Physiologie der Blutgerinnung und Fibrinolyse

Zusammenfassung

Die Prinzipien der Auslösemechanismen, Initiator- und Amplifikationsreaktionen der Blutgerinnung und Fibrinolyse werden dargestellt und in Zusammenhang mit Regulationskreisläufen der Hämostase diskutiert. Besonders der Charakter der zelloberflächenkontrollierten Aktivierungsund Inhibierungsreaktionen in Form der Multikomponenten- Enzymkomplexe erlaubt die endogene physiologische Kontrolle des Systems und ermöglicht bei Störungen der Hämostase eine therapeutische Intervention mit unterschiedlichen pro- und antikoagulatorischen Wirkstoffen.

Summary

The principles of initiator and amplifications reactions of blood coagulation and fibrinolysis will be presented and discussed in relation to various regulatory pathways of haemostasis. In particular, cell surface-dependent activation and inhibition reactions are characteristics of multicomponent enzyme complexes that also allow the endogenous control of the haemostasis system. The understanding of these relationships in complications of haemo stasis has lead to different strategies for the therapeutic intervention with pro- and anticoagulant substances.

Schlüsselwörter

Multi-Komponenten-Enzymkomplexe - Thrombin - Feedback- Regulation - Oberflächenreaktionen - Enzymkaskade - Inhibitoren - Gendefekte

Keywords

Multicomponent enzyme complexes - thrombin - feedback regulation - surface reactions - enzyme cascade - inhibitors - gene defects

• Literatur

• 1 Cines DB, Pollak ES, Buck CA. et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91: 3527-3561.
• 2 Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964; 145: 1310-1312.
• 3 Zillmann A, Luther T, Müller I. et al. Platelet-associated tissue factor contributes to the collagentriggered activation of blood coagulation. Biochem Biophys Res Commun 2001; 281: 603-609.
• 4 Rauch U, Nemerson Y. Circulating tissue factor and thrombosis. Curr Opin Hematol 2000; 7: 273-277.
• 5 Engelmann B, Luther T, Müller I. Intravascular tissue factor pathway: A model for rapid initiation of coagulation within the blood vessel. Thromb Haemost 2003; 89: 3-8.
• 6 Bevers EM, Comfurius P, Dekkers DW, Zwaal RF. Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1999; 1439: 317-330.
• 7 Rosing J, Tans G, Govers-Riemslag JWP. et al. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255: 274-283.
• 8 Furie B, Furie BC. In vivo thrombus formation. J Thromb Haemost 2007; 5 (Suppl. 01) 12-17.
• 9 Reinhardt C, von Brühl ML, Manukyan D. et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118: 1110-1122.
• 10 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-174.
• 11 Coughlin SR. Protease-activated receptors in vascular biology. Thromb Haemost 2001; 86: 298-307.
• 12 Broze GJ, Gailani D. The role of factor XI in coagulation. Thromb Haemost 1993; 70: 72-74.
• 13 Tollefsen D. 2007 http://tollefsen.wustl.edu/projects/coagulation/coagulation.html.
• 14 Preissner KT. Extracellular RNA: A new player in blood coagulation and vascular permeability. Haemostaseologie 2007; 27: 373-377.
• 15 Smith SA, Mutch NJ, Baskar D. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908.
• 16 Renné T, Gailani D. Role of factor XII in hemostasis and thrombosis: clinical implications. Expert Rev Cardiovasc Ther 2007; 5: 733-741.
• 17 Esmon CT. The protein C pathway: New insights. Thromb Haemost 1997; 78: 70-74.
• 18 Müller-Berghaus G, ten Cate H, Levi M. Disseminated intravascular coagulation: Clinical spectrum and established as well as new diagnostic approaches. Thromb Haemost 1999; 82: 706-712.
• 19 Noll T, Wozniak G, McCarson K. et al. Effect of factor XIII on endothelial barrier function. J Exp Med 1999; 189: 1373-1382.
• 20 Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 1995; 9: 946-955.
• 21 Parkinson JF, Koyama T, Bang NU, Preissner KT. Thrombomodulin: an anticoagulant cell surface proteoglycan with physiologically relevant glycosaminoglycan moiety. In: Lane DA, Björk I, Lindahl U. (eds). Heparin and Related Polysaccharides. New York: Plenum Press; 1992: 177-188.
• 22 Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-26491.
• 23 Dahlbäck B. Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism. J Clin Invest 1994; 94: 923-927.
• 24 Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost 1999; 82: 601-609.
• 25 Broze GJ. Tissue factor pathway inhibitor and the revised hypothesis of blood coagulation. Trends Cardio Med 1992; 2: 72-77.
• 26 Preissner KT, Seiffert D. Role of vitronectin and its receptors in haemostasis and vascular remodeling. Thromb Res 1998; 89: 1-21.
• 27 Broze GJ. Protein Z-dependent regulation of coagulation. Thromb Haemost 2001; 86: 8-13.
• 28 Preissner KT. Physiological role of vessel wall related antithrombotic mechanisms: Contribution of endogenous and exogenous heparin-like components to the anticoagulant potential of the endothelium. Haemostasis 1990; 20: 30-49.
• 29 Carmeliet P, Collen D. Molecular genetics of the fibrinolytic and coagulation systems in haemostasis, thrombogenesis, restenosis and atherosclerosis. Curr Opin Lipidol 1997; 8: 118-125.
• 30 Plow EF, Felez J, Miles LA. Cellular regulation of fibrinolysis. Thromb Haemost 1991; 66: 32-36.
• 31 Nesheim ME, Wang W, Boffa M. et al. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-391.
• 32 Chavakis T, Preissner KT. Potential pharmacological applications of the antithrombotic molecule high molecular weight kininogen. Curr Vasc Pharmacol 2003; 1: 59-64.
• 33 Plow EF, Allampallam K, Redlitz A. The plasma carboxypeptidases and the regulation of the plasminogen system. Trends Cardiovas Med 1997; 7: 71-75.
• 34 Wells PS. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb Haemost 2007; 5 (Suppl. 01) 41-50.
• 35 Carmeliet P, Mackman N, Moons L. et al. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75.
• 36 Ossowski L, Clunie G, Masucci MT, Blasi F. In vivo paracrine interaction between urokinase and its receptor: Effect on tumor cell invasion. J Cell Biol 1991; 115: 1107-1112.
• 37 O’Reilly MS, Holmgren L, Shing Y. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-328.
• 38 O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285: 1926-1928.
• 39 Herz J, Clouthier DE, Hammer RE. LDL receptorrelated protein internalizes and degrades uPAPAI- 1 complexes and is essential for embryo implantation. Cell 1992; 71: 411-421.
• 40 Westrick RJ, Eitzman DT. Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets 2007; 8: 966-1002.
• 41 Preissner KT, Kanse SM, May AE. Urokinase receptor: a molecular organizer in cellular communication. Curr Opin Cell Biol 2000; 12: 621-628.
• 42 Repke D, Gemmell CH, Guha A. et al. Hemophilia as a defect of the tissue factor pathway of blood coagulation: Effect of factors VIII and IX on 22 factor X activation in a continuous-flow reactor. Proc Natl Acad Sci USA 1990; 87: 7623-7627.
• 43 Oldenburg J, Marinova M, Müller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm 2008; 78: 35-62.
• 44 Neerman-Arbez M. Molecular basis of fibrinogen deficiency. Pathophysiol Haemost Thromb 2006; 35: 187-198.
• 45 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 46 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Eng J Med 1994; 330: 517-522.
• 47 Öhlin AK, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997; 78: 392-395.
• 48 Rosenberg RD. Thrombomodulin gene disruption and mutation in mice. Thromb Haemost 1997; 78: 705-709.
• 49 Taylor FB, Chang A, Esmon CT. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusions in the baboon. J Clin Invest 1987; 79: 918-925.
• 50 Esmon CT. Role of coagulation inhibitors in inflammation. Thromb Haemost 2001; 86: 51-56.
• 51 Samad F, Loskutoff DJ. The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM. Thromb Haemost 1997; 78: 652-655.
• 52 Preissner KT. Hemostatic protease receptors and entothelial cell function: insights from gene targeting in mice. Semin Thromb Hemost 2000; 5: 451-462.
• 53 Degen JL. Hemostatic factors and inflammatory disease. Thromb Haemost 1999; 82: 8858-864.