Acquired thrombotic thrombocytopenic purpura

 

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Summary

The von Willebrand factor (VWF)-cleaving metalloprotease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs-13) is the only known target of the dysregulated immune response in acquired TTP. Autoantibodies to ADAMTS13 either neutralize its activity or accelerate its clearance, thereby causing a severe deficiency of ADAMTS13 in plasma. As a consequence, size regulation of VWF is impaired and the persistence of ultra-large VWF (ULVWF) multimers facilitates micro vascular platelet aggregation causing microangiopathic haemolytic anaemia and ischaemic organ damage. Autoimmune TTP although a rare disease with an annual incidence of 1.72 cases has a mortality rate of 20% even with adequate therapy.

We describe the mechanisms involved in ADAMTS13 autoimmunity with a focus on the role of B- and T-cells in the pathogenesis of this disorder. We discuss the potential translation of recent experimental findings into future therapeutic concepts for the treatment of acquired TTP.

Zusammenfassung

Die von-Willebrand-Faktor(VWF)-spaltende Protease ADAMTS13 (a disintegrin and metallo protease with thrombospondin type 1 motifs-13) ist das bisher einzig bekannte Ziel der fehlgeleiteten Immunantwort der erworbenen TTP. Autoantikörper, die an ADAMTS13 binden, neutralisieren entweder deren Aktivität oder beschleunigen den Abbau, was zu schwerer Defizienz von ADAMTS13 im Plasma führt. Die zur Regulation der Größe benötigte Spaltung (Proteolyse) von VWF ist somit stark beeinträchtigt, in Folge kommt es zur Akkumulation ultralanger VWF-Multi meren, die eine Aggregation der Thromobozyten in der Mikrozirkulation bewirken, was schließ-lich zu mikroangiopathischer hämo lytischer Anämie und ischämischer Organschädigung führt. TTP ist eine seltene Krankheit, mit einer jährlichen Inzidenz von 1,72 Fällen pro Million. TTP führt selbst mit adäquater Therapie bei 20% der Patienten zum Tod.

Wir beschreiben die Mechanismen, die in der ADAMTS13-Autoimmunität involviert sind, wobei wir uns auf die Rolle der B- und T-Zellen in der Pathogenese dieser Krankheit konzentrieren. Wir diskutieren, wie die bisherigen experimentellen Ergebnisse in zukünftige therapeutische Anwendungen zur Behandlung der erworbenen TTP eingesetzt werden können.

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