Natürliche und synthetische Glykosaminoglykane

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 7 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (Suppl. 01) 12-20.
• 8 Alban S. Kapitel 20. Kohlenhydrate III: Aminoglykane und Glykosaminoglykane. In: Hänsel R, Sticher O. (Hrsg). Pharmakognosie – Phytopharmazie. Heidelberg: Springer; 2006: 655-704.
• 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.
• 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.
• 11 Bauersachs R, Alban S. Perioperative bridging with fondaparinux in a woman with antithrombin deficiency. Thromb Haemost 2007; 97: 498-499.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 18 Dawa J, Pepper DS. Catabolism of low-dose in man. Thromb Res 1986; 43: 1-6.
• 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.
• 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.
• 21 Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 (Suppl. 02) 24-38.
• 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.
• 23 Gray E, Cesmeli S, Lormeau JC. et al. Low affinity heparin is an antithrombotic agent. Thromb Haemost 1994; 71: 203-207.
• 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.
• 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.
• 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.
• 27 Hartmann A, Stöbe J, Mickley F. Niedermolekulare Heparine bei Niereninsuffizienz: Klinischer Einsatz. Hämostaseologie 2005; 25: 213-217.
• 28 Herault JP, Bernat A, Roye F. et al. Pharmacokinetics of new synthetic heparin mimetics. Thromb Haemost 2002; 87: 985-989.
• 29 Herbert JM, Hérault JP, Bernat A. et al. SR123781A, a synthetic heparin mimetic. Thromb Haemost 2001; 85: 852-860.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 37 Lindahl U, Kusche-Gullberg M, Kjellén L. Regulated diversity of heparan hulfate. J Biol Chem 1998; 273: 24979-24982.
• 38 Liu J, Pedersen LC. Anticoagulant heparan sulfate: structural specificity and biosynthesis. Appl Microbiol Biotechnol 2007; 74: 263-272.
• 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.
• 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.
• 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.
• 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.
• 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.
• 44 Meuleman DG. Orgaran (Org 10172): Its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65.
• 45 Mulloy B. The specificity of interactions between proteins and sulfated polysaccharides. An Acad Bras Cienc 2005; 77: 651-664.
• 46 N. N. Niedermolekulare Heparine. Ph. Eur. 5.0, 2005: Monographie 2318.
• 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.
• 48 Petitou M, Herault JP, Bernat A. et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417-422.
• 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.
• 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.
• 51 Rabenstein DL. Heparin and heparan sulfate: structure and function. Nat Prod Rep 2002; 19: 312-333.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 64 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653-2655.
• 65 Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843-1853.