Abstract
ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor, is crucial for normal hemostasis. Acquired autoantibody-mediated deficiency of plasma ADAMTS13 results in a potentially fatal blood disorder, immune thrombotic thrombocytopenic purpura (iTTP). Plasma ADAMTS13 protease appears to exist in multiple conformations. Under physiological conditions, plasma ADAMTS13 exists predominantly in its "closed" conformation (or latent form), which may be activated by lowering pH, ligand binding, and binding of an antibody against the distal domains of ADAMTS13. In patients with iTTP, polyclonal antibodies target at various domains of ADAMTS13. However, nearly all inhibitory antibodies bind the spacer domain, whereas antibodies that bind the distal C-terminal domains may activate ADAMTS13 through removing its allosteric inhibition. Additionally, the anti-C-terminal antibodies may alter the potency of inhibitory antibodies towards ADAMTS13 activity. This review summarizes some of the most recent knowledge about the ADAMTS13 conformation and its mechanism of inhibition by its autoantibodies.