Mutation analysis and clinical implications of von Willebrand factor–cleaving protease deficiency

Assink, Karin; Schiphorst, R.H.M.; Allford, Sarah L.; Karpman, Diana; Etzioni, Amos; Brichard, Bénédicte; Kar, Nicole C. A. J. van de; Monnens, L.A.H.; Heuvel, Lambertus van den

doi:10.1046/j.1523-1755.63.6s.1.x

Cited by 91 publications

(85 citation statements)

References 26 publications

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“…Complete absence of enzyme activity is thought to be lethal in utero. 3 A recent report that 2 brothers with congenital TTP are homozygous for this mutation 8 supports the notion that the mutant retains at least some of its biologic activity in vivo.…”

Section: Resultsmentioning

confidence: 75%

“…3,4 A number of mutations, spread throughout the ADAMTS13 gene, have been reported in association with congenital TTP. 3,[5][6][7][8][9] The CUB domains at the C-terminus of ADAMTS13 are of uncertain physiologic relevance. The findings that the CUB domains are not required for VWF-cleaving proteinase activity measured under static conditions 10,11 and that certain strains of mice have a variant form of murine ADAMTS13 that lacks the CUB domains (together with the seventh and eighth thrombospondin type 1 (TSP-1) repeats) support the premise that these domains are dispensable in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13

Pimanda

Maekawa

Wind

et al. 2004

Blood

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IntroductionThrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by a schistocytic hemolytic anemia and consumptive thrombocytopenia with varying degrees of neurologic and renal impairment. The presence of ultralarge von Willebrand factor (VWF) multimers in the plasmas of patients with chronic relapsing TTP during remission that disappear during an attack led to the implication of these multimers in the pathogenesis of the platelet-rich, fibrin-poor thrombi that occlude arterioles and are the hallmark of this disorder. 1 The VWF-cleaving metalloproteinase, ADAMTS13, hydrolyzes the ultralarge VWF multimers as they emerge from endothelial cells and undergo conformational strain due to shear stress in arterioles and capillaries. 2 A severe deficiency of VWF-cleaving proteinase activity is associated with the pathogenesis of congenital TTP (the SchulmanUpshaw syndrome). 3,4 A number of mutations, spread throughout the ADAMTS13 gene, have been reported in association with congenital TTP. 3,[5][6][7][8][9] The CUB domains at the C-terminus of ADAMTS13 are of uncertain physiologic relevance. The findings that the CUB domains are not required for VWF-cleaving proteinase activity measured under static conditions 10,11 and that certain strains of mice have a variant form of murine ADAMTS13 that lacks the CUB domains (together with the seventh and eighth thrombospondin type 1 (TSP-1) repeats) support the premise that these domains are dispensable in vivo. 12 However, a report that peptides from the CUB domains inhibit VWF-cleaving proteinase activity under flow, but not static, conditions suggests a functional role for these domains. 13 We studied a patient with congenital TTP who is a compound heterozygote for the Thr196Ile mutation in the metalloproteinase domain and the insertion of a nucleotide (A) at 4143-4144. This insertion results in a frameshift in the second CUB domain and loss of the last 49 amino acids of the protein. The CUB mutation had little effect on the specific activity of the enzyme but its secretion from COS-7 cells was impaired. Study design Case historyWe investigated an 8-year-old white girl with congenital TTP. Diagnosis was made when she was 18 months of age; she receives a plasma infusion every 2 to 3 months when her platelet count falls below 30 ϫ 10 9 /L. Assay of plasma VWF-cleaving proteinase activityAn assay based on the collagen-binding activity of digested VWF 14 was used to measure the VWF-cleaving proteinase activity in the plasma of the patient (during remission) and her family. ADAMTS13 sequence analysisDNA was extracted from peripheral blood leukocytes and all the exons and intron-exon boundaries of the ADAMTS13 gene were amplified by polymerase chain reaction (PCR) and sequenced. 5 The study was conducted with parental consent and institutional ethics approval. Transient expression of the ADAMTS13 mutantThe 4143insA mutant of the ADAMTS13 cDNA 15 was created using PCR-based mutagenesis. The wild-type and mutant constructs were subcloned into the mam...

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Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13

Pimanda

Maekawa

Wind

et al. 2004

Blood

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“…Inherited TTP is a rare autosomal recessive disorder due to homozygous or double heterozygous mutations in the ADAMTS-13 gene, causing a severe decrease of ADAMTS-13 level and activity (10)(11)(12)(13)(14)(15)(16). About 100 mutations causing inherited ADAMTS-13 deficiency have been identified so far in regions of the gene encoding different domains (10)(11)(12)(13)(14)(15)(16)(17) with only a few of them characterized by in vitro expression studies (12,15,(18)(19)(20)(21)(22). In this manuscript, we report cases of congenital TTP, due to the homozygous mutation in ADAMTS-13 gene in two young brothers born from two consanguineous parents of Romanian origin.…”

Section: Introductionmentioning

confidence: 99%

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

Lancellotti¹,

Peyvandi²,

Pagliari³

et al. 2016

Thromb Haemost

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“…[21][22][23] The cleavage can be stimulated by shear forces like those occurring at sites of arterial thrombosis or by low ionic strength and 1.5 M urea or guanidine. 19,20 Congenital ADAMTS13 deficiency is rare and associated with missense or frame-shift mutations of the ADAMTS13 gene, 18,[24][25][26][27][28][29] whereas acquired ADAMTS13 deficiency is more common and often caused by immunoglobulin G (IgG) inhibitors. 13,[30][31][32][33] Therefore, the efficacy of plasma infusion or therapeutic plasma exchange probably depends on replenishing the missing ADAMTS13 metalloprotease or removing the inhibitory antibodies.…”

Section: Introductionmentioning

confidence: 99%

Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

Zheng

Kaufman

Goodnough

et al. 2004

Blood

426

407

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Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P < .00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% (Ϸ 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P < .02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment. (Blood. 2004;103:4043-4049)

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Mutation analysis and clinical implications of von Willebrand factor–cleaving protease deficiency

Abstract: We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions.

Cited by 91 publications

References 26 publications

Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13

Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

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