Inactivation of ADAMTS13 by plasmin as a potential cause of thrombotic thrombocytopenic purpura

H. B. Feys, N. Vandeputte, R. Palla, F. Peyvandi, K. Peerlinck, H. Deckmyn, H. R. Lijnen, K. Vanhoorelbeke

Research output: Contribution to journalArticlepeer-review

Abstract

Background: ADAMTS13 deficiency causes accumulation of unusually large von Willebrand factor molecules, which cross-link platelets in the circulation or on the endothelial surface. This process of intravascular agglutination leads to the microangiopathy thrombotic thrombocytopenic purpura (TTP). Most TTP patients have acquired anti-ADAMTS13 autoantibodies that inhibit enzyme function and/or clear it from the circulation. However, the reason for ADAMTS13 deficiency is not always easily identified in a subset of patients. Objectives: To determine the origin of ADAMTS13 deficiency in a case of acquired TTP. Methods: Western blotting of ADAMTS13 in plasmas from acute and remission phases was used. Results: The ADAMTS13 deficiency was not caused by mutations or (detectable) autoantibodies; however, an abnormal ADAMTS13 truncated fragment (100 kDa) was found in acute-phase but not remission-phase plasma. This fragment resulted from enzymatic proteolysis, as recombinant ADAMTS13 was also cleaved when in the presence of acute-phase but not remission-phase plasma. Inhibitor screening showed that ADAMTS13 was cleaved by a serine protease that could be dose-dependently inhibited by addition of exogenous α2-antiplasmin. Examination of the endogenous α2-antiplasmin antigen and activity confirmed deficiency of α2-antiplasmin function in acute-phase but not remission-phase plasma. To investigate the possibility of ADAMTS13 cleavage by plasmin in plasma, urokinase-type plasminogen activator was added to an (unrelated) congenital α2-antiplasmin-deficient plasma sample to activate plasminogen. This experiment confirmed cleavage of endogenous ADAMTS13 similar to that observed in our TTP patient. Conclusion: We report the first acquired TTP patient with cleaved ADAMTS13 and show that plasmin is involved.

Original languageEnglish
Pages (from-to)2053-2062
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 2010

Keywords

  • ADAMTS13
  • Plasmin
  • TTP

ASJC Scopus subject areas

  • Hematology

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