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Hamostaseologie 2008; 28(01/02): 51-61
DOI: 10.1055/s-0037-1616922
Original Article
Schattauer GmbH

Natürliche und synthetische Glykosaminoglykane

Molekulare Charakteristika als Grundlage unterschiedlicher ArzneistoffprofileNatural and synthetic glycosaminoglycansMolecular characteristics as the basis of distinct drug profiles
S. Alban
1   Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel
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Publication History

Publication Date:
29 December 2017 (online)

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Zusammenfassung

Antikoagulanzien auf der Basis von Glykosaminoglykanen (GAG) sind seit Jahrzehnten dominierend in der Therapie und Prophylaxe thromboembolischer Erkrankungen. Grundsätzlich ist zwischen den natürlichen GAG-Antikoagulanzien, komplex zusammengesetzten Molekülgemischen, und den synthetischen GAG-Antikoagulanzien, chemisch definierten Oligosacchariden, zu unterscheiden. Zur ersten Gruppe zählen unfraktioniertes Heparin, die verschiedenen niedermolekularen Heparine und Danaparoid. Vertreter der zweiten Gruppe sind Fondaparinux, Idraparinux und das Hexadecasaccharid SR123781A.

Allen gemeinsam ist lediglich eines der Wirkprinzipien des endogenen Antithromboticums Heparansulfat, nämlich die Katalyse der Antithrombin-vermittelten Hemmung von Faktor Xa. Die strukturellen Unterschiede der GAG-Antikoagulanzien bedingen ansonsten zum Teil sehr distinkte Arzneistoffprofile. Dies betrifft ihre Pharmakodynamik, Pharmakokinetik und auch praxisrelevante Aspekte wie Dosierung, Monitoring, Akkumulationsneigung, Antagonisierbarkeit und HIT Typ II.

Summary

For several decades, anticoagulants based on glycosaminoglycans (GAG) are drugs of choice in the therapy and prophylaxis of thromboembolic diseases. In principle, it has to be differentiated between the natural GAG-anticoagulants, which are molecular mixtures with complex composition, and the synthetic GAG-anticoagulants, which are chemically defined oligosaccharides. The former include unfractionated heparin, the various low molecular weight heparins and danaparoid. Representatives of the second group are fondaparinux, idraparinux and the hexadecasaccharide SR123781A.

They share a common mechanism of action together with the endogenous antithrombotic heparan sulfate, i.e. the catalysis of the antithrombin-mediated inhibition of factor Xa. Besides, considerable structural differences between the various GAG-anticoagulants result in rather distinct product characteristics. This concerns their pharmacodynamics, pharmacokinetics as well as practice-related aspects such as dosage, monitoring, accumulation tendency, antagonisation and HIT-Typ II.

Schlüsselwörter

Glykosaminoglykane - unfraktioniertes Heparin - niedermolekulare Heparine - Fondaparinux

Keywords

Glycosaminoglacans - unfractionated heparin - low molecular weight heparins - fondaparinux
 

  • References

  • 1 Abildgaard U. Heparin / low molecular weight heparin and tissue factor pathway inhibitor. Haemostasis 1993; 23 (Suppl. 01) 103-106.
    PubMedGoogle Scholar
  • 2 Al Dieri R, Alban S, Beguin S. et al. Fixed dosage of low-molecular-weight heparins causes large individual variation in coagulability, only partly correlated to body weight. J Thromb Haemost 2006; 4: 83-89.
    PubMedGoogle Scholar
  • 3 Alban S, Gastpar R. Plasma levels of total and free tissue factor pathway inhibitor (TFPI) as individual pharmacological parameters of various heparins. Thromb Haemost 2001; 85: 824-829.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Alban S, Greinacher A. Role of sulfated polysaccharides in the pathogenesis of heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A. (eds). Heparin-Induced Thrombocytopenia. 4th edition. New York: Marcel Dekker; 2007: 67-116.
    Google Scholar
  • 5 Alban S, Scriba GKE. Kommentar zur Monographie ˶Danaparoid sodium” PhEur 5.5, 2090. In: Arzneibuch-Kommentar, Band 5, Monographien D bis H. Stuttgart: Wissenschaftliche Verlagsgesellschaft, Govi-Verlag; 2007: 26. Lieferung.
    Google Scholar
  • 6 Alban S. Chapter 6: Carbohydrates with anticoagulant and antithrombotic properties. In: Witczak ZJ, Nieforth KA. (eds). Carbohydrates in Drug Design. New York: Marcel Dekker; 1997: 209-276.
    Google Scholar
  • 7 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (Suppl. 01) 12-20.
    CrossrefPubMedGoogle Scholar
  • 8 Alban S. Kapitel 20. Kohlenhydrate III: Aminoglykane und Glykosaminoglykane. In: Hänsel R, Sticher O. (Hrsg). Pharmakognosie – Phytopharmazie. Heidelberg: Springer; 2006: 655-704.
    Google Scholar
  • 9 Alban S. Molecular weight-dependent influence of heparin on the form of tissue factor pathway inhibitor circulating in plasma. Semin Thromb Hemost 2001; 27: 503-511.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Barrowcliffe TW, Merton RE, Havercroft SJ. et al. Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides. Thromb Res 1984; 34: 125-133.
    CrossrefPubMedGoogle Scholar
  • 11 Bauersachs R, Alban S. Perioperative bridging with fondaparinux in a woman with antithrombin deficiency. Thromb Haemost 2007; 97: 498-499.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Bendetowicz AV, Kai H, Knebel R. et al. The effect of subcutaneous injection of unfractionated and low molecular weight heparin on thrombin generation in platelet rich plasma--a study in human volunteers. Thromb-Haemost 1994; 72: 705-712.
    PubMedGoogle Scholar
  • 13 Bianchini P, Liverani L, Spelta F. et al. Variability of heparins and heterogeneity of low molecular weight heparins. Semin Thromb Hemost 2007; 33: 496-502.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Bradner JE, Eikelboom JW. Emerging anticoagulants and heparin-induced thrombocytopenia: Indirect and direct factor Xa inhibitors and oral thrombin inhibitors. In: Warkentin T, Greinacher A. (eds). Heparin-Induced Thrombocytopenia. 4th edition. New York: Marcel Dekker; 2007: 441-486.
    Google Scholar
  • 15 Büller HR, van Doormaal FF, van Sluis GL. et al. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 5 (Suppl. 01) 246-254.
    CrossrefPubMedGoogle Scholar
  • 16 Cines DB, Rauova L, Arepally G. et al. Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/ disassembly. J Clin Apheresis 2007; 22: 31-36.
    CrossrefPubMedGoogle Scholar
  • 17 Crowther MA, Berry LR, Monagle PT. et al. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2000; 116: 178-186.
    PubMedGoogle Scholar
  • 18 Dawa J, Pepper DS. Catabolism of low-dose in man. Thromb Res 1986; 43: 1-6.
    CrossrefPubMedGoogle Scholar
  • 19 Depasse F, Gonzalez de Suso MJ, Lagoutte I. et al. Comparative study of the pharmacokinetic profiles of two LMWHs – bemiparin (3500 IU, anti- Xa) and tinzaparin (4500 IU, anti-Xa) – administered subcutaneously to healthy male volunteers. Thromb Res 2003; 109: 109-117.
    CrossrefPubMedGoogle Scholar
  • 20 Forsberg E, Pejler G, Ringvall M. et al. Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature 1999; 400: 773-776.
    CrossrefPubMedGoogle Scholar
  • 21 Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 (Suppl. 02) 24-38.
    PubMedGoogle Scholar
  • 22 Geerts WH, Pineo GF, Heit JA. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 338S-400S.
    CrossrefPubMedGoogle Scholar
  • 23 Gray E, Cesmeli S, Lormeau JC. et al. Low affinity heparin is an antithrombotic agent. Thromb Haemost 1994; 71: 203-207.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Greinacher A, Alban S, Dummel V. et al. Characterization of the structural requirements for a carbohydrate based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost 1995; 74: 886-892.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Greinacher A, Gopinadhan M, Gunther JU. et al. Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies. Arterioscler Thromb Vasc Biol 2006; 26: 2386-2389.
    CrossrefPubMedGoogle Scholar
  • 26 Hamano S, Nishiyama M, Kikuchi S. et al. Study of low molecular weight heparin effect on the relation between anticoagulant activity and antithrombin III affinity. Thromb Res 1992; 66: 299-307.
    CrossrefPubMedGoogle Scholar
  • 27 Hartmann A, Stöbe J, Mickley F. Niedermolekulare Heparine bei Niereninsuffizienz: Klinischer Einsatz. Hämostaseologie 2005; 25: 213-217.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Herault JP, Bernat A, Roye F. et al. Pharmacokinetics of new synthetic heparin mimetics. Thromb Haemost 2002; 87: 985-989.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Herbert JM, Hérault JP, Bernat A. et al. SR123781A, a synthetic heparin mimetic. Thromb Haemost 2001; 85: 852-860.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Herbert JM, Hérault JP, Bernat A. et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91: 4197-4205.
    PubMedGoogle Scholar
  • 31 Hirsh J, Raschke R. Heparin and low moleuclar weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 188S-203S.
    CrossrefPubMedGoogle Scholar
  • 32 Humphries DE, Wong GW, Friend DS. et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 1999; 400: 769-772.
    CrossrefPubMedGoogle Scholar
  • 33 Jeske W, Lormeau JC, Callas D. et al. Antithrombin III affinity dependence on the anticoagulant, antiprotease, and tissue factor pathway inhibitor actions of heparins. Semin Thromb Hemost 1995; 21: 193-200.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Laforest MD, Linhart CN, Guiraud-Vitaux F. et al. Pharmakokinetics and biotransformation of technetium- 99m labelled standard heparin and a low molecular weight heparin (enoxaparin) after intravenous injection in normal volunteers. Br J Haematol 1991; 77: 201-208.
    CrossrefPubMedGoogle Scholar
  • 35 Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A. (eds). Heparin-Induced Thrombocytopenia. 4th edition. New York: Marcel Dekker; 2007: 67-116.
    Google Scholar
  • 36 Lim W, Dentali F, Eikelboom JW. et al. Meta-analysis: Low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006; 144: 673-684.
    CrossrefPubMedGoogle Scholar
  • 37 Lindahl U, Kusche-Gullberg M, Kjellén L. Regulated diversity of heparan hulfate. J Biol Chem 1998; 273: 24979-24982.
    CrossrefPubMedGoogle Scholar
  • 38 Liu J, Pedersen LC. Anticoagulant heparan sulfate: structural specificity and biosynthesis. Appl Microbiol Biotechnol 2007; 74: 263-272.
    CrossrefPubMedGoogle Scholar
  • 39 Ludwig RJ, Alban S, Bistrian R. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory ca- pacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Ludwig RJ, Alban S, Boehncke WH. Structural requirements of heparin and related molecules to exert a multitude of anti-inflammatory activities. Mini Rev Med Chem 2006; 6: 1009-1023.
    CrossrefPubMedGoogle Scholar
  • 41 Mahé I, Aghassarian M, Drouet L. et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 2007; 97: 581-586.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Massonnet-Castel S, Pelissier E, Bara L. et al. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis 1986; 16: 139-146.
    PubMedGoogle Scholar
  • 43 Merton RE, Thomas DP, Havercroft SJ. et al. High and low affinity heparin compared with unfractionated heparin as antithrombotic drugs. Thromb Haemost 1984; 51: 254-256.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Meuleman DG. Orgaran (Org 10172): Its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65.
    PubMedGoogle Scholar
  • 45 Mulloy B. The specificity of interactions between proteins and sulfated polysaccharides. An Acad Bras Cienc 2005; 77: 651-664.
    CrossrefPubMedGoogle Scholar
  • 46 N. N. Niedermolekulare Heparine. Ph. Eur. 5.0, 2005: Monographie 2318.
    PubMed
  • 47 Petitou M, Driguez PA, Duchaussoy P. et al. Synthetic oligosaccharides having various functional domains: potent and potentially safe heparin mimetics. Bioorg Med Chem Lett 1999; 9: 1161-1166.
    CrossrefPubMedGoogle Scholar
  • 48 Petitou M, Herault JP, Bernat A. et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417-422.
    CrossrefPubMedGoogle Scholar
  • 49 Pouplard C, Couvret C, Regina S. et al. Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux. J Thromb Haemost 2005; 3: 2813-2815.
    CrossrefPubMedGoogle Scholar
  • 50 Psuja P. Kinetics of radiolabelled (99mTc) heparin and a low molecular weight heparin fractions CY 216, CY 222 in patients with uncomplicated myocardial infarction. Folia Haematol (Leipz) 1988; 115: 661-668.
    PubMedGoogle Scholar
  • 51 Rabenstein DL. Heparin and heparan sulfate: structure and function. Nat Prod Rep 2002; 19: 312-333.
    CrossrefPubMedGoogle Scholar
  • 52 Rauova L, Poncz M, McKenzie SE. et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105: 131-138.
    CrossrefPubMedGoogle Scholar
  • 53 Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiological role of this natural anticoagulant mechanism. Amer J Med 1989; 87 suppl 3b 2-9.
    CrossrefPubMedGoogle Scholar
  • 54 Samama MM, Bara L, Gerotziafas GT. Mechanisms for the antithrombotic activity in man of low molecular weight heparins (LMWHs). Haemostasis 1994; 24: 105-117.
    PubMedGoogle Scholar
  • 55 Schauerte A, Welzel D, Franz G. et al. Is there any accordance between the in vitro and ex vivo anti factor Xa/anti-thrombin ratio of UFH and LMWHs?. Ann Hematol 1998; 76 (Suppl. 01) V59.
    PubMedGoogle Scholar
  • 56 Simonis D, Fritzsche J, Alban S. et al. Kinetic analysis of heparin and glucan sulfates binding to P-selectin and its impact on the general understanding of selectin inhibition. Biochemistry 2007; 46: 6156-6164.
    CrossrefPubMedGoogle Scholar
  • 57 Smorenburg SM, van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 2001; 53: 93-105.
    PubMedGoogle Scholar
  • 58 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
    CrossrefPubMedGoogle Scholar
  • 59 Valentin S, Larnkjer A, Ostergaard P. et al. Characterization of the binding between tissue factor pathway inhibitor and glycosaminoglycans. Thromb Res 1994; 75: 173-183.
    CrossrefPubMedGoogle Scholar
  • 60 Valentin S, Ostergaard P, Kristensen H. et al. Synergism between full length TFPI and heparin: evidence for TFPI as an important factor for the antithrombotic activity of heparin. Blood Coagul Fibrinolysis 1992; 3: 221-222.
    CrossrefPubMedGoogle Scholar
  • 61 Van Gogh Investigators. Buller HR, Cohen AT, Davidson B. et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
    CrossrefPubMedGoogle Scholar
  • 62 Van Gogh Investigators. Buller HR, Cohen AT, Davidson B. et al. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 2007; 357: 1105-1112.
    CrossrefPubMedGoogle Scholar
  • 63 Warkentin TE, Cook RJ, Marder VJ. et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106: 3791-3796.
    CrossrefPubMedGoogle Scholar
  • 64 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653-2655.
    CrossrefPubMedGoogle Scholar
  • 65 Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843-1853.
    CrossrefPubMedGoogle Scholar