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J Thromb Haemost. 2010 Sep;8(9):2053-62. doi: 10.1111/j.1538-7836.2010.03942.x.

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

Author information

1
Laboratory for Thrombosis Research, Katholieke Universiteit Leuven Campus Kortrijk, Kortrijk, Belgium.

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.

[Indexed for MEDLINE]
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