin - molecular weight - NMR spectroscopy - anticoagulant activity - International Standard

• References

• 1 Memorandum on a provisional International Standard for heparin. Bulletin of the Health Organisation of the League of Nations 1942; 151-4.
• 2 Report of the Expert Committee on Biological Standardisation. Bull World Health Organ 1947; 01: 7-20.
• 3 Gray E, Walker AD, Mulloy B, Barrowcliffe TW. A collaborative study to establish the 5th International Standard for Unfractionated Heparin. Thromb Haemost 2000; 84: 1017-22.
• 4 Thomas DP, Curtis AD, Barrowcliffe TW. A collaborative study designed to establish the 4^th International Standard for Heparin. Thromb Haemost 1984; 52: 148-53.
• 5 Bangham DR, Mussett MV. The Second International Standard for Heparin. Bull World Health Organ 1959; 20: 1201-8.
• 6 Bangham DR, Woodward PM. A collaborative study of heparins from different sources. Bull World Health Organ 1970; 42: 129-49.
• 7 European Pharmacopoeia. 3rd Edition.. 1997. Assay of Heparin in Biological Assays. 113.
• 8 European Pharmacopoeia. 3rd Edition.. 1997. Monograph for Heparins; Low Molecular Mass: 1997. 0828 934-7.
• 9 Mulloy B, Gee C, Wheeler SF, Wait R, Gray E, Barrowcliffe TW. Molecular weight measurements of low molecular weight heparins by gel permeation chromatography. Thromb Haemost 1997; 77: 668-74.
• 10 Mulloy B, Johnson EA. Assignment of the ¹H-n.m.r. spectra of heparin and heparan sulphate. Carbohydr Res 1987; 170: 151-65.
• 11 Neville GA, Mori F, Holme KR, Perlin AS. Monitoring the purity of pharmaceutical heparin preparations by high-field ¹H-nuclear magnetic resonance spectroscopy. J Pharm Sci 1989; 78: 101-4.
• 12 Shah GA, Dhall TZ, Ferguson I, Davis MR, Graham DT, Pomeroy AR, Dhall DP. An evaluation of the British Pharmacopoeial assay of heparin: a comparison with other methods. J Clin Pathol 1980; 33: 562-5.
• 13 Barrowcliffe TW, Johnson EA, Eggleton CA, Thomas DP. Anticoagulant activities of lung and mucous heparins. Thromb Res 1978; 12: 27-36.