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TTP and ADAMTS13 (Carla Clem)

Here is a question from Carla Clem at Clarian in Indianapolis. Carla works with Kim Kinney and teaches with Bernadette (Bunny) Rodak for the Clarian/Indiana University Clinical Laboratory Science program.

Hi George,
I am Bunny’s “partner in crime;” we team-teach in Heme at Clarian/IU. Would you please give us a kindergarten version of ADAMTS-13 with regard to principle and typical results in TTP?

Thanks, Carla

Hi, Carla. I’ll be glad to describe thrombotic thrombocytopenic purpura (TTP) and the role of von Willebrand factor (VWF)- cleaving protease (ADAMTS13). There is an excellent free public access review: Tsai H. Thrombotic thrombocytopenic purpura: A thrombotic disorder caused by ADAMTS13 deficiency. Hematol Oncol Clin North Am 2007; 21:1-25 that you can access for detail.
TTP is an accumulation of clots in the brain and other microvascular organs that causes moderate thrombocytopenia, hemolysis with schistocytes on peripheral blood films, cognitive changes, seizures and coma. The treatment is repeated plasmapheresis. Untreated, TTP is fatal.

Von Willebrand factor (VWF) is produced by endothelial cells and stored in their Weibel-Palade bodies. Intracellular monomers of 2050 amino acids polymerize to 20 million Dalton MW multimers, their storage form. Upon release, plasma VWF-cleaving protease, a disintegrin and metalloprotease with thrombospondin type I motif (ADAMTS13), cleaves VWF at Y1605-M1606. Cleavage is triggered when multimers uncoil in a high shear-rate environment, and produces the familiar range of large to small VWF multimers.
TTP is a congenital or acquired deficiency of ADAMTS13. The congenital form is caused by one of several possible mutations at the ADAMTS13 locus on chromosome 9q34. The acquired form is caused by ADAMTS13 autoantibodies.

TTP is diagnosed by the combination of symptoms, thrombocytopenia, and microangiopathic hemolytic anemia with schistocytes. Plasma VWF multimeric analysis on SDS agarose gel may show ultra-large VWF multimers. ADAMTS13 activity may be assessed using VWF as a substrate in an enzyme immunoassay, gel electrophoresis, or fluorescence resonance energy transfer (FRET) system. Plasma mixing studies are used to detect ADAMTS13 autoantibodies, present in up to 90% of cases. ADAMTS13 levels remain less than 2 Bethesda units.

ADAMTS13 assays are technically complex and are affected by several interferences. The precision and accuracy are relatively low, so results are interpreted in the light of clinical information. The assay is performed in high complexity specialty laboratories such as Esoterix, Blood Center of Wisconsin, or Machaon, and may be used to differentiate from hemolytic-uremic syndrome or disseminated intravascular coagulation

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