Regulation der primären Hämostase durch von-Willebrand-Faktor und ADAMTS13

Summary

Von Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10–1 to 105 s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other.

Zusammenfassung

Der von-Willebrand-Faktor (VWF) ist ein adhäsives, riesiges, multimerisiertes Protein mit multiplen Domänen, die u.a. für die Bindung an Kollagen, Thrombozytenrezeptoren und Faktor VIII (FVIII) verantwortlich sind. Über diese funktionellen Domänen bindet VWF an die verletzte Gefäßwand, rekrutiert Thrombozyten an die verletzte Oberfläche mittels Adhäsion und Aggregation, und bindet und schützt FVIII mit seiner essenziellen Rolle in der Gerinnungskaskade. Der VWF übt seine Funktion vor allem in der arteriellen und in der Mikro-Zirkulation aus. In dieser Umgebung unterliegt er hohen Scherkräften mit hydro dynamischen Scherraten über mehrere Größenordnungen von 10–1 bis 105 s-1, was besondere Mechanismen für die Plättchenadhäsion und -aggregation unter diesen unterschiedlichen Bedingungen voraussetzt. Diese spezifischen Funktionen des VWF korrelieren sehr eng mit seiner Multimergröße. Fehlen oder Reduktion der großen VWF-Multimere sind charakteristisch für Patienten mit von-Willebrand-Syndrom Typ 2A, was mit funktionellen Einschränkungen der Bindung von VWF an Thrombozytenglykoprotein Ib und an Kollagen sowie einer Blutungsneigung einhergeht. Um eine ungebremste Thrombozyten-Aggregation, wie bei der thrombotisch- thrombo - zytopenischen Purpura (TTP) zu verhindern, wird die Funktion des VWF durch seine spezifische Protease ADAMTS13 reguliert. Während eine höhere Empfindlichkeit des VWF für die ADAMTS13-vermittelte Proteolyse ursächlich für einen häufigen Typ des VWS, den Typ 2A ist, verursachen das Fehlen oder Dysfunktion von ADAMTS13, entweder Autoantikörper- vermittelt oder durch den hereditären ADAMTS13-Mangel (Upshaw-Schulman-Syndrom), eine TTP. Somit repräsentieren VWS und TTP die eng miteinander verbundenen gegensätzlichen Manifestationen der VWF-vermittelten Krankheitsbilder

Keywords

Von Willebrand disease - von Willebrand factor - TTP - ADAMTS13

Schlüsselwörter

Von-Willebrand-Syndrom - von-Willebrand-Faktor - TTP - ADAMTS13

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