Abstract
ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type-1 motif, member 13) and von Willebrand factor (VWF) can be considered as scale weights which control
platelet adhesion during primary haemostasis. In a very uncommon condition designated
thrombotic thrombocytopenic purpura (TTP), functional absence of ADAMTS13 tips the
balance toward VWF-mediated platelet adhesion in the microcirculation. TTP is associated
with a high mortality and arises from either a congenital or acquired autoimmune deficiency
of the plasma enzyme ADAMTS13. In case of acquired ADAMTS13 deficiency, autoantibodies
bind to and inhibit the function of ADAMTS13. Currently available treatments of TTP
aim to supply ADAMTS13 through plasma exchange or are aimed at B-cell depletion with
rituximab. None of the available therapeutics, however, aims at protection of ADAMTS13
from circulating autoantibodies. In this review, our aim is to describe the structure–function
relationship of ADAMTS13 employing homology models and previously published crystal
structures. Structural bioinformatics investigation of ADAMTS13 reveals many insights
and explains how mutations and autoantibodies may lead to the pathophysiology of TTP.
The results of these studies provide a roadmap for the further development of rationally
designed therapeutics for the treatment of patients with acquired TTP. In addition,
we share our opinion on the state of the art of the open–closed conformations of ADAMTS13
which regulate the activity of this highly specific VWF cleaving protease.
Keywords
ADAMTS13 - von Willebrand factor - thrombosis - thrombotic thrombocytopenic purpura
- autoimmune diseases
