Koagulatorische Aktivität der Thrombozyten

Zusammenfassung

Hämostase ist die konzertierte Aktion von Blutkomponenten, um Blutverlust bei Verletzung von Blutgefäßen zu verhindern. Thrombose stellt die Kehrseite dieses physiologischen Prozesses dar, d. h., fehlgeleitet läuft eine hämostatische Reaktion an einer krankhaft veränderten Gefäßwand ab. Durch hämodynamische Kräfte werden die Thrombozyten in eine wandnahe Grenzschicht gedrängt und strömen entlang des Endothels auf der Suche nach Defekten. Wird eine Verletzungsstelle entdeckt, kommt es zur sofortigen Anlagerung der Thrombozyten, die mit der initialen Abbremsung und Adhäsion durch Glykoprotein(GP)-Ibα-Rezeptorbindung an von-Willebrand-Faktor (VWF) beginnt. GPIb benötigt keine Stimulierung im Gegensatz zu den nachfolgend durch „outside-in“ und „inside-out signalling“ aktivierten weiteren Rezeptoren wie Integrin αIIbβ3 (GPIIb/IIIa), Integrin α2β1, GP VI. Letztere binden an ihre entsprechenden Liganden wie VWF, Fibrinogen, Kollagen und andere subendotheliale Proteine. An dem ersten Rasen haftender Thrombozyten kommt es durch VWF vermittelt zu weiterer transienter Plättchenanlagerung, die durch Fibrinogenbrückenbildung zwischen Integrin-αIIbβ3-Rezeptoren auf benachbarten Plättchen gefestigt wird. Solche Aggregate stellen eine große Masse an prokoagulatorischen Membranen dar, an deren Oberflächen Gerinnungsfaktoren komplexiert und aktiviert werden. Damit läuft die Fibrinpolymerisation um ein Vielfaches beschleunigt ab. Zusätzlich besitzen Thrombozyten mRNA zur schnellen Produktion von TF (tissue factor), dem effektivsten Trigger der extrinsischen Gerinnung. Die entstandenen Fibrinfasern stabilisieren die Thrombozytenaggregate gegen Abriss durch Scherkräfte. Aus Thrombozyten unter hohen Scherraten durch GPIb-VWF-Interaktion entstandene Mikropartikel weisen ebenfalls aktivierte Membranen auf, wodurch es in Koagulationstests zu einer Verkürzung der Gerinnungszeit kommt. Somit scheinen Thrombozyten und thrombozytäre Mikropartikel nicht nur bei der Fokussierung der hämostatischen Antwort auf die Verletzungsregion sondern auch bei der Initiierung und Beschleunigung der nachfolgenden Gerinnung eine wesentliche Rolle zu spielen.

Summary

Haemostasis is the concerted action of blood components aimed at prevention of blood loss after vessel injury. Thrombosis is the other side of the coin, a misled physiological process, i.e. a haemostatic reaction occurring at a diseased vessel wall. Haemodynamic forces enrich platelets in a fluid boundary layer adjacent to the vessel wall where they flow along the endothelium scanning it for defects. Once the platelets detect an injury they immediately adhere – a process beginning with initial deceleration and attachment via glykoprotein (GP) Ibα receptor-binding to immobilized von Willebrand factor (VWF). The GPIb receptor requires no stimulation. This is in contrast to subsequently interacting receptors such as integrin αIIbβ3 (GPIIb/IIIa), integrin α2β1, and GP VI, which are activated via outsidein and inside-out signalling. The latter receptors bind to their respective ligands: VWF, fibrinogen, collagen and other subendothelial proteins. Upon the first layer of adherent platelets additional accrual of platelets is transient when mediated by VWF, but is then stabilized by fibrinogen bridging integrin αIIbβ3 receptors on neighboring platelets. Such aggregates present a large mass of procoagulant membranes, the surface of which serves for complexation and activation of clotting factors. Thereby fibrin polymerization is accelerated manyfold. In addition, platelets contain mRNA for fast production of tissue factor, the most effective trigger of extrinsic coagulation. The formed fibrin fibers stabilize the platelet aggregates against detachment by shear forces. A shortened clotting time probably due to activated membranes was also found with microparticles generated at high shear rates through GPIb-VWF-interaction. Thus, platelets and platelet derived microparticles seem to play an important role not only in focussing the haemostatic response to the region of injury but also in initiating and accelerating the subsequent clotting reaction.

Schlüsselwörter

Thrombozyten - Thrombose - Hämostase

Keywords

Platelets - thrombosis - haemostasis

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