ADAMTS13 phenotype in health and disease with special reference to thrombotic thrombocytopenic purpura

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Von Willebrand factor (VWF) is synthesized and secreted by endothelial cells into the plasma as a series of multimers. VWF induces the formation of platelet plugs at sites of vascular injury and high shear stress. Biological activity is dependent on multimeric size, which is regulated in plasma by the VWF-cleaving protease ADAMTS13. Severe ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura (TTP), a life threatening thrombotic microangiopathic disorder characterized by thrombocytopenia, hemolytic anemia, neurological and renal manifestations, and fever. Congenital TTP occurs due to ADAMTS13 mutations, while acquired TTP is associated with autoantibodies against the protease. Severe ADAMTS13 deficiency results in the accumulation of ultra-large (UL) VWF multimers, which induce the formation of disseminated thrombi in the microcirculation. The present study aimed to describe the ADAMTS13 phenotype in plasma and kidney (one of the main target organs in TTP) from normal controls and TTP patients. In addition, ADAMTS13 expression was studied in renal tissue and urine from patients with tubular damage.

Patients with congenital TTP had undetectable ADAMTS13 antigen in the plasma as detected by immunoblotting. Patients with acquired TTP expressed the normal phenotype but the protease circulated in complex with inhibitory autoantibodies. In normal kidney expression was detected in glomeruli (podocytes, endothelial cells and the glomerular basement membrane) and tubuli. Patients with congenital TTP exhibited a similar staining pattern but with seemingly higher intensity, presumably due to impaired secretion resulting in intracellular accumulation. Podocytes and tubular cells were shown to synthesize biologically active ADAMTS13. Tubular damage altered the tubular expression pattern and resulted in detection of ADAMTS13 antigen in urine.

Details

Authors
  • Minola Manea Hedström
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pediatrics

Keywords

  • Urology, tubular cells, podocytes, kidney, plasma, ADAMTS13, thrombotic thrombocytopenic purpura, nephrology, Urologi, nefrologi, Pediatrics, Pediatri
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 Sep 18
Publisher
  • Paediatrics, Faculty of Medicine, Lund University
Print ISBNs978-91-85897-05-6
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 2007-09-18 Time: 09:00 Place: Segerfalksalen, Wallenberg Neurocentrum, BMC, Sölvegatan 17, Lund External reviewer(s) Name: Voorberg, Jan Title: Docent Affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam ---