An open conformation of ADAMTS-13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura

J Thromb Haemost. 2018 Feb;16(2):378-388. doi: 10.1111/jth.13922. Epub 2018 Jan 23.


Essentials Conformational changes in ADAMTS-13 are part of its mode-of-action. The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). Our study forms an important basis to fully elucidate the pathophysiology of TTP.

Summary: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.

Keywords: ADAMTS-13 protein; antibodies; epitopes; protein conformation; thrombotic thrombocytopenic purpura.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS13 Protein / blood
  • ADAMTS13 Protein / chemistry*
  • ADAMTS13 Protein / immunology
  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • Case-Control Studies
  • Enzyme-Linked Immunosorbent Assay
  • Epitope Mapping
  • Epitopes
  • Humans
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Purpura, Thrombotic Thrombocytopenic / blood
  • Purpura, Thrombotic Thrombocytopenic / diagnosis
  • Purpura, Thrombotic Thrombocytopenic / enzymology*
  • Purpura, Thrombotic Thrombocytopenic / immunology
  • Structure-Activity Relationship


  • Autoantibodies
  • Epitopes
  • ADAMTS13 Protein
  • ADAMTS13 protein, human

Supplementary concepts

  • Thrombotic thrombocytopenic purpura, acquired