Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease

Furlan, Miha; Lämmle, Bernhard

doi:10.1053/beha.2001.0142

Cited by 241 publications

(240 citation statements)

References 88 publications

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“…7 The reported N-terminal amino acid sequence 8,9 and complementary DNA 10,11 of VWF-cleaving protease characterize it as a new member of the ADAMTS family of metalloproteinases (ADAMTS13). Genetic linkage studies in 4 pedigrees with congenital TTP, 12 sometimes referred to as Upshaw-Schulman syndrome, 13,14 led to identification of 12 different mutations in the gene for ADAMTS13 that accounted for 14 of the 15 disease alleles studied. 12 Clinically affected patients with constitutional TTP were homozygous or doubly heterozygous for ADAMTS13 mutations and had protease activity levels less than 10% of normal values.…”

Section: Introductionmentioning

confidence: 99%

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Bianchi

Robles

Alberio

et al. 2002

Blood

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300

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A severe deficiency in von Willebrand factor-cleaving protease (ADAMTS13) activity (< 5% that in normal plasma) has been observed in most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but not in those with a diagnosis of hemolytic uremic syndrome. However, ADAMTS13 deficiency has been claimed not to be specific for TTP, since it was observed in various thrombocytopenic and other conditions. We studied 68 patients with thrombocytopenia due to severe sepsis or septic shock (n ‫؍‬ 17), heparin-induced thrombocytopenia (n ‫؍‬ 16), idiopathic thrombocytopenic purpura (n ‫؍‬ 10), or other hematologic (n ‫؍‬ 15) or miscellaneous conditions (n ‫؍‬ 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity (< 30%), but none had less than 10%. Thus, the study showed that AD-AMTS13 activity is decreased in a substantial proportion of patients with thrombocytopenia of various causes. A severe deficiency of ADAMTS13 (< 5%), identified in more than 120 patients during 1996 to 2001 in our laboratory, is specific for a thrombotic microangiopathy commonly labeled TTP. (Blood. 2002;100:710-713)

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Section: Introductionmentioning

confidence: 99%

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Bianchi

Robles

Alberio

et al. 2002

Blood

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300

231

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“…About half of patients with congenital TTP have their first acute episode in childhood, whereas the other half have their first acute episode in adulthood. Symptoms in adults often develop in association with the stress of infection or pregnancy (4). TTP with neonatal onset and frequent relapses is often diagnosed as Upshaw-Schulman syndrome (USS) (5,6).…”

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confidence: 99%

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

Kokame

Matsumoto

Soejima

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

389

388

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von Willebrand factor (VWF) is synthesized primarily in vascular endothelial cells and secreted into the plasma as unusually large VWF multimers. Normally, these multimers are quickly degraded into smaller forms by a plasma metalloproteinase, VWF-cleaving protease (VWF-CP). Decreases in the activity of this enzyme result in congenital and acquired thrombotic thrombocytopenic purpura (TTP). The human VWF-CP has recently been purified. Cloning of the corresponding cDNA revealed that the 1,427-aa polypeptide is a member of the ADAMTS gene family, termed ADAMTS13. Twelve rare mutations in this gene have been identified in patients with congenital TTP. Here, we report missense and nonsense mutations in two Japanese families with Upshaw-Schulman syndrome, congenital TTP with neonatal onset and frequent relapses. The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWF-CP containing either the R268P or C508Y mutations was not secreted from cells. In contrast, Q449stop and P475S mutants were normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWF-CP activity. We report on a single-nucleotide polymorphism associated with alterations in VWF-CP activity; it will be important to assess this single-nucleotide polymorphism as a risk factor for thrombotic disorders.

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“…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)(2)(3). If untreated, the mortality can exceed 90%, but plasma-exchange therapy has reduced the mortality to less than 20% (4).…”

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confidence: 99%

“…The complex multidomain structure of ADAMTS13 is conserved across vertebrates as diverse as mammals, birds, and fish (17), 2 suggesting that motifs outside the metalloprotease domain are required for its biological function. 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).…”

mentioning

confidence: 99%

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

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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...

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Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease

Cited by 241 publications

References 88 publications

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

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

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