Pharmakologie der Heparine und der direkten Antikoagulanzien

S. Alban

doi:10.1055/s-0037-1617187

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 2008; 28(05): 400-420
DOI: 10.1055/s-0037-1617187

Hämostaseologie

Schattauer GmbH

Pharmakologie der Heparine und der direkten Antikoagulanzien

Pharmacology of heparins and direct anticoagulants

S. Alban

¹Pharmazeutisches Institut, Christian-Albrechts-Universität, Kiel

› Institutsangaben

Abstract

Zusammenfassung

Jahrzehntelang beschränkten sich die Optionen für die Anti koagulation auf unfraktioniertes Heparin (UFH) und Vitamin-K-Antagonististen (VKA). Mit der Einführung der niedermolekularen Heparine (NMH) wurde die kurz- und mittelfristige Antikoagulation entscheidend verbessert; eine Alternative zu den VKA für die Langzeitanwendung steht noch aus. Da die Heparine belegen, dass Faktor Xa und Thrombin geeignete Angriffspunkte für die Antikoagulation darstellen, konzentriert sich die industrielle Antikoagulanzien- Forschung auf die Entwicklung direkter Thrombin- (DTI) und Faktor-Xa-Inhibitoren (DXI). Die verfügbaren bzw. in der Entwicklung am weitesten fortgeschrittenen Antikoagulanzien lassen sich in zwei Klassen einteilen: 1.) Glyko-Antikoagulanzien mit den natürlichen sulfatierten Glykosaminoglykanen (GAG) (UFH, NMH, Danaparoid) und den synthetisch hergestellten Oligosacchariden (Fondaparinux, Idraparinux und SR123781A), 2.) Xenobiotika, d. h. Proteine und chemisch-synthetische Moleküle. Die Glyko-Antikoagulanzien wirken partiell (GAG) oder ausschließlich (Oligosaccharide) durch die Katalyse von Antithrombin (AT), während die Xenobiotika direkt Thrombin oder Faktor Xa hemmen. Zurzeit stehen mit Lepirudin, Bivalirudin, Argatroban drei parenterale DTI sowie mit Dabigatranetelxilat ein oraler DTI für begrenzte Anwendungsgebiete zur Verfügung. Mit Rivaroxaban wurde kürzlich der erste orale DXI zugelassen. In dieser Übersicht werden die Entwicklung der Antikoagulanzien und das pharmakologische Profil der in der Praxis eingesetzten Antikoagulanzien beschrieben.

Summary

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short- and medium-term anticoagulation could be much improved, but an alternative to VKA is still missing The heparins provided the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focuses on inhibitors of thrombin (DTI) or FXa (DXI). Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three parenteral DTI (lepirudin, argatroban, and bivalirudin) and since March 2008 one oral DTI (dabigatran etexilate) are clinically used for limited indications. In September 2008 rivaroxaban has been approved as the first oral DXI. This review describes the development of the anticoagualants as well as the pharmacological profile of the clinically used anticoagualants.

Schlüsselwörter

Glykosaminoglykane - niedermolekulare Heparine - Danaparoid - Fondaparinux - Idraparinux - SR123781A - direkte Thrombininhibitoren - direkte Faktor-Xa-Inhibitoren - Lepirudin - Bivalirudin - Argatroban - Ximelagatran - Dabigatranetexilat - Rivaroxaban

Keywords

Glycosaminoglycans - low molecular weight heparins - fondaparinux - idraparinux - SR123781A - direct thrombin inhibitors - direct factor Xa inhibitors - lepirudin - bivalirduin - argatroban - ximelagatran - dabigatran etexilate - rivaroxaban

Volltext

Referenzen

Literatur
1 Abildgaard U. Heparin/low molecular weight heparin and tissue factor pathway inhibitor. Haemostasis 1993; 23 (Suppl. 01) 103-106.
2 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.
3 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.
4 Alban S, Scriba GKE. Kommentar zur Monographie „Danaparoid sodium“ PhEur 5.5, 2090. In: Arzneibuch- Kommentar. Band 5, Monographien D bis H. Stuttgart, Eschborn, Wissenschaftliche Verlagsgesellschaft, Govi-Verlag. 2007 26. Lieferung (PhEur 5.5).
5 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 Suppl I 12-20.
6 Alban S. Kapitel 20. Kohlenhydrate III: Aminoglykane und Glykosaminoglykane. In: Hänsel R, Sticher O. (eds) Pharmakognosie – Phytopharmazie. Heidelberg: Springer; 2006: 655-704.
7 Alban S. Paradigm change in anticoagulation. Natural substances that are selective factor Xa inhibitors. Pharm Unserer Zeit 2004; 33: 190-194.
8 Alban S. The ‘precautionary principle’ as a guide for future drug development. Eur J Clin Invest 2005; 35 Suppl I 33-44.
9 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. Thromb Haemost 2006; 4: 83-89.
10 Alhenc-Gelas M, Jestin-Le Guernic C, Vitoux JF. et al. Adjusted versus fixed doses of the low-molecularweight heparin fragmin in the treatment of deep vein thrombosis. Fragmin-Study Group. Thromb Haemost 1994; 71: 698-702.
11 Amiral J, Lormeau JC, Marfaing-Koka A. et al. Absence of cross-reactivity of SR90107A/ORG 31540 pentasaccharide with antibodies to heparin- PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 1997; 8: 114-117.
12 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004; 126: 204S-33S.
13 Barrowcliffe TW, Merton RE, Havercroft SJ. et al. Low-affinity heparin potentiates the action of highaffinity heparin oligosaccharides. Thromb Res 1984; 34: 125-133.
14 Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis 2005; 19: 183-188.
15 Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Invasive Cardiol 2000; 12 Suppl F 27F-32F.
16 Bates SM, Weitz JI. The status of new anticoagulants. Br J Haematol 2006; 134: 3-19.
17 Bauer KA, Hawkins DW, Peters PC. et al. Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents – the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20: 37-52.
18 Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ Program 2006; 450-456.
19 Bauer KA. New anticoagulants: anti IIa vs anti Xa-- is one better?. J Thromb Thrombolysis 2006; 21 (Suppl. 01) 67-72.
20 Bauersachs R, Alban S. Perioperative bridging with fondaparinux in a woman with antithrombin deficiency. Thromb Haemost 2007; 97: 498-499.
21 Beguin S, Welzel D, Al Dieri R. et al. Conjectures and refutations on the mode of action of heparins. The limited importance of anti-factor Xa activity as a pharmaceutical mechanism and a yardstick for therapy. Haemostasis 1999; 29: 170-178.
22 Berry CN, Girardot C, Lecoffre C. et al. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant hirudin. Thromb Haemost 1994; 72: 381-386.
23 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.
24 Biemond BJ, Perzborn E, Friederich PW. et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor. Thromb Haemost 2007; 97: 471-477.
25 Bijsterveld NR, Moons AH, Boekholdt SM. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-2554.
26 Björk I, Olson ST, Shore JD. Molecular mechanisms of the accelerating effect of heparin on the reactions between antithrombin and clotting proteinases. In: Lane DA, Lindahl U. (eds). Heparin, chemical and biological properties, clinical applications. Boca Raton, Fl: CRC Press; 1989: 229-256.
27 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
28 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.
29 Brufatto N, Ward A, Nesheim ME. Factor Xa is highly protected from antithrombin-fondaparinux and antithrombin-enoxaparin when incorporated into the prothrombinase complex. J Thromb Haemost 2003; 1: 1258-1264.
30 Buller HR, van Doormaal FF, van Sluis GL. et al. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; (Suppl. 01) 246-254.
31 Cheng-Lai A. Cardiovascular drug highlight: hirudin. Heart Dis 1999; 1: 41-49.
32 Choay J, Petitou M, Lormeau JC. et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 1983; 116: 492-499.
33 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.
34 Collignon F, Frydman A, Caplain H. et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins – dalteparin, enoxaparin and nadroparin – administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73: 630-640.
35 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.
36 Dahlbäck B. Blood coagulation. Lancet 2000; 355: 1627-1632.
37 Dawa J, Pepper DS. Catabolism of low-dose in man. Thromb Res 1986; 43: 1-6.
38 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.
39 Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028-1040.
40 Dunwiddie C, Thornberry NA, Bull HG. et al. Antistasin, a leech-derived inhibitor of factor Xa. Kinetic analysis of enzyme inhibition and identification of the reactive site. J Biol Chem 1989; 264: 16694-16699.
41 Dyke CM, Aldea G, Koster A. et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg 2007; 84: 836-839.
42 Eisenberg PR, Siegel JE, Abendschein DR. et al. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91: 1877-1883.
43 EMEA.. European Public Assessment Report for Angiox. H-C-562-N-12. 13.07.2007. http://www.emea.europa.eu/humandocs/Humans/EPAR/angiox/angiox.htm. Accessed: 13.05.2008.
44 EMEA.. European Public Assessment Report for Refludan. H-C-122-IA-31. 15.10.2007. http://www.emea.europa.eu/humandocs/Humans/EPAR/refludan/refludan.htm. Accessed: 13.05.2008.
45 FDA, CDER.. Label information for Angiomax. NDA 20–873/S-011. 30.11.2005. http://www.fda.gov/cder/foi/label/2005/020873s011lbl.pdf. Accessed: 13.05.2008.
46 FDA, CDER.. Label information for Argatroban. 20–883/S-004. 04.03.2002. http://www.fda.gov/cder/foi/label/2002/20883s4lbl.pdf. Accessed: 13.05.2008.
47 FDA, CDER.. Label information for Refludan. 20–807/S-015. 11.07.2006. http://www.fda.gov/cder/foi/label/2006/020807s011lbl.pdf. Accessed: 13.05.2008.
48 Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 (Suppl. 02) 24-38.
49 Garon JE. Monitoring low molecular weight heparins. Clin Leadersh Manag Rev 2003; 17: 47-50.
50 Gerotziafas GT, Elalamy I, Depasse F. et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 5: 886-888.
51 Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf 2006; 15: 213-220.
52 Graff J, von Hentig N, Misselwitz F. et al. Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet- induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47: 1398-1407.
53 Gray E, Cesmeli S, Lormeau JC. et al. Low affinity heparin is an antithrombotic agent. Thromb Haemost 1994; 71: 203-207.
54 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.
55 Greinacher A, Alban S, Omer-Adam MA. et al. Heparin- induced thrombocytopenia: A stoichiometry-based model to explain the different immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux. Thromb Res 2008; 122: 211-220.
56 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.
57 Guzzi LM, McCollum DA, Hursting MJ. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2006; 22: 169-176.
58 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.
59 Hara T, Yokoyama A, Ishihara H. et al. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb Haemost 1994; 71: 314-319.
60 Harder S, Graff J, Klinkhardt U. et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time. Thromb Haemost 2004; 91: 1137-1145.
61 Hauel NH, Nar H, Priepke H. et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
62 Hauptmann J, Kaiser B, Nowak G. et al. Comparison of the anticoagulant and antithrombotic effects of synthetic thrombin and factor Xa inhibitors. Thromb Haemost 1990; 63: 220-223.
63 Hérault JP, Bernat A, Pflieger AM. et al. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharmacol Exp Ther 1997; 283: 16-22.
64 Herault JP, Bernat A, Roye F. et al. Pharmacokinetics of new synthetic heparin mimetics. Thromb Haemost 2002; 87: 985-989.
65 Herbert JM, Herault JP, Bernat A. et al. SR123781A, a synthetic heparin mimetic. Thromb Haemost 2001; 85: 852-860.
66 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.
67 Hjelm R, Schedin-Weiss S. High affinity interaction between a synthetic, highly negatively charged pentasaccharide and alpha- or beta-antithrombin is predominantly due to nonionic interactions. Biochemistry 2007; 46: 3378-3384.
68 Hoffman M, Monroe 3rd DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-965.
69 http://clinicaltrials.gov/ct2/results?intr=%22SR123781A%22. Accessed: 13.05.2008.
70 Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2005; 11: 79-87.
71 Ieko M. Dabigatran etexilate, a thrombin inhibitor for the prevention of venous thromboembolism and stroke. Curr Opin Investig Drugs 2007; 8: 758-768.
72 Irie A, Takami M, Kubo H. et al. Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity. Bone 2007; 41: 165-174.
73 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.
74 Jurk K, Kehrel BE. Platelets and the new comprehension of haemostasis. Hamostaseologie 2005; 25: 39-49.
75 Kakar P, Watson T, Lip GY. Rivaroxaban. Drugs Today (Barc) 2007; 43: 129-136.
76 Kakkar AK, Brenner B, Dahl OE. et al; RECORD2 Investigators.. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double- blind, randomised controlled trial. Lancet 2008; 372: 31-39.
77 Kenne K, Skanberg I, Glinghammar B. et al. Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro 2008; 22: 730-746.
78 Kikumoto R, Tamao Y, Tezuka T. et al. Selective inhibition of thrombin by (2R,4R)-4-methyl- 1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-qui nolinyl) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid. Biochemistry 1984; 23: 85-90.
79 Klement P, Rak J. Emerging anticoagulants: mechanism of action and future potential. Vnitr Lek. 2006 52 Suppl 1 119-122.
80 Koopman MM, Buller HR. Short- and long-acting synthetic pentasaccharides. J Intern Med 2003; 254: 335-342.
81 Koster A, Dyke CM, Aldea G. et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83: 572-577.
82 Kubitza D, Becka M, Mueck W. et al. Rivaroxaban (BAY 59–7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007; 63: 469-476.
83 Kubitza D, Becka M, Mueck W. et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban – an oral, direct factor Xa inhibitor – are not affected by aspirin. J Clin Pharmacol 2006; 46: 981-990.
84 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
85 Kubitza D, Becka M, Zuehlsdorf M. et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects. J Clin Pharmacol 2007; 47: 218-226.
86 Kubitza D, Becka M, Zuehlsdorf M. et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59–7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006; 46: 549-558.
87 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.
88 Lassen MR, Ageno W, Borris LC. et al; RECORD3 Investigators.. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
89 Laux V, Perzborn E, Kubitza D. et al. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor. Semin Thromb Hemost 2007; 33: 515-523.
90 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.
91 Leizorovicz A, Bara L, Samama MM. et al. Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage. Haemostasis 1993; 23 (Suppl. 01) 89-98.
92 Levine MN, Raskob G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 287S-310S.
93 Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129: 1167-1175.
94 Liesenfeld KH, Schäfer HG, Trocóniz IF. et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62: 527-537.
95 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.
96 Lindahl U, Kusche-Gullberg M, Kjellén L. Regulated diversity of heparan hulfate. J Biol Chem 1998; 273: 24979-24982.
97 Lormeau JC, Herault JP. The effect of the synthetic pentasaccharide SR 90107/ORG 31540 on thrombin generation ex vivo is uniquely due to ATIII-mediated neutralization of factor Xa. Thromb Haemost 1995; 74: 1474-1477.
98 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 capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
99 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.
101 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.
102 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.
103 Matthai Jr WH. Safety and efficacy of argatroban in patients with heparin-induced thrombocytopenia. Curr Hematol Rep 2006; 5: 95-99.
104 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.
105 Monroe DM, Hoffman M. What does it take to make the perfect clot?. Arterioscler Thromb Vasc Biol 2006; 26: 41-48.
106 Mueck W, Becka M, Kubitza D. et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor xa inhibitor-- in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335-344.
107 Mueck W, Eriksson BI, Bauer KA. et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor Xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-216.
108 Mungall D. BIBR-1048 Boehringer Ingelheim. Curr Opin Investig Drugs 2002; 3: 905-907.
109 N.N. Danaparoid sodium.. European Pharmacopoeia 5.5. 2006 No. 07/2006:2090.
110 N.N. Low molecular weight heparins.. European Pharmacopoeia 5.0. 2004 No. 2318.
111 Nagahara T, Yokoyama Y, Inamura K. et al. Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. J Med Chem 1994; 37: 1200-1207.
112 Nelson-Piercy C. Hazards of heparin: allergy, heparin- induced thrombocytopenia and osteoporosis. Baillieres Clin Obstet Gynaecol 199 11: 489-509.
113 Nieuwenhuis HK, Albada J, Banga JD. et al. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood 1991; 78: 2337-2343.
114 Norrby K. Low-molecular-weight heparins and angiogenesis. APMIS 2006; 114: 79-102.
115 Ofosu FA. Antithrombotic mechanisms of heparin and related compounds. In: Lane DA, Lindahl U. (eds). Heparin, chemical and biological properties, clinical applications. Boca Raton, Fl: CRC Press; 1989: 433-454.
116 Okamoto S, Hijikata A, Kikumoto R. et al. Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereostructure of its hydrophobic carboxamide portion. Biochem Biophys Res Commun 1981; 101: 440-446.
117 Olson ST, Björk I, Sheffer R. et al. Role of the antithrombin- binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992; 267: 12528-12538.
118 Papadopoulos S, Flynn JD, Lewis DA. Fondaparinux as a treatment option for heparin-induced thrombocytopenia. Pharmacotherapy 2007; 27: 921-926.
119 Perzborn E, Kubitza D, Misselwitz F. Rivaroxaban. A novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Hamostaseologie 2007; 27: 282-289.
120 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
121 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.
122 Petitou M, Duchaussoy P, Driguez PA. et al. New synthetic heparin mimetics able to inhibit thrombin and factor Xa. Bioorg Med Chem Lett 1999; 9: 1155-1160.
123 Petitou M, Duchaussoy P, Jaurand G. et al. Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540). J Med Chem 1997; 40: 1600-1607.
124 Petitou M, Herault JP, Bernat A. et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417-422.
125 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.
126 Rauova L, Poncz M, McKenzie SE. et al. Ultra - large complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105: 131-138.
127 Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin- antithrombin complex. Blood 2001; 97: 2308-2313.
128 Roehrig S, Straub A, Pohlmann J. et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)- 2-oxo-3–[4-(3-oxomorpholin-4-yl) phenyl]-1,3- oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59–7939): an oral, direct factor Xa inhibitor. J Med Chem 2005; 48: 5900-5908.
129 Rosenberg RD, Bauer KA. The heparin-antithrombin system: a natural anticoagulant mechanism. In: Colman RW, Hirsh J, Marder VJ. et al (eds). Hemostasis and thrombosis: Basic principles and clinical practice. 3rd ed. Philadelphia, PA: JB Lippincott; 1994: 837-860.
130 Sanofi-Aventis.. Idraparinux shows encouraging results in van Gogh clinical trials program. Press release 10.12.2006.
131 Schwienhorst A. Direct thrombin inhibitors – a survey of recent developments. Cell Mol Life Sci 2006; 63: 2773-2791.
132 Serebruany MV, Malinin AI, Serebruany VL. Argatroban, a direct thrombin inhibitor for heparin-induced thrombocytopaenia: present and future perspectives. Expert Opin Pharmacother 2006; 7: 81-89.
133 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.
134 Sitko GR, Ramjit DR, Stabilito I. et al. Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis. Circulation 1992; 85: 805-815.
135 Smogorzewska A, Brandt JT, Chandler WL. et al. Effect of fondaparinux on coagulation assays: results of College of American Pathologists proficiency testing. Arch Pathol Lab Med 2006; 130: 1605-1611.
136 Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 2001; 53: 93-105.
137 Stangier J, Eriksson BI, Dahl OE. et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45: 555-563.
138 Stangier J, Rathgen K, Stähle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
139 Steinmetzer T, Stürzebecher J. From fibrinogen and hirudin to synthetic anticoagulants. Rational design of thrombin inhibitors. Pharm Unserer Zeit 2004; 33: 196-205.
140 Steinmetzer T, Stürzebecher J. Progress in the development of synthetic thrombin inhibitors as new orally active anticoagulants. Curr Med Chem 2004; 11: 2297-2321.
141 Stephens JL, Koerber JM, Mattson JC. et al. Effect of lepirudin on the international normalized ratio. Ann Pharmacother 2005; 39: 28-31.
142 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.
143 Stringer KA, Lindenfeld J. Hirudins: antithrombin anticoagulants. Ann Pharmacother 1992; 26: 1535-1540.
144 Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20: 318-329.
145 Swan SK, St Peter JV, Lambrecht LJ. et al. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20: 756-770.
146 Turpie A, Bauer K, Davidson B. et al. Comparison of rivaroxaban – an oral, direct factor Xa inhibitor – and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement (RECORD4: a phase 3 study). European Federation of National Associations of Orthopaedics and Traumatology (EFFORT) 2008 Annual Meeting; May 29–June 1,. 2008 Nice, France. Abstract F85.
147 Tuszynski GP, Gasic TB, Gasic GJ. Isolation and characterization of antistasin. An inhibitor of metastasis and coagulation. J Biol Chem 1987; 262: 9718-9723.
148 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 [letter]. Blood Coagul Fibrinolysis 1992; 3: 221-222.
149 van Gogh Investigators. Buller HR, Cohen AT. et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
150 van Gogh Investigators. Buller HR, Cohen AT. et al. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 2007; 357: 1105-1112.
151 Vlasuk GP, Ramjit D, Fujita T. et al. Comparison of the in vivo anticoagulant properties of standard heparin and the highly selective factor Xa inhibitors antistasin and tick anticoagulant peptide (TAP) in a rabbit model of venous thrombosis. Thromb Haemost 1991; 65: 257-262.
152 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.
153 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653-2655.
154 Waxman L, Smith DE, Arcuri KE. et al. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. Science 1990; 248: 593-596.
155 Weitz J, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected frominhibition by heparinantithrombin but susceptible to inactivation by antithrombinindependent inhibitors. Circulation 1998; 97: 544-552.
156 Weitz JI, Crowther M. Direct thrombin inhibitors. Thromb Res 2002; 106: V275-284.
157 Weitz JI. A novel approach to thrombin inhibition. Thromb Res 2003; 109 Suppl 1 S17-22.
158 Wienen W, Stassen JM, Priepke H. et al. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost 2007; 5: 1237-1242.
159 Wienen W, Stassen JM, Priepke H. et al. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost 2007; 98: 333-338.
160 Wienen W, Stassen JM, Priepke H. et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98: 155-162.
161 Yu G, LeBrun L, Gunay NS. et al. Heparinase I acts on a synthetic heparin pentasaccharide corresponding to the antithrombin III binding site. Thromb Res 2000; 100: 549-556.