100 Jahre Thrombotisch-thrombozytopenische Purpura (TTP) – Was haben wir gelernt?

Zusammenfassung

Vor 100 Jahren hat Dr. Eli Moschcowitz den ersten Fall einer thrombotisch-thrombozytopenischen Purpura beschrieben. Viele Jahrzehnte gab es keine anerkannten Therapieoptionen und die Letalität war extrem hoch. Anfang der 90iger-Jahre setzte sich dann zunehmend die Therapie mit Steroiden und Plasmaaustausch durch, wobei die Letalität immer noch über 20 % lag. Es dauerte bis kurz vor die Jahrtausendwende, bis in Bern und New York die Krankheitsmechanismen (ADAMTS13-Defizienz) entschlüsselt und somit der Weg für neue Therapieoptionen frei gemacht wurde. Es wurde nun klar, dass die erworbene TTP (iTTP) eine Autoimmunerkrankung ist und der Autoantikörper gegen ADAMTS13 gerichtet ist, eine Protease, die große von-Willebrand Faktor-Multimere fragmentiert. Dadurch entsteht ein schwerer ADAMTS13-Mangel. Die Multimere überschießender Größe persistieren und binden Thrombozyten, wodurch mikrovaskuläre Thrombosierungen entstehen. Abgegrenzt davon wird die kongenitale TTP (cTTP), die durch Mutationen im ADAMTS13-Gen verursacht wird (Upshaw-Schulman-Syndrom). Bei anderen Formen der thrombotischen Mikroangiopathie (TMA, z. B. aHUS) tritt keine schwere ADAMTS13-Defizienz auf. Zwei randomisierte kontrollierte Studien belegten den Nutzen des 2019 zugelassenen, selektiven bivalenten Anti-von-Willebrand-Faktor (vWF) Nanobodies Caplacizumab in der Behandlung der iTTP. Diverse Publikationen nationaler iTTP-Kohorten verbesserten die Datenlage und zeigten konsistente Verringerungen der Zeit bis zur Normalisierung der Thrombozyten, eine drastische Reduktion refraktärer Verläufe und Exazerbationen (insbesondere bei Therapiesteuerung nach ADAMTS13-Aktivität) sowie Hinweise für eine verringerte Mortalität, die insbesondere bei korrekter und frühzeitiger Anwendung der heutigen Therapieoptionen (Plasmaaustausch, Steroide, Caplacizumab, Rituximab) bei 2–6 % anzusetzen ist. Moderne Therapieoptionen umfassen Strategien zur präemptiven Therapie bei ADAMTS13-Rezidiven sowie die plasmaaustauschfreie Behandlung. Möglicherweise wird zukünftig der Einsatz von rekombinantem ADAMTS13, auch bei iTTP-Patienten, die therapeutischen Optionen erweitern.

Abstract

100 years ago Dr. Eli Moschcowitz described the first case of thrombotic thrombocytopenic purpura. For many decades there were no recognized treatment options, and the mortality rate was extremely high. At the beginning of the 1990 s, therapy with steroids and plasma exchange became increasingly popular, although the mortality rate was still over 20 %. It took until the turn of the millennium for the disease mechanisms (ADAMTS13-deficiency) to be decoded in Bern and New York, thus paving the way for new therapy options. It has now become clear that acquired TTP (iTTP) is an autoimmune disease, and the autoantibodies are directed against ADAMTS13, a protease that cleaves large von-Willebrand multimers. This causes a severe ADAMTS13-deficiency. The ultralarge multimers persist and bind platelets, resulting in microvascular thrombosis. This is distinguished from congenital TTP (cTTP), in which severe ADAMTS13-deficiency is caused by mutations in the ADAMTS13-gene (Upshaw-Schulman syndrome). In other forms of thrombotic microangiopathy (TMA, e. g. aHUS), severe ADAMTS13-deficiency does not occur. Two randomized controlled studies demonstrated the benefit of the selective bivalent anti-von-Willebrand factor (vWF) nanobody Caplacizumab, approved in 2019, in the treatment of iTTP. Various publications from national iTTP cohorts improved the data and showed consistent reductions in the time until platelet normalization, a reduction in refractory courses and exacerbations (especially when therapy is controlled according to ADAMTS13-activity) as well as evidence of reduced mortality. Modern therapeutic options include strategies for preemptive therapy for ADAMTS13-relapse as well as plasma exchange-free treatment. The use of recombinant ADAMTS13 may also expand the therapeutic options in iTTP patients in the future.

Keywords

TTP - iTTP - Moschcowitz - TMA - Caplacizumab

Publication History

Article published online:
06 November 2024

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