Inhibition der plasmatischen Koagulation

Zusammenfassung

Das wichtigste Ziel bei der Entwicklung neuer Antikoagulanzien ist eine effektivere Wirkung mit weniger unerwünschten Arzneimittelwirkungen. Bisher eingesetzte Therapeutika wie Heparin und Phenprocoumon inhibieren mehrere Faktoren in verschiedenen Phasen der Blutgerinnung. Die moderne Arzneimittelentwicklung und detaillierte Kenntnis über die molekularen Mechanismen der Koagulation ermöglichen den gezielten Eingriff in ganz spezifischen Phasen der Gerinnung. In dieser Übersichtsarbeit werden die neuen Entwicklungen in diesem Bereich vorgestellt und deren Wirkungsmechanismen erläutert.

Summary

The major goal in the development of new anticoagulant drugs is a more effective action with less adverse effects. Until now the mainly used agents are heparin and phenprcoumon or warfarin. These drugs inhibit multiple coagulation factors in different stages of the coagulation cascade. Modern drug development and the knowledge about the molecular mechanisms of the coagulation cascade allow specific inhibition of distinct phases of thrombus formation. This review focuses on the new developments in this area.

Schlüsselwörter

Koagulation - Antikoagulanzien

Keywords

Coagulation - anticoagulants

• References

• 1 Abraham E, Reinhart K, Opal S. et al. OTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290: 238-47.
• 2 Abraham E, Reinhart K, Svoboda P. et al. Assesment of the safety of recombinant tissue factor pathway inhibitor in severe sepsis: a multicenter, randomized, placebo-controlled, single.blind, dose escalation study. Crit Care Med 2001; 29: 2081-9.
• 3 Bauer KA, Eriksson BI. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
• 4 Becker RC. Cell-based models of coagulation: a paradigm in evolution. J Thromb Thrombol 2005; 20: 65-8.
• 5 Bernard GR, Vincent J-L, Laterre P-F. et al The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group.. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N Engl J Med 2001; 344: 699-709.
• 6 Davie EW. Biochemical and molecular aspects of the coagulation cascade. Thromb Haemost 1995; 74: 1-6.
• 7 Eriksson BI, Bergqvist D, Kalebo P. et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441-7.
• 8 Eriksson H, Wahlander K, Gustafsson D. et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003; 1: 41-7.
• 9 Giesen PL, Rauch U, Bohrmann B. et al. Bloodborne tissue factor: another view of thrombosis. Proc Nat Acad Sci USA 1999; 96: 2311-5.
• 10 Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005; 105: 453-63.
• 11 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565-74.
• 12 Jang Y, Guzmann I, Lincoff A. et al. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabit atherosclerotic femoral artery injury model. Circulation 1995; 92: 3041-50.
• 13 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: 412-21.
• 14 Lassen M, Davidson B, Gallus A. A phase II randomized, double-blind, five-arm, parallel-group, dose-response study of new oral, diracly-acting, factor Xa inhibitor, Razaxabaan, for pervention of deep vein thrombosis in knee replacement surgery. Blood 2003; 102: 41.
• 15 Lee A, Agnelli G, Buller H. et al. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 2001; 104: 74-8.
• 16 Lincoff AM, Bittl JA, Harrington RA. et al. for the REPLACE-2 Investigators. Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade Compared With Heparin and Planned Glycoprotein IIb/ IIIa Blockade During Percutaneous Coronary Intervention: REPLACE-2 Randomized Trial. JAMA 2003; 289: 853-63.
• 17 Lincoff AM. First clinical investigation of a tissue- factor inhibitor administered during percutaneous coronary revascularistion: a randomized, double-blinded, dose-escalation trial assessing safety and efficacy of FFR-FVIa in percutaneous transluminal coronary angioplasty (ASIS) trial. JACC 2000; 36: 1654-9.
• 18 Moll S, Lindley C, Pescatore S. et al, 2nd. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2: 1745-51.
• 19 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: 514-21.
• 20 Prager N, Abendschein D, McKenzie C. et al. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1992; 119: 962-7.
• 21 Schrör K. Haemostaseology. Internist 2005; 46: 873-81.
• 22 Schulman S, Wahlander K, Lundstrom T. et al. for the THRIVE III Investigators. Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran. N Engl J Med 2003; 349: 1713-21.
• 23 Stassens P, Bergum P, Gansemans J. et al. Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Nat Acad Sci USA 1996; 93: 2149-54.
• 24 Turpie A, Bauer K. et al. Efficacy and safety of fondaparinux in major orthopedic surgery according to the timing of its first administration”. Thromb Haemost 2003; 90: 364-6.
• 25 Turpie AG, Eriksson BI, Lassen MR. et al. Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol 2003; 10: 327-32.
• 26 Turpie AG. Fondaparinux: a factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004; 5: 1373-84.
• 27 Wahlander K, Eriksson-Lepkowska M, Frison L. et al. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 755-64.
• 28 Wahlander K, Lapidus L, Olsson CG. et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 2002; 107: 93-9.
• 29 Wolzt M, Wollbratt M, Svensson M. et al. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol 2003; 59: 537-43.