Abstract
Unfractionated heparin (UFH) remains the agent of choice for the prevention and treatment of venous thromboembolism (VTE).1 The anticoagulant activity of UFH is primarily mediated through its specific binding to antithrombin III (AT-III)2,3 resulting in a marked enhancement of its ability to inactivate thrombin, factor Xa, and other blood coagulation serine-proteases. UFH is known to bind to a number of plasma proteins including hystidine-rich glycoprotein,4 vitronectin,5 fibronectin,6 von Willebrand factor,7 and platelet factor-48. The binding of UFH to AT-III and HC-II is mediated by a specific saccharide sequence,1,3,9 that is present in approximately one-third of the molecules of commercial UFH,10,11 while the non-specific binding of UFH to the other plasma proteins appears to be related to heparin molecular size, the higher molecular weight chains showing a greater affinity binding than those of lower molecular weight12.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hirsh J. Heparin. N Eng J Med 1991; 324: 1565–74.
Rosemberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490–505.
Choay J, Petitou M, Lormeau JC, Sinay P, Casu B, Gatti G. Structure activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Comm 1983; 116: 492–99.
Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidine-rich glycoprotein: mechanism and role in the neutralization of heparin in plasma. J Biol Chem 1983; 258:3803–08.
Preissner KT, Muller-Berghaus G. Neutralization and binding of heparin by S-protein/vitronectin in the inhibition of factor Xa by antithrombin III. J Biol Chem 1987; 262:12247–53.
Mosesson MV, Amrani DL. The structure and biologic activities of plasma fibronectin. Blood 1980; 56: 145–158.
Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, Marques D. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest 1991; 87: 1787–93.
Rucinski B, Niewiarowski S, Strzyzewski M, Holt JC, Mayo KH. Human platelet factor 4 and its C-terminal peptides: heparin binding and clearance from the circulation. Thromb Haemost 1990; 63: 493–98.
Lindahl U, Backström G, Höök M, Thunberg L, Fransson LA, Linker A. Structure of the antithrombin-binding-site of heparin. Proc Natl Acad Sci USA 1979; 76: 3198–202.
Höök, Björk I, Hopwood J, Lindhai U. Anticoagulant activity of heparin: separation of high-activity and low-activity species by affinity chromatography on immobilized antithrombin. FEBS Lett 1976; 66:90–93.
Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive form of heparin. Biochem Biophys Res Comm 1976; 69:570–77.
Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Söderström G. Molecular weight dependency of the heparin potentiated inhibition of thrombin and activated factor X. Effect of heparin neutralization in plasma. Thromb Res 1979; 15: 531–41.
Young E, Hirsh J. Contribution of red blood cells to the saturable mechanism of heparin clearance. Thromb Haemost 1990: 64; 559–63.
Casu B, Diamantini G, Fedeli G, Mantovani M, Oreste P, Pescador R, Porta R, Prino G, Torri G. Zoppetti G. Retention of antilipemic activity by periodate-oxidized non-anticoagulant heparins. Arzneim Forsch/Drug Res 1986; 637–42.
Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 10: 399–410.
Rowland M and Tozer TN. Clinical Pharmacokinetics: Concepts and Applications. 2nd ed., Lea and Febiger, Kent, UK, 1989.
Cipolle RJ and Rodvold KA. Heparin. In: Applied Pharmacokinetics. Principles of Therapeutic Drug Monitoring. Evans WE, Schentag JJ, Jusko WJ Eds., 3rd ed., Applied Therapeutics, Inc. Vancouver WA, 1986, Chapter 30, pp 1–39.
Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151: 333–37.
Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparine resistance. Thromb Haemost 1992; 67: 639–43.
Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1–16.
Agnelli G, lorio A, Renga C, Boschetti E, Nenci GG, Ofosu FA and Hirsh J. Prolonged anti-thrombin activity of low molecular weight heparins: clinical implications for the treatment of thromboembolic diseases. Circulation, 1995 (in press)
Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular wieght heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39: 631–36.
Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama M. The antithrombotic activity and pharmacokinetics of enoxaparin, a low molecular weight heparin, in human given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988; 28: 609–18.
Handeland GF, Abildgaard U, Holm U, Amesen KE. Dose adjusted heparin treatment of deep vein thrombosis: a comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39: 10712.
Barzu T, Molho P, Tobelem G, Petitou M, Caen J. Binding and endocytosis of heparin by human endothelial cell in culture. Biochim Biophys Acta 1985; 845: 196–203.
Lane DA, Pejler G, Glynn AM, Thompson EA, Lindhai U. Neutralization of heparin-related saccharides by histidine-rich glycoprotein and platelet factor 4. J Biol Chem 1986; 261: 3980–86.
Dawes J, Pavuk N. Sequestration of therapeutic glycosaminoglycans by plasma fibronectin. Thromb Haemost 1991; 65: 829 (abstr).
Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, Marques D. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest 1991; 87: 1787–93.
Young E, Cosmi B, Weitz J, Hirsh J. Comparison of non-specific binding of unfractionated heparin and low molecular weight heparin (enoxaparin) to plasma proteins. Thromb Haemost 1993; 70: 625–630.
Agnelli G, Renga C, lorio A, Nenci GG, Young E, Hirsh J. Ex-vivo comparison of the non-specific binding of unfractionated heparin and enoxaparin to plasma proteins. Thromb Haemost 1993; 69: 857 (Abstr).
Agnelli G, lorio A, Renga C, Nenci GG. Non-specific binding of unfractionated and low molecular weight heparins to plasma proteins after administration in healthy volunteers, (submitted)
Young E, Wells P, Holloway S, Weitz J, Hirsh J. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994; 71:300–04.
Hirsh J. Low molecular weight heparins. Decker Periodicals Inc., Hamilton, Canada, 1994.
Cosmi B, Young E, Weitz JI, Hirsh J. A comparison of the plasma recovery of unfractionated heparin with that of dermatan sulfate in patients with thromboembolic diseases. Thrombosis and Haemostasis 1993, 69(6), 413.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Plenum Press, New York
About this chapter
Cite this chapter
Iorio, A., Alatri, A., Agnelli, G. (1996). Non-Anticoagulant Actions of Glycosaminoglycans. In: Harenberg, J., Casu, B. (eds) Nonanticoagulant Actions of Glycosaminoglycans. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0371-8_8
Download citation
DOI: https://doi.org/10.1007/978-1-4613-0371-8_8
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-8021-4
Online ISBN: 978-1-4613-0371-8
eBook Packages: Springer Book Archive