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

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.

• Authors: H B Feys, N Vandeputte, R Palla, F Peyvandi, K Peerlinck, H Deckmyn, H R Lijnen, K Vanhoorelbeke
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 8 Issue 9 Pg. 2053-62 (Sep 2010) ISSN: 1538-7836 [Electronic] England
• PMID: 20553378 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 International Society on Thrombosis and Haemostasis.

Chemical References

• Autoantibodies
• alpha-2-Antiplasmin
• Fibrinolysin
• ADAM Proteins
• ADAMTS13 Protein
• ADAMTS13 protein, human

Topics

• ADAM Proteins (antagonists & inhibitors, physiology)
• ADAMTS13 Protein
• Adult
• Autoantibodies (chemistry)
• Autoimmunity
• Blotting, Western
• Fibrinolysin (metabolism)
• Humans
• Male
• Mutation
• Protein Structure, Tertiary
• Purpura, Thrombotic Thrombocytopenic (blood, metabolism)
• Remission Induction
• alpha-2-Antiplasmin (metabolism)