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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-08-2399.
Submitted August 6, 2002
Accepted October 2, 2002
Von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP
Reinhard Schneppenheim*, Ulrich Budde, Florian Oyen, Dorothea Angerhaus, Volker Aumann, Elke Drewke, Wolf A Hassenpflug, Johannes Haberle, Karim Kentouche, Elisabeth Kohne, Karin Kurnik, Dirk E Mueller-Wiefel, Tobias Obser, Rene Santer, and Karl-Walter Sykora
Pediatric Hematology and Oncology, Childrens University Hospital Hamburg-Eppendorf, Hamburg, Germany
Coagulation Laboratory, Lab Association Prof. Arndt and Partners, Hamburg, Germany
Childrens University Hospital Magdeburg, Magdeburg, Germany
Childrens University Hospital Muenster, Muenster, Germany
Childrens University Hospital Jena, Jena, Germany
Childrens University Hospital Ulm, Ulm, Germany
Childrens University Hospital Muenchen, Muenchen, Germany
Childrens University Hospital Kiel, Kiel, Germany
Childrens Hospital, Medical School Hannover, Hannover, Germany
* Corresponding author; email: schneppenheim{at}uke.uni-hamburg.de.
Thrombotic thrombocytopenic purpura (TTP) is caused by the persistence of the highly reactive high molecular weight multimers of von Willebrand factor (VWF) due to deficiency of the specific VWF cleaving protease (VWF-CP) ADAMTS 13, resulting in microangiopathic disease. The acquired form is caused by autoantibodies against VWF-CP, whereas homozygous or compound heterozygous mutations of ADAMTS 13 are responsible for recessively inherited TTP. We investigated 83 children with hemolytic and/or thrombocytopenic episodes with or without additional neurologic symptoms or renal failure. The presumed diagnosis was chronic ITP (n=50), TTP (n=8), HUS (n=24) and Evans syndrome (n=1). A severe deficiency of VWF-CP ( 5%) was found in all investigated patients with TTP and in none of the cases with HUS. Additionally, 2/50 patients with a prior diagnosis of ITP were deficient for VWF-CP. Antibodies against VWF-CP were found in 4 children. Mutation analysis of the ADAMTS 13 gene in the VWF-CP deficient patients by direct sequencing of all 29 exons identified 8 different mutations, suggesting the hereditary form of TTP in one of the ITP patients, in the patient with Evans syndrome and in 5 of the 9 patients with TTP. The phenotype of TTP in childhood can be rather variable. Besides the classical clinical picture, oligosymptomatic forms may occur that can delay the identification of patients at risk.
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