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

TY - THES

T1 - ADAMTS13 phenotype in health and disease with special reference to thrombotic thrombocytopenic purpura

AU - Manea Hedström, Minola

N1 - 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 --- <div class="article_info">M Manea, A Kristoffersson, HM Tsai, W Zhou, I Winqvist, G Oldaeus, R Billström, P Björk, L Holmberg and D Karpman. <span class="article_issue_date">2007</span>. <span class="article_title">ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura.</span> <span class="journal_series_title">Eur J Pediatr</span>, <span class="journal_volume">vol 166</span> <span class="journal_pages">pp 249-57</span>.</div> <div class="article_info">M Manea, A Kristoffersson, R Schneppenheim, MA Saleem, PW Mathieson, M Mörgelin, P Björk, L Holmberg and D Karpman. <span class="article_issue_date">2007</span>. <span class="article_title">Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura.</span> <span class="journal_series_title">Br J Haematol</span>, <span class="journal_volume">vol 138</span> <span class="journal_pages">pp 651-62</span>.</div> <div class="article_info">M Manea, J Karlsson, ZD Békássy and D Karpman. <span class="article_issue_date"></span>. <span class="article_title">ADAMTS13 is expressed in renal tubular epithelial cells.</span> (manuscript)</div>

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - Urology

KW - tubular cells

KW - podocytes

KW - kidney

KW - plasma

KW - ADAMTS13

KW - thrombotic thrombocytopenic purpura

KW - nephrology

KW - Urologi

KW - nefrologi

KW - Pediatrics

KW - Pediatri

M3 - Doctoral Thesis (compilation)

SN - 978-91-85897-05-6

PB - Paediatrics, Faculty of Medicine, Lund University

ER -