von Willebrand factor cleaving protease and ADAMTS13mutations in childhood TTP

Schneppenheim, Reinhard; Budde, Ulrich; Oyen, Florian; Angerhaus, Dorothea; Aumann, V.; Drewke, Elke; Hassenpflug, Wolf; Häberle, Johannes; Kentouche, Karim; Kohne, E.; Kurnik, Karin; Mueller-Wiefel, Dirk E; Obser, Tobias; Santer, René; Sykora, K.-W.

doi:10.1182/blood-2002-08-2399

Cited by 214 publications

(212 citation statements)

References 27 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…This concept is supported by the finding that missense mutations in domains far from the metalloprotease domain cause inherited AD-AMTS13 deficiency and thrombotic microangiopathy (15,18,19). The specificity of ADAMTS13 for a single bond in VWF and the remarkable regulation of cleavage by tensile stress on the substrate suggest that accessory domains are critical for substrate recognition.…”

supporting

confidence: 59%

“…If these C-terminal domains were necessary in vivo, one might predict the occurrence of patients with inherited TTP caused by mutations in the ADAMTS13 gene but with normal plasma ADAMTS13 activity upon laboratory testing. To date, however, all reported mutations distal to the spacer domain have been associated with severe ADAMTS13 deficiency (15,19,34).…”

Section: Fig 5 Adamts13 Variants Expressed In Cos-7 Cellsmentioning

confidence: 99%

“…For example, the mutation P475S in the ADAMTS13 Cys-rich domain was identified in a Japanese patient with inherited TTP; the corresponding recombinant mutant ADAMTS13 was secreted efficiently but had extremely low activity toward VWF (18). Other missense mutations that cause inherited ADAMTS13 deficiency have been found in the disintegrin, Cys-rich, and first TSP1 domains (15,19), but protein expression studies have not yet been reported for them.…”

Section: Fig 5 Adamts13 Variants Expressed In Cos-7 Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Cleavage of von Willebrand Factor Requires the Spacer Domain of the Metalloprotease ADAMTS13

Zheng

Nishio

Majerus

et al. 2003

Journal of Biological Chemistry

180

236

View full text Add to dashboard Cite

ADAMTS13 consists of a reprolysin-type metalloprotease domain followed by a disintegrin domain, a thrombospondin type 1 motif (TSP1), Cys-rich and spacer domains, seven more TSP1 motifs, and two CUB domains. ADAMTS13 limits platelet accumulation in microvascular thrombi by cleaving the Tyr 1605 -Met 1606 bond in von Willebrand factor, and ADAMTS13 deficiency causes a lethal syndrome, thrombotic thrombocytopenic purpura. ADAMTS13 domains required for substrate recognition were localized by the characterization of recombinant deletion mutants. Constructs with C-terminal His 6 and V5 epitopes were expressed by transient transfection of COS-7 cells or in a baculovirus system. No association with extracellular matrix or cell surface was detected for any ADAMTS13 variant by immunofluorescence microscopy or chemical modification. Both plasma and recombinant full-length ADAMTS13 cleaved von Willebrand factor subunits into two fragments of 176 kDa and 140 kDa. Recombinant ADAMTS13 was divalent metal ion-dependent and was inhibited by IgG from a patient with idiopathic thrombotic thrombocytopenic purpura. ADAMTS13 that was truncated after the metalloprotease domain, the disintegrin domain, the first TSP1 repeat, or the Cys-rich domain was not able to cleave von Willebrand factor, whereas addition of the spacer region restored protease activity. Therefore, the spacer region is necessary for normal ADAMTS13 activity toward von Willebrand factor, and the more Cterminal TSP1 and CUB domains are dispensable in vitro.Thrombotic thrombocytopenic purpura (TTP) 1 is a syndrome characterized by microangiopathic hemolytic anemia and thrombocytopenia, and it may be accompanied by neurological dysfunction, renal failure, and fever (1-3). If untreated, the mortality can exceed 90%, but plasma-exchange therapy has reduced the mortality to less than 20% (4). Although the pathophysiology of TTP is not fully understood, a plausible model has been proposed in which the proteolysis of von Willebrand factor (VWF) plays a central role (5). VWF is a multimeric protein that binds receptors on the surface of platelets and in connective tissue, thereby mediating the adhesion of platelets to sites of vascular injury. If unchecked, the process can lead to microvascular thrombosis. A plasma VWF-cleaving protease has been described that acts on the Tyr 1605 -Met 1606 bond in the central A2 domain of the VWF subunit, and cleavage is stimulated by shear forces like those occurring at sites of thrombosis or by low concentrations of urea or guanidine (6, 7). This proteolytic reaction limits VWF-dependent platelet adhesion, and most adults with idiopathic TTP have an acquired autoantibody that inhibits the VWF-cleaving protease (8, 9). Therefore, therapeutic plasma exchange may ameliorate TTP by replacing the missing protease and removing the inhibitory antibody.The VWF-cleaving protease was recently purified and identified as a new member of the ADAMTS family of metalloproteases (10, 11), so named for the combination of a disintegrin-like and metalloprote...

show abstract

supporting

confidence: 59%

Section: Fig 5 Adamts13 Variants Expressed In Cos-7 Cellsmentioning

confidence: 99%

Section: Fig 5 Adamts13 Variants Expressed In Cos-7 Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Cleavage of von Willebrand Factor Requires the Spacer Domain of the Metalloprotease ADAMTS13

Zheng

Nishio

Majerus

et al. 2003

Journal of Biological Chemistry

180

236

View full text Add to dashboard Cite

show abstract

“…Although not recommended as a test to establish the diagnosis of TTP in the acute setting, ADAMTS13 activity can be used to identify patients with inherited forms of TTP [4,21] and can also be used to determine the risk of relapse of TTP. Peyvandi et al measured ADAMTS13 and anti-ADAMTS13 levels in 109 patients during remission following a first acute episode of TTP and compared it with the risk of subsequent recurrence [22].…”

Section: Applications and Limitationsmentioning

confidence: 99%

ADAMTS13 activity and inhibitor

Doldan-Silvero¹,

Acevedo-Gadea²,

Habib³

et al. 2008

American J Hematol

View full text Add to dashboard Cite

Thrombotic thrombocytopenic purpura (TTP) is often associated with acquired or congenital deficiency of the von Willebrand factor-cleaving metalloprotease, ADMATS13 (Lammle B et al., J Thromb Haemost 2005;3:1663-1675 Schneppenheim et al., Blood 2003;101:1845-1850. Although undetectable levels of enzyme activity (<10%) are diagnostic of inherited or acquired TTP in the correct clinical setting (absence is specific), not all patients diagnosed with TTP have severe protease deficiency, and it is therefore not recommended as an initial test for diagnosis (Copelovitch and Kaplan, Pediatr Nephrol, in press). Many prospective and retrospective studies have demonstrated that patients with severe protease deficiency have a higher likelihood of relapse, making it helpful as an indicator of recurrence. The short-term prognostic usefulness of ADAMTS13 testing during acute TTP warrants further investigation because of limited prospective studies (Ferrari S et al., Blood 2007;109:2815-2822 Peyvandi et al., Haematologica 2008;93:232-239). Am. J. Hematol. 83:811-814, 2008. V

show abstract

“…It occurs primarily in neonates and children, but adult onset cases have been reported [33,34]. Acquired TTP occurs mostly in adults [35].…”

Section: Thrombotic Thrombocytopenic Purpuramentioning

confidence: 99%

Atypical hemolytic uremic syndrome: from diagnosis to treatment

Franchini¹

2015

Clinical Chemistry and Laboratory Medicine (CCLM)

View full text Add to dashboard Cite

Thrombotic microangiopathy (TMA) is a relatively rare condition but a medical urgency requiring immediate intervention to avoid irreversible organ damage or death. Symptoms on presentation include microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The most frequent direct causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). The most common form of HUS is related to Shiga toxin producing Escherichia coli (STEC) infection while approximately 10% of cases are due to dysregulation of the complement pathway (atypical haemolytic uremic syndrome, aHUS). Optimal treatment regimens differ depending on the underlying cause; however, differential diagnosis may be difficult. The most accurate method of diagnosis is based on exclusion and should consider, beyond the symptoms common to TMA, ADAMTS13 activity levels and STEC infection status. For the management of TTP, plasma exchange (PE) is the most important acute intervention and is associated with lower mortality and better outcomes than plasma infusion. In most patients with STEC-HUS, the course of disease is selflimiting although management of acute kidney injury is often required. Until recently, the management of aHUS consisted of early and intensive PE, although this was mostly ineffective in protecting from subsequent organ damage. Eculizumab, an inhibitor of the alternative complement pathway, produces a rapid and sustained inhibition of the TMA process, with significant improvements in long-term clinical outcomes. Due to the significant improvement achieved, eculizumab has subsequently been approved as first-line therapy when an unequivocal diagnosis of aHUS has been made.

show abstract

von Willebrand factor cleaving protease and ADAMTS13mutations in childhood TTP

Cited by 214 publications

References 27 publications

Cleavage of von Willebrand Factor Requires the Spacer Domain of the Metalloprotease ADAMTS13

Cleavage of von Willebrand Factor Requires the Spacer Domain of the Metalloprotease ADAMTS13

ADAMTS13 activity and inhibitor

Atypical hemolytic uremic syndrome: from diagnosis to treatment

Contact Info

Product

Resources

About