Thrombin: thrombosehemmende Wirkungen und pharmakologische Konsequenzen

Zusammenfassung

In den vergangenen Jahren trugen Endothelzellkulturen aus verschiedenen Körperregionen erheblich zum Verständnis der komplexen pro- und antithrombotischen Mechanismen des Gefäßsystems bei. Wichtigstes Schlüsselenzym dabei ist Thrombin. Aufgrund seiner hämostatischen Eigenschaften katalysiert diese Serinprotease Fibrinbildung, Aktivierung der Faktoren V, VIII und XIII sowie irreversible Plättchenaggregation. Im Falle einer Stimulation des Endothels zur Expression von Bindungsstellen für die Faktoren IX, IXa, X, Xa, von-Willebrand-Protein und PAF (z. B. durch Entzündungsmediatoren) finden diese Prozesse im menschlichen Kreislauf statt. Dann resultiert eine beschleunigte Gerinnungskaskade und eine verstärkte Plättchen/ Granulozyten-Interaktion. Paradoxerweise ist bei geringer intravasaler Konzentration Thrombin in Kombination mit einer gesunden Endothelschicht der kritische Faktor zur Verhinderung von Thrombosen. Entsprechende antithrombogene Eigenschaften spielen sich hauptsächlich am venolären Endothel der Mikrozirkulation ab; im Detail sind dies: Thrombin-induzierte Bildung endothelialer Autakoide, antikoagulatorische Protein-C-Aktivierung, Bindung aktivierter Gerinnungsfaktoren an endothelialen Heparan-ATIII-Komplexen, Ausschüttung des profibrinolytischen Plasminogenaktivators endothelialen Ursprungs. Das Verständnis dieser komplexen Regulation ermöglicht nicht nur eine kritische Erfassung aktuell diskutierter hämostaseologischer Risikofaktoren (erhöhte Plättchenaktivität, hohe Konzentrationen von Faktor VII, VIII, Fibrinogen, PAI, ATIII), sondern auch die Entwicklung neuer pharmakologischer Strategien zur Thromboseinhibition.

Summary

During the last few years, the availability of endothelial cell cultures isolated from different vascular regions contributed to a significant increase in understanding the complex pro- and antithrombotic mechanisms in our circulatory system. The most important key enzyme is thrombin. Due to its haemostatic properties this serin protease catalyzes fibrin formation, activation of factors V, VIII and XIII as well as irreversible platelet aggregation. These processes may occur even within the circulatory system in case of endothelial stimulation (e. g. by inflammation mediators) for expression of binding sites for factors IX, IXa, X, Xa, von Willebrand protein and PAF. Thus not only catalytically activated coagulatory cascades, but also enhanced cooperation of platelets and granulocytes will occur. Paradoxically, in low intravascular concentration, thrombin, in combination with a healthy endothelial layer, may be the critical factor for the inhibition of thromboses. Respective antithrombogenic properties will mainly affect pre-venous microvascular circulation. In detail, they include thrombin-induced endothelial formation of antiaggregatory autacoids from platelet release products, anticoagulatory activation of protein C and absorption of active coagulation factors at endothelial heparan/ATIII complexes as well as release of profibrinolytic plasminogen activator of endothelial origin. The understanding of these complex regulatory functions enables not only a critical evaluation of actually discussed haemostasiologic risk factors (enhanced platelet reactivity, high concentrations of factor VII, VIII, fibrinogen, PAI, ATIII), but also the development of new pharmacologic strategies for prevention of thrombosis.

Schlüsselwörter

Thrombin - Antithrombogenität

Keywords

Thrombin - antithrombogenicity

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