An International Standard for Low Molecular Weight Heparin

Summary

An international collaborative study has been carried out with the aim of establishing an international standard for low molecular weight (LMW) heparin. Three preparations of LMW heparin were assayed against the International Standard for unfractionated heparin (UFH) by 25 laboratories in 13 countries, using nine different assay methods. The results confirmed previous findings of non-parallel assays, wide interlaboratory variability and differences between methods when LMW heparins are assayed against a UFH standard. Use of one of the LMW heparins as a standard for the other two gave parallel assays and much closer agreement between laboratories. The preparation in ampoules coded 85/600 was selected as likely to give the best agreement with the largest number of LMW heparins; potencies were assigned by taking the mean of all the anti-Xa assays, and the mean of the thrombin and APTT assays, to represent the two major groups of activities. Preparation 85/600 has been established by WHO as the 1st International Standard for LMW heparin, with potencies of 1,680 iu/ampoule by anti-Xa assays and 665 iu/ampoule by thrombin inhibition and APTT assays.

Key words

Low molecular weight heparin - Assays - Standardisation

• References

• 1 Kakkar VV, Murray WJ G. Efficacy and safety of low-molecular-weight heparin (CY 216) in preventing postoperative venous thromboembolism: a cooperative studys. Br J Surg 1985; 72: 786-981
• 2 Low molecular weight heparin and its clinical use. In: International Enoxaparin Symposium, San Diego. Samama M, Hemker HC. (eds) Haemostasis 1986; 16: 65-188
• 3 Fragmin Satellite Symposium to the Xth Congress of the International Society for Thrombosis and Haemostasis, San Diego. Salzman EW, Sherry S. (eds) Haemostasis. 1986 16. Suppl 02
• 4 New approaches to thromboprophylaxis. Bergqvist D, Hedner U. (eds) Acta Chir Scand 1988 Suppl 543
• 5 Thomas DP, Barrowcliffe TW, Curtis AD. Low molecular weight heparin: a better drug. Haemostasis 1986; 16: 87-92
• 6 Thomas DP. Current status of low molecular weight heparin. Thromb Haemostas 1986; 56: 241-242
• 7 Salzman EW. Low molecular weight heparin – is small beautiful. N Engl J Med 1986; 315: 957-959
• 8 Schmitz-Huebner U, Bünte H, Freise G, Reers B, Rüschemeyer C, Scherer R, Schulte H, van de LooJ. Clinical efficacy of low molecular weight heparin in postoperative thrombosis prophylaxis. Klin Wochenschr 1984; 62: 349-353
• 9 Koller M, Schoch U, Buchmann P, Largrader F, Von Felten A, Frick PG. Low molecular weight heparin (Kabi 2165) as thromboprophylaxis in elective visceral surgery. A randomized, double-blind study versus unfractionated heparin Thromb Haemostas 1986; 56: 243-246
• 10 Johnson EA, Kirkwood TB L, Stirling Y, Perez-Requejo JL, Ingram GI C, Bangham DR, Brozović M. Four heparin preparations: anti-Xa potentiating effect of heparin after subcutaneous injection. Thromb Haemostas 1976; 35: 586-591
• 11 Lane DA, MacGregor IR, Michalski R, Kakkar VV. Anticoagulant activities of four unfractionated and fractionated heparins. Thromb Res 1978; 12: 257-271
• 12 Barrowcliffe TW, Curtis AD, Tomlinson TP, Hubbard AR, Johnson EA, Thomas DP. Standardization of low molecular weight heparins: a collaborative study. Thromb Haemostas 1985; 54: 675-679
• 13 Hirsh J, Barrowcliffe TW. Standardisation and clinical use of LMW heparin: Report of the ICTH Heparin Subcommittee, Brussels, July 1987. Thromb Haemostas 1988; 59: 333
• 14 Campbell PJ. International biological standards and reference preparations. II: Procedures used for the production of biological standards and reference preparations. J Biol Stand 1974; 2: 259-267
• 15 Yin ET, Wessler S, Butler JV. Plasma heparin: a unique, practical, submicrogram-sensitive assay. J Lab Clin Med 1973; 91: 298-305
• 16 Denson KW E, Bonnar J. The measurement of heparin: a method based on the potentiation of anti-factor Xa. Thromb Diath Haemorrh 1973; 30: 471-479
• 17 Eggleton CA, Barrowcliffe TW, Merton RE, Thomas DP. In vitro and in vivo studies of the anti-Xa activity of heparin. Thromb Res 1981; 24: 319-328
• 18 Finney DJ. Statistical Method in Biological Assay. Griffin & Co Ltd; London: 1952
• 19 Thomas DP, Curtis AD, Barrowcliffe TW. A collaborative study designed to establish the 4th International Standard for heparin. Thromb Haemostas 1984; 52: 148
• 20 Thomas DP, Merton RE, Barrowcliffe TW, Thunberg L, Lindahl U. Effects of heparin oligosaccharides with high affinity for antithrombin III in experimental venous thrombosis. Thromb Haemostas 1982; 47: 244-248
• 21 Walenga JM, Fareed J, Petitou M, Samama M, Lormeau JC, Choay J. Intravenous antithrombotic activity of a synthetic heparin pentasaccharide in a human serum induced stasis thrombosis model. Thromb Res 1986; 43: 243-248
• 22 Ofosu FA, Blajchman MA, Modi GJ, Smith LM, Buchanan MR, Hirsh J. The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dematan sulphate, low molecular weight heparin and pentosan polysulphate. Br J Haematol 1985; 60: 695-704
• 23 Fernandez FA, Buchanan MR, Hirsh J, Fenton II JW, Ofosu FA. Catalysis of thrombin inhibition provides an index for estimating the antithrombotic potential of glycosaminoglycans in rabbits. Thromb Haemostas 1987; 57: 286-293
• 24 Bara L, Samama M. The need for standardization of low molecular weight heparin (LMWH). Thromb Haemostas 1986; 56: 418
• 25 WHO Technical Report Series. 1987; 760: 22