* 604134

A DISINTEGRIN-LIKE AND METALLOPROTEASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 13; ADAMTS13


Alternative titles; symbols

VON WILLEBRAND FACTOR-CLEAVING PROTEASE; VWFCP


HGNC Approved Gene Symbol: ADAMTS13

Cytogenetic location: 9q34.2     Genomic coordinates (GRCh38): 9:133,414,337-133,459,386 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q34.2 Thrombotic thrombocytopenic purpura, hereditary 274150 AR 3

TEXT

Description

Von Willebrand factor (VWF; 613160) is a multimeric plasma glycoprotein that plays a critical role in platelet adhesion and aggregation on vascular lesions. ADAMTS13 is a multidomain protease that cleaves VWF in circulating blood and thereby limits platelet thrombosis (summary by Banno et al., 2009).

For general information on the ADAMTS family of zinc-dependent proteases, which includes ADAMTS13, see ADAMTS1 (605174).


Cloning and Expression

By cDNA library screening, RT-PCR, and genomic sequence analysis of the thrombotic thrombocytopenic purpura (TTP; 274150) interval on 9q34, Levy et al. (2001) isolated a full-length cDNA encoding ADAMTS13. ADAMTS13 encodes a predicted 1,427-amino acid protein. The ADAMTS13 protein has a signal peptide, followed by a short propeptide domain ending in a potential propeptide convertase cleavage site at amino acids 71 to 74 (RQRR), suggesting that proteolytic processing, either in the trans Golgi or the cell surface, is required for activation. The protease domain that follows has a perfect match for the HEXGHXXGXXHD (where X is any amino acid) consensus sequence of the extended catalytic site shared between snake venom metalloproteinases and the ADAM family members. The catalytic domain is followed by a thrombospondin-1-like (THBS1; 188060) domain and spacer domains characteristic of members of the ADAMTS family. An RGD sequence, present in only 1 other mature ADAMTS protein (ADAMTS2; 604539), is located immediately C terminal to the first THBS1 domain of ADAMTS13. The C terminus of ADAMTS13 contains 6 additional THBS1 repeats, followed by a segment homologous to the CUB domain of several developmentally regulated proteins (e.g., CUBN; 602997). The authors found evidence for alternative splicing of exon 17 due to a frameshift, predicting a truncated 842-amino acid form of the ADAMTS13 protein that lacks the 6 C-terminal THBS1 repeats. Northern blot analysis detected a 4.7-kb ADAMTS13 transcript specifically in liver, with an approximately 2.3-kb transcript faintly visible in placenta. These data suggested that the plasma VWF-cleaving protease may be derived primarily from ADAMTS13 expression in liver. A strong RT-PCR signal in ovary and variable expression in other tissues pointed to other potential functions for ADAMTS13.


Gene Structure

Levy et al. (2001) determined that the ADAMTS13 gene contains 29 exons and spans approximately 37 kb.


Mapping

By genomic sequence analysis, Levy et al. (2001) mapped the ADAMTS13 gene to chromosome 9q34.


Gene Function

Furlan et al. (1996) and Tsai (1996) independently reported that a metal-containing proteolytic enzyme (metalloprotease) in normal plasma cleaves the peptide bond between tyrosine at position 842 and methionine at position 843 in monomeric subunits of von Willebrand factor, thereby degrading the large multimers. Fujikawa et al. (2001) and Gerritsen et al. (2001) confirmed that the ADAMTS13 gene encodes the von Willebrand factor-cleaving protease (VWFCP).

Plaimauer et al. (2002) cloned the complete cDNA sequence of ADAMTS13 in a eukaryotic expression vector and transiently expressed the encoded recombinant ADAMTS13 in HEK293 cells. The expressed protein degraded VWF multimers and proteolytically cleaved VWF to the same fragments as those generated by plasma VWF-cleaving protease. Furthermore, recombinant ADAMTS13-mediated degradation of VWF multimers was entirely inhibited by the presence of plasma from a patient with acquired TTP. These data showed that ADAMTS13 is responsible for the physiologic proteolytic degradation of VWF multimers.

ADAMTS13 specifically cleaves a peptidyl bond between tyr1605 and met1606 in the A2 domain of VWF. Kokame et al. (2004) identified a 73-amino acid peptide, which they designated VWF73, as the minimal VWF substrate cleavable by ADAMTS13. VWF73 contains asp1596 to arg1668 of VWF.

Wu et al. (2006) cleaved VWF73 into shorter peptides and found that a 24-amino acid peptide encompassing pro1645 to lys1668 was the shortest peptide that could bind ADAMTS13 and competitively inhibit its cleavage of a VWF-derived substrate. This peptide and longer peptides containing this core sequence also inhibited cleavage of multimeric VWF by ADAMTS13. These results suggested the presence of a complementary extended binding site, or exosite, on ADAMTS13. Asp1653-to-ala and asp1663-to-ala mutations in the VWF-derived substrate significantly reduced the rate of cleavage of the substrate peptide by ADAMTS13, whereas a glu1655-to-ala mutation significantly enhanced the rate of cleavage. Wu et al. (2006) concluded that ionic interactions between the exosite on ADAMTS13 and a region of VWF spanning pro1645 to lys1668 play a significant role in substrate recognition.

Cao et al. (2008) showed that, under shear stress and at physiologic pH and ionic strength, coagulation factor VIII (300841) accelerated, by a factor of about 10, the rate of ADAMTS13-mediated cleavage of the tyr1605/met1606 bond in VWF. Multimer analysis revealed that factor VIII preferentially accelerated the cleavage of high molecular weight multimers. The ability of factor VIII to enhance VWF cleavage by ADAMTS13 was rapidly lost after pretreatment of factor VIII with thrombin (F2; 176930). Cao et al. (2008) concluded that factor VIII regulates proteolytic processing of VWF by ADAMTS13 under shear stress, which depends on the high-affinity interaction between factor VIII and VWF.

Using recombinant variants of ADAMTS13 and VWF for kinetic analysis, Gao et al. (2008) determined that segments between gln1624 and arg1668 in the VWF A2 domain interacted with the first thrombospondin-1 domain, the cys-rich domain, and the spacer domain of ADAMTS13. The individual interactions were relatively weak, but together they increased the rate of substrate cleavage. Internal deletion of gln1624 to arg1641 in the VWF A2 domain did not affect the cleavage rate, but short deletions on either side of the tyr1605-met1606 cleavage site abolished cleavage. Adding residues N-terminal to glu1554 in VWF reduced the rate of VWF cleavage by ADAMTS13.

Calcium and zinc are critical for the proteolysis of VWF by ADAMTS13. Gardner et al. (2009) found that Ca(2+) fully activated ADAMTS13 only after a 40-minute incubation. Calcium and zinc had independent roles in protease activity, with both ions absolutely required for expression of activity. Various in vitro kinetic and site-directed mutagenesis studies indicated that residues glu83 and asp173, in conjunction with cys281 and asp284, comprise a potential low-affinity Ca(2+)-binding site. Residues asp187 and glu212, in conjunction with asp182 or glu184, comprise a high-affinity Ca(2+)-binding site in the ADAMTS13 metalloprotease domain.

Tati et al. (2013) demonstrated deposition of complement C3 (120700) and C5b (120900)-C9 (120940) in renal cortex of 2 TTP patients using immunofluorescence microscopy and immunohistochemical analysis, respectively. Flow cytometric analysis showed that plasma from TTP patients contained significantly higher levels of complement-coated endothelial particles than control plasma. Histamine-stimulated glomerular endothelial cells exposed to patient platelet-rich plasma or patient platelet-poor plasma combined with normal platelets induced C3 deposition, via the alternative pathway, on VWF platelet strings and on endothelial cells in an in vitro perfusion system under shear conditions. No complement was detected when cells were exposed to control plasma or to patient plasma treated with EDTA or that had been heat inactivated. Tati et al. (2013) concluded that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and endothelium and may contribute to thrombotic microangiopathy.


Molecular Genetics

Bianchi et al. (2002) found that although ADAMTS13 activity is decreased in a 'substantial proportion of patients with thrombocytopenia of various causes,' severe deficiency with levels less than 5% of normal were specific for thrombotic thrombocytopenic purpura (TTP).

Hereditary Thrombotic Thrombocytopenic Purpura

Furlan et al. (1997) found that the von Willebrand factor-cleaving protease was deficient in 4 patients with chronic relapsing thrombotic thrombocytopenic purpura, 2 of whom were brothers. Because no inhibitor of the enzyme was detected in plasma, the deficiency was ascribed to an abnormality in the production, survival, or function of the protease. Furlan et al. (1998) found that 6 patients with familial thrombocytopenic purpura (TTP; 274150) lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was found to function normally in all 12 patients.

Levy et al. (2001) identified mutations in ADAMTS13 (604134.0001-604134.0012) in 7 pedigrees with congenital TTP, also known as Schulman-Upshaw syndrome. The 12 mutations identified accounted for all but 1 of the 15 disease alleles expected in this set of patients. No recurrent mutation was observed, except in family A. All 3 affected individuals of this family were homozygous for the same mutation carried on the same extended haplotype, suggesting recent common ancestry. Although there was no known consanguinity, the parents of affected individuals AIII-2, AIII-3, and AIII-8 were all from the same small village where the families had lived for several generations. Two of the 12 identified mutations resulted in frameshifts, 1 was a splice site mutation, and 9 were nonconservative amino acid substitutions at positions perfectly conserved between the human and murine genes. Levy et al. (2001) suggested that the absence of null alleles was notable and that perhaps complete deficiency of ADAMTS13 is lethal, consistent with the low levels of residual VWF-cleaving protease activity observed in all 10 deficient patients they studied.

In 2 Japanese families with Upshaw-Schulman syndrome, characterized by congenital TTP with neonatal onset and frequent relapses, Kokame et al. (2002) reported 4 novel mutations in the ADAMTS13 gene: 3 missense and 1 nonsense. Comparison of individual ADAMTS13 genotypes and plasma VWFCP activities indicated that 3 of the mutations, arg268 to pro (R268P; 604134.0014), gln449 to ter (Q449X; 604134.0013), and cys508 to tyr (C508Y; 604134.0015), abrogated activity of the enzyme, whereas the fourth, pro475 to ser (P475S; 604134.0016), retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWFCP containing either of the mutations R268P or C508Y was not secreted from cells; in contrast, VWFCP containing either Q449X or P475S was normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that the P475S mutation was heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWFCP activity. Thus, the mutation represents a SNP associated with alterations in VWFCP activity that may be a risk factor for thrombotic disorders.

Peyvandi et al. (2004) investigated the mechanisms of TTP in 100 patients diagnosed on the basis of the presence of at least 3 of the following: thrombocytopenia, hemolytic anemia, elevated serum levels of lactate dehydrogenase, and neurologic symptoms. Plasma levels of ADAMTS13 were severely reduced (less than 10% of normal) in 48%, moderately reduced (between 10% and 46%) in 24%, and normal (more than 46%) in 28%. A neutralizing antibody was the cause of the deficiency in 38% of the cases, with a higher prevalence of this mechanism (87%) in the 48 patients with severely reduced ADAMTS13. Three different mutations of the ADAMTS13 gene were identified in 2 patients with chronic recurrent TTP and no family history of the disease (see 604134.0022-604134.0024).

Van Dorland et al. (2019) presented data on 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017. Disease onset ranged from birth to 70 years of age. All patients were considered biallelic for mutated ADAMTS13; a table listed 47 homozygotes and 76 compound heterozygotes, but in the text it was stated that in 1 patient, whose phenotype was confirmed by a plasma infusion trial, only 1 mutation could be found. The most frequent mutation was c.4143_4144dupA (604134.0023), present on 60 of 246 alleles, followed by R1060W (604134.0025) on 13 of 246 alleles.

Acquired Thrombotic Thrombocytopenic Purpura

Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, Furlan et al. (1998) found that 20 had severe and 4 had moderate von Willebrand factor-cleaving protease deficiency during an acute event. An inhibitor of VWFCP found in 20 of the 24 patients (in all 5 plasma samples tested) was shown to be an IgG antibody to the protease.

Tsai and Lian (1998) likewise found severe deficiency of von Willebrand factor-cleaving protease in 37 patients with acute thrombotic thrombocytopenic purpura. No deficiency was detected in 16 samples of plasma from patients in remission. Inhibitory activity against the protease was detected in 26 of 39 plasma samples obtained during the acute phase of the disease. The inhibitors were IgG antibodies.

Atypical Hemolytic-Uremic Syndrome

Furlan et al. (1998) found that all 10 patients with familial hemolytic-uremic syndrome (HUS; 235400) had normal VWF-cleaving protease activity.

Remuzzi et al. (2002) studied ADAMTS13 activity, VWF antigen, and multimeric pattern in 20 patients with recurrent and familial TTP and in 29 patients with HUS. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted after remission. Remuzzi et al. (2002) found complete ADAMTS13 deficiency in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with heterozygous carrier state. In patients with TTP and HUS, there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. Remuzzi et al. (2002) concluded that ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and that it is not the only determinant of VWF abnormalities in these conditions.

In 41 children with diarrhea-positive HUS (D+HUS) and 23 children with diarrhea-negative or atypical HUS (D-HUS), Veyradier et al. (2003) found that von Willebrand factor-cleaving protease activity was normal in over 50% of patients, but was undetectable in 1 D+HUS and 6 D-HUS children. After a 3-month remission, the D+HUS patient recovered 100% VWFCP activity, whereas the 6 D-HUS patients kept an undetectable level. In these 6 D-HUS patients, the disease was characterized by a neonatal onset and several relapses of hemolytic anemia, thrombocytopenia, acute renal failure, and cerebral ischemia. Arterial hypertension and end-stage renal failure sometimes occurred. Veyradier et al. (2003) concluded that a subgroup of patients with D-HUS is related to VWFCP and may actually correspond to Upshaw-Schulman syndrome.


Animal Model

Motto et al. (2005) generated AdamtS13-deficient mice, which were viable and exhibited normal survival. Introduction of a genetic background from a mouse strain with elevated plasma vWF resulted in the appearance of spontaneous thrombocytopenia in a subset of Adamts13-deficient mice and significantly decreased survival. Challenge of these mice with Shiga toxin (derived from bacterial pathogens associated with the related human disease hemolytic uremic syndrome) resulted in a striking syndrome closely resembling human TTP. The data suggested that microbe-derived toxins, or possibly other sources of endothelial injury, together with additional genetic susceptibility factors, are required to trigger TTP in the setting of ADAMTS13 deficiency.

Banno et al. (2009) created a strain of mice harboring an intracisternal A-particle (IAP) retrotransposon in intron 23 of the Adamts13 gene, resulting in expression of a truncated Adamts13 protein that lacked the last 2 Tsp1 domains and the 2 C-terminal CUB domains. Mice expressing the truncated protein displayed a normal size distribution of plasma VWF multimers under steady-state conditions. However, compared with full-length Adamts13, truncated Adamts13 showed inefficient VWF cleavage under high shear stress in vitro and in vivo, with exacerbated platelet thrombosis after thrombogenic stimulation. Banno et al. (2009) concluded that the C-terminal domains of ADAMTS13 may play a role in efficient processing of VWF multimers during platelet thrombus growth.

Tati et al. (2013) observed complement deposits in kidney glomeruli and tubules of mice lacking Adamts13 and treated with Shiga toxin-2 (Stx2). Wildtype and heterozygous kidneys did not show complement deposition after Stx2 challenge.


ALLELIC VARIANTS ( 25 Selected Examples):

.0001 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, HIS96ASP
  
RCV000006154

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-G transversion at nucleotide 286 of the ADAMTS13 gene, resulting in a his96-to-asp (H96D) substitution. This mutation was found in compound heterozygosity with the cys951-to-gly mutation (C951G; 604134.0002) in this family. The H96D mutation was not identified in 180 normal control chromosomes.


.0002 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS951GLY
  
RCV000006155

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a T-to-G transversion at nucleotide 2851 in exon 22 of the ADAMTS13 gene, resulting in a cys951-to-gly (C951G) substitution. This mutation was not identified in 180 control normal chromosomes. It was found in compound heterozygosity with the H96D mutation (604134.0001) in affected family members.


.0003 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG102CYS
  
RCV000006156

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 304 of the ADAMTS13 gene, resulting in an arg102-to-cys (R102C) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals of this family were compound heterozygous for this mutation and the thr196-to-ile mutation (T196I; 604134.0004).


.0004 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, THR196ILE
  
RCV000006157...

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 587 of the ADAMTS13 gene, resulting in a thr196-to-ile substitution (T196I). This mutation was not identified in 180 normal control chromosomes. Affected family members were compound heterozygotes for this mutation and the R102C mutation (604134.0003).

Pimanda et al. (2004) described a patient with congenital thrombotic thrombocytopenic purpura who was a compound heterozygote for the T196I mutation in the metalloproteinase domain of ADAMTS13 and a frameshift mutation (4143-4144insA; 604134.0018).


.0005 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG398HIS
  
RCV000006158

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a G-to-A transition at nucleotide 1193 in exon 10 of the ADAMTS13 gene, resulting in an arg398-to-his (R398H) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals of this family were compound heterozygous for this mutation and the C1024G mutation (604134.0006).


.0006 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS1024GLY
  
RCV000006159...

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a T-to-G transversion at nucleotide 3070 in exon 24 of the ADAMTS13 gene, resulting in a cys1024-to-gly (C1024G) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals in this family were compound heterozygotes for this mutation and the R398H mutation (604134.0005).


.0007 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG528GLY
  
RCV000006160...

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified an A-to-G transition at nucleotide 1582 in exon 13 of the ADAMTS13 gene, resulting in an arg528-to-gly (R528G) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals in this family were compound heterozygous for this mutation and a frameshift mutation in exon 27 (604134.0008).


.0008 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP INS, 3769T
  
RCV000006161

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a frameshift mutation in exon 27 of the ADAMTS13 gene, the insertion of a thymidine after nucleotide 3769. Affected individuals in this family were compound heterozygotes for this mutation and the R528G mutation (604134.0007).


.0009 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 25-BP DEL, NT2376
  
RCV000006162

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a 25-bp deletion in exon 19 of the ADAMTS13 gene. This mutation was found in compound heterozygosity with the C1213Y mutation (604134.0010).


.0010 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS1213TYR
  
RCV000006164

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a G-to-A transition at nucleotide 3638 in exon 26 of the ADAMTS13 gene, resulting in a cys1213-to-tyr (C1213Y) substitution. This mutation was found in compound heterozygosity with a frameshift in exon 19 (604134.0009).


.0011 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG692CYS
  
RCV000006165...

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 2074 in exon 17 of the ADAMTS13 gene, resulting in an arg692-to-cys (R692C) substitution. All 3 affected individuals were homozygous for the same mutation, suggesting recent common ancestry. Although there was no known consanguinity, the parents of affected individuals were all from the same small village, where the families had lived for several generations. This mutation was not identified in 180 control normal chromosomes.


.0012 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS13DS, G-A, +5
  
RCV000006166...

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a splice site mutation, 1584G-A+5. The second allele in this family was not identified. This substitution markedly reduced or eliminated utilization of the normal intron 13 splice donor and activated a cryptic donor splice site at the +70 position, resulting in a 23-codon insertion. This mutation was not identified in 180 control normal chromosomes.


.0013 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, GLN449TER
  
RCV000006167

Kokame et al. (2002) described a patient from a Japanese family who had Schulman-Upshaw syndrome (TTP; 274150) and was homozygous for a gln449-to-ter (Q449X) mutation in the ADAMTS13 gene. The proband had less than 3% of normal VWFCP activity; the activities of the father and mother were moderately decreased to 45% and 60% of control levels, respectively, and did not contain inhibitors of VWFCP activity.


.0014 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG268PRO
  
RCV000006168

In the family of a Japanese male with Schulman-Upshaw syndrome (TTP; 274150), Kokame et al. (2002) identified 4 missense mutations in the ADAMTS13 gene. The proband had an arg268-to-pro (R268P) mutation on 1 allele and 2 mutations on the other allele: gln448 to glu (Q448E) and cys508 to tyr (C508Y) (604134.0015), the effects of which were indistinguishable from each other because of their location on a single allele. The R268P mutation completely abrogated VWFCP activity; the mother carried the Q448E/C508Y diplotype and had intermediate (36%) VWFCP activity. The father was compound heterozygous for the R268P and pro475-to-ser (P475S; 604134.0016) mutations. He had a VWF-cleaving protease activity level of 5.6% but was asymptomatic. The sister of the proband, who was heterozygous for the P475S mutation, had a VWFCP activity of 30%.


.0015 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, GLN448GLU AND CYS508TYR
  
RCV000006169...

For discussion of the gln448-to-glu (Q448E) and cys508-to-tyr (C508Y) in cis mutations in the ADAMTS13 gene that were found in compound heterozygous state in a patient with Schulman-Upshaw syndrome (TTP; 274150) by Kokame et al. (2002), see 604134.0014.


.0016 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, PRO475SER
  
RCV000006170...

Kokame et al. (2002) reported a Japanese family in which a pro475-to-ser (P475S) mutation of the ADAMTS13 gene caused reduction in VWFCP activity, although that activity was not completely abrogated. The proband, who had Schulman-Upshaw syndrome (TTP; 274150), had VWFCP activity below 3% of normal; VWFCP activity of the proband's mother and sister were 36% and 30% of normal, respectively, and the father had activity 5.6% of normal. The father and daughter were heterozygous for the P475S mutation. Studies in HeLa cells demonstrated that this mutant form of VWFCP, like the gln449-to-ter (Q449X; 604134.0013) form, was normally secreted but showed 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 VWFCP activity. Thus, this mutation represents a SNP associated with alterations in VWFCP activity that may be a risk factor for thrombotic disorders.


.0017 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 2-BP DEL, 1783TT
  
RCV000006171

Savasan et al. (2001) reported a patient who had thrombocytopenia and microangiopathic hemolysis in early infancy that was responsive to plasma infusion, but who was thought to have normal ADAMTS13 activity. Savasan et al. (2003) reinvestigated this case of reportedly normal levels of VWF-cleaving protease activity despite the presence of features that were characteristic of congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150). Using a different method for analyzing plasma VWF-cleaving protease activity, they found that the patient had less than 0.1 U/L ADAMTS13 protease activity, whereas the parents were both partially deficient. Sequence analysis showed that the patient was homozygous for a 2-nucleotide (TT) deletion at the end of exon 15 (corresponding to positions 1783-1784 of the ADAMTS13 cDNA), resulting in a frameshift after his594, followed by a predicted 18-amino acid extension and premature termination. Savasan et al. (2003) concluded that hereditary TTP always results from genetic deficiency of ADAMTS13, since gene mutations had been identified in all patients studied at the molecular level.


.0018 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP INS, 4143A
  
RCV000006163...

In a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Pimanda et al. (2004) found compound heterozygosity for a thr196-to-ile amino acid substitution (T196I; 604134.0004) in ADAMTS13 and a frameshift mutation, 4143-4144insA, in the second CUB domain that resulted in loss of the last 49 amino acids of the protein. The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wildtype enzyme but its secretion from transfected COS-7 cells was about 14% of wildtype.


.0019 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS4DS, G-A, +1
  
RCV000006173

In 2 Japanese families segregating Upshaw-Schulman syndrome (TTP; 274150), Matsumoto et al. (2004) found homozygosity for an ADAMTS13 splice mutation, 414+1G-A in the cDNA. In 1 family the parents were cousins; the proband was reported by Miura et al. (1984) when he was 12 years old. His father died of cerebral infarction at 63 years of age, and another brother died of melena soon after birth. The proband showed hyperbilirubinemia during the newborn period, and he received phototherapy for 3 days without exchange blood transfusion. Thereafter, he had repeated episodes of thrombocytopenia and hemolytic anemia; he had received prophylactic infusion of 2 units of fresh frozen plasma (FFP) every 2 to 4 weeks since the age of 8 years. However, he gradually developed chronic nephritis and required continuous ambulatory peritoneal dialysis, switching to hemodialysis 4 years later. The proband of the second family, a Japanese female, was reported at the age of 4 years by Shinohara et al. (1982). She had an episode of severe hyperbilirubinemia soon after birth that required 2 exchange blood transfusions. After the age of 4 years, she received 1 unit of FPP every 3 weeks until the age of 21 years, following which the dosage was increased to 5 units of FFP every 2 weeks because of worsening renal function.


.0020 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ALA250VAL
  
RCV000006174

In a 51-year-old Japanese male with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Uchida et al. (2004) identified compound heterozygosity for mutations in the ADAMTS13 gene: an ala250-to-val (A250V) substitution in the metalloproteinase domain in exon 7, and a G-to-A transition at the 5-prime end of intron 3 (604134.0021). In vitro expression studies revealed that the A250V mutation markedly reduced ADAMTS13 activity and the intron 3 G-to-A transition caused abnormal mRNA synthesis. The patient had a past history of thrombocytopenia of unknown etiology; it was impossible to determine whether he had such episodes during early childhood. A diagnosis of TTP was made because of progressive renal failure and decreased platelet counts. Fresh frozen plasma (FFP) infusion was effective. Later, thrombotic microangiopathy with severe thrombocytopenia developed, which was refractory to FFP infusion. The patient died of gastrointestinal bleeding and renal failure.


.0021 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS3DS, G-A
  
RCV000006175

For discussion of the G-to-A transition at the 5-prime end of intron 3 in the ADAMTS13 gene that was found in compound heterozygous state in a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150) by Uchida et al. (2004), see 604134.0020.


.0022 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 29-BP DEL, NT291
  
RCV000006176

In a 20-year-old man from Turkey with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Peyvandi et al. (2004) identified compound heterozygosity for 2 truncating mutations of the ADAMTS13 gene: a 29-bp deletion in exon 3 (291del29) and a 1-bp insertion in exon 29 (4143insA; 604134.0023). These 2 mutations led to premature stops at codons 368 and 1387, respectively. The 1-bp insertion had previously been described by Schneppenheim et al. (2003).


.0023 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP DUP, 4143A
   RCV000006163...

For discussion of the 1-bp insertion in the ADAMTS13 gene (4143insA) that was found in compound heterozygous state in a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150) by Peyvandi et al. (2004), see 604134.0022.

Among 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017 studied by van Dorland et al. (2019), the most frequent mutation was c.4143_4144dupA, present on 60 of 246 alleles. Van Dorland et al. (2019) noted the effect of the mutation on the protein as Glu1382ArgfsTer6.


.0024 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 6-BP DEL, NT2930
  
RCV000006177

In a 21-year-old man from Iran with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Peyvandi et al. (2004) identified a homozygous 6-bp deletion in exon 23 of the ADAMTS13 gene (2930del6), resulting in a cys977-to-trp (C977W) substitution and deletion of 2 amino acids, ala978 and arg979.


.0025 THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY, ADULT-ONSET

ADAMTS13, ARG1060TRP
  
RCV000059767...

In 6 of 53 (11%) patients with adult-onset hereditary thrombotic thrombocytopenic purpura (TTP; 274150), Camilleri et al. (2008) reported a C-to-T transition at nucleotide 3178 (c.3178C-T) in exon 24 of the ADAMTS13 gene, resulting in an arginine-to-tryptophan substitution in codon 1060 (R1060W) within the TSP1-7 domain. This change was not identified in 100 healthy controls. One homozygous and 5 heterozygous patients were identified. Three of the patients had pregnancy-associated TTP and 3 (including 1 female) had chronic relapsing TTP of unknown etiology. In vitro expression studies demonstrated that R1060W caused severe intracellular retention of ADAMTS13 (less than 5%) without affecting its metalloprotease activity. Camilleri et al. (2008) also identified 6 asymptomatic first-degree relatives of the probands who carried the mutation in heterozygosity; all but 1 had subnormal ADAMTS13 activity.

In Norway, von Krogh et al. (2016) found the R1060W allele in 0.3 to 1.0% of the population.

Joly et al. (2018) studied 56 patients from 51 families with TTP. In the 22 patients with adult-onset disease, 18 (82%) carried the R1060W variant (c. NM_139025.4), 15 in heterozygosity and 3 in homozygosity. In all 22 adult-onset patients, TTP had been triggered by pregnancy.

Among 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017 studied by Van Dorland et al. (2019), the second most frequent mutation was R1060W, present on 13 of 246 alleles.

Delmas et al. (2020) found the R1060W mutation in homozygosity in a 75-year-old man who had a history of 5 ischemic strokes from the age of 63 years. No thrombocytopenia had been observed in more than 50 platelet measurements in over 10 years of follow-up. His parents were first cousins. He had had prolonged neonatal jaundice.


REFERENCES

  1. Banno, F., Chauhan, A. K., Kokame, K., Yang, J., Miyata, S., Wagner, D. D., Miyata, T. The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 113: 5323-5329, 2009. [PubMed: 19109562, images, related citations] [Full Text]

  2. Bianchi, V., Robles, R., Alberio, L., Furlan, M., Lammle, B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood 100: 710-713, 2002. [PubMed: 12091372, related citations] [Full Text]

  3. Camilleri, R. S., Cohen, H., Mackie, I. J., Scully, M., Starke, R. D., Crawley, J. T. B., Lane, D. A., Machin, S. J. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 6: 331-338, 2008. [PubMed: 18031293, related citations] [Full Text]

  4. Cao, W., Krishnaswamy, S., Camire, R. M., Lenting, P. J., Zheng, X. L. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc. Nat. Acad. Sci. 105: 7416-7421, 2008. [PubMed: 18492805, related citations] [Full Text]

  5. Delmas, Y., Renou, P., Sibon, I. Hereditary thrombotic thrombocytopenic purpura. New Eng. J. Med. 382: 393-394, 2020. [PubMed: 31971692, related citations] [Full Text]

  6. Fujikawa, K., Suzuki, H., McMullen, B., Chung, D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 98: 1662-1666, 2001. [PubMed: 11535495, related citations] [Full Text]

  7. Furlan, M., Robles, R., Galbusera, M., Remuzzi, G., Kyrle, P. A., Brenner, B., Krause, M., Scharrer, I., Aumann, V., Mittler, U., Solenthaler, M., Lammle, B. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. New Eng. J. Med. 339: 1578-1584, 1998. [PubMed: 9828245, related citations] [Full Text]

  8. Furlan, M., Robles, R., Lammle, B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 87: 4223-4234, 1996. [PubMed: 8639781, related citations]

  9. Furlan, M., Robles, R., Solenthaler, M., Wassmer, M., Sandoz, Pl, Lammle, B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89: 3097-3103, 1997. [PubMed: 9129011, related citations]

  10. Gao, W., Anderson, P. J., Sadler, J. E. Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity. Blood 112: 1713-1719, 2008. [PubMed: 18492952, images, related citations] [Full Text]

  11. Gardner, M. D., Chion, C. K. N. K., de Groot, R., Shah, A., Crawley, J. T. B., Lane, D. A. A functional calcium-binding site in the metalloprotease domain of ADAMTS13. Blood 113: 1149-1157, 2009. [PubMed: 19047683, related citations] [Full Text]

  12. Gerritsen, H. E., Robles, R., Lammle, B., Furlan, M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood 98: 1654-1661, 2001. [PubMed: 11535494, related citations] [Full Text]

  13. Joly, B. S., Boisseau, P., Roose, E., Stepanian, A., Biebuyck, N., Hogan, J., Provot, F., Delmas, Y., Garrec, C., Vanhoorelbeke, K., Coppo, P., Veyradier, A. ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age-onset in the French cohort of Upshaw-Schulman syndrome. Thromb. Haemost. 118: 1902-1917, 2018. [PubMed: 30312976, related citations] [Full Text]

  14. Kokame, K., Matsumoto, M., Fujimura, Y., Miyata, T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 103: 607-612, 2004. [PubMed: 14512308, related citations] [Full Text]

  15. Kokame, K., Matsumoto, M., Soejima, K., Yagi, H., Ishizashi, H., Funato, M., Tamai, H., Konno, M., Kamide, K., Kawano, Y., Miyata, T., Fujimura, Y. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Nat. Acad. Sci. 99: 11902-11907, 2002. [PubMed: 12181489, images, related citations] [Full Text]

  16. Levy, G. G., Nichols, W. C., Lian, E. C., Foroud, T., McClintick, J. N., McGee, B. M., Yang, A. Y., Slemieniak, D. R., Stark, K. R., Gruppo, R., Sarode, R., Shurin, S. B., Chandrasekaran, V., Stabler, S. P., Sabio, H., Bouhassira, E. E., Upshaw, J. D., Jr., Ginsburg, D., Tsai, H.-M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413: 488-494, 2001. [PubMed: 11586351, related citations] [Full Text]

  17. Matsumoto, M., Kokame, K., Soejima, K., Miura, M., Hayashi, S., Fujii, Y., Iwai, A., Ito, E., Tsuji, Y., Takeda-Shitaka, M., Iwadate, M., Umeyama, H., Yagi, H., Ishizashi, H., Banno, F., Nakagaki, T., Miyata, T., Fujimura, Y. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103: 1305-1310, 2004. [PubMed: 14563640, related citations] [Full Text]

  18. Miura, M., Koizumi, S., Nakamura, K., Ohno, T., Tachinami, T., Yamagami, M., Taniguchi, N., Kinoshita, S., Abildgaard, C. F. Efficacy of several plasma components in a young boy with chronic thrombocytopenia and hemolytic anemia who responds repeatedly to normal plasma infusions. Am. J. Hemat. 17: 307-319, 1984. [PubMed: 6433703, related citations] [Full Text]

  19. Motto, D. G., Chauhan, A. K., Zhu, G., Homeister, J., Lamb, C. B., Desch, K. C., Zhang, W., Tsai, H.-M., Wagner, D. D., Ginsburg, D. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J. Clin. Invest. 115: 2752-2761, 2005. [PubMed: 16200209, images, related citations] [Full Text]

  20. Peyvandi, F., Ferrari, S., Lavoretano, S., Canciani, M. T., Mannucci, P. M. von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Brit. J. Haemat. 127: 433-439, 2004. [PubMed: 15521921, related citations] [Full Text]

  21. Pimanda, J. E., Maekawa, A., Wind, T., Paxton, J., Chesterman, C. N., Hogg, P. J. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood 103: 627-629, 2004. [PubMed: 14512317, related citations] [Full Text]

  22. Plaimauer, B., Zimmermann, K., Volkel, D., Antoine, G., Kerschbaumer, R., Jenab, P., Furlan, M., Gerritsen, H., Lammle, B., Schwarz, H. P., Scheiflinger, F. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 100: 3626-3632, 2002. [PubMed: 12393399, related citations] [Full Text]

  23. Remuzzi, G., Galbusera, M., Noris, M., Canciani, M. T., Daina, E., Bresin, E., Contaretti, S., Caprioli, J., Gamba, S., Ruggenenti, P., Perico, N., Mannucci, P. M. van Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 100: 778-785, 2002. [PubMed: 12130486, related citations] [Full Text]

  24. Savasan, S., Lee, S.-K., Ginsburg, D., Tsai, H.-M. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood 101: 4449-4451, 2003. [PubMed: 12576319, related citations] [Full Text]

  25. Savasan, S., Taub, J. W., Buck, S., Botterill, M., Furlan, M., Ravindranath, Y. Congenital microangiopathic hemolytic anemia and thrombocytopenia with unusually large von Willebrand factor multimers and von Willebrand factor-cleaving protease. J. Pediat. Hemat. Oncol. 23: 364-367, 2001. [PubMed: 11563771, related citations] [Full Text]

  26. Schneppenheim, R., Budde, U., Oyen, F., Angerhaus, D., Aumann, V., Drewke, E., Hassenpflug, W., Haberle, J., Kentouche, K., Kohne, E., Kurnik, K., Mueller-Wiefel, D., Obser, T., Santer, R., Sykora, K. W. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 101: 1845-1850, 2003. [PubMed: 12393505, related citations] [Full Text]

  27. Shinohara, T., Miyamura, S., Suzuki, E., Kobayashi, K. Congenital microangiopathic hemolytic anemia: report of a Japanese girl. Europ. J. Pediat. 138: 191-193, 1982. [PubMed: 7094941, related citations] [Full Text]

  28. Tati, R., Kristoffersson, A.-C., Stahl, A., Rebetz, J., Wang, L., Licht, C., Motto, D., Karpman, D. Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy. J. Immun. 191: 2184-2193, 2013. Note: Erratum: J. Immun. 192: 1990 only, 2014. [PubMed: 23878316, images, related citations] [Full Text]

  29. Tsai, H.-M., Lian, E. C.-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. New Eng. J. Med. 339: 1585-1594, 1998. [PubMed: 9828246, images, related citations] [Full Text]

  30. Tsai, H.-M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87: 4235-4244, 1996. [PubMed: 8639782, related citations]

  31. Uchida, T., Wada, H., Mizutani, M., Iwashita, M., Ishihara, H., Shibano, T., Suzuki, M., Matsubara, Y., Soejima, K., Matsumoto, M., Fujimura, Y., Ikeda, Y., Murata, M. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood 104: 2081-2083, 2004. [PubMed: 15126318, related citations] [Full Text]

  32. van Dorland, H. A., Taleghani, M. M., Sakai, K., Friedman, K. D., George, J. N., Hrachovinova, I., Knobl, P. N., von Krogh, A. S., Schneppenheim, R., Aebi-Huber, I., Butikofer, L., Largiader, C. R., and 11 others. The International Hereditary Thrombotic Thrombocytopenic Purpura registry: key findings at enrollment until 2017. Haematologica 104: 2107-2116, 2019. [PubMed: 30792199, images, related citations] [Full Text]

  33. Veyradier, A., Obert, B., Haddad, E., Cloarec, S., Nivet, H., Foulard, M., Lesure, F., Delattre, P., Lakhdari, M., Meyer, D., Girma, J.-PO., Loirat, C. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome. J. Pediat. 142: 310-317, 2003. Note: Erratum: J. Pediat. 142: 616 only, 2003. [PubMed: 12640381, related citations] [Full Text]

  34. von Krogh, A. S., Quist-Paulsen, P., Waage, A., Langseth, O. O., Thorstensen, K., Brudevold, R., Tjonnfjord, G. E., Largiader, C. R., Lammle, B., Kremer Hovinga, J. A. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J. Thromb. Haemost. 14: 73-82, 2016. [PubMed: 26566785, related citations] [Full Text]

  35. Wu, J.-J., Fujikawa, K., McMullen, B. A., Chung, D. W. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc. Nat. Acad. Sci. 103: 18470-18474, 2006. [PubMed: 17121983, images, related citations] [Full Text]


Ada Hamosh - updated : 03/02/2020
Bao Lige - updated : 09/19/2019
Paul J. Converse - updated : 04/04/2016
Patricia A. Hartz - updated : 11/15/2010
Cassandra L. Kniffin - updated : 6/24/2009
Patricia A. Hartz - updated : 7/11/2008
Matthew B. Gross - updated : 4/30/2007
Patricia A. Hartz - updated : 4/30/2007
Victor A. McKusick - updated : 11/4/2005
Victor A. McKusick - updated : 1/31/2005
Victor A. McKusick - updated : 12/20/2004
Victor A. McKusick - updated : 4/16/2004
Cassandra L. Kniffin - updated : 3/8/2004
Natalie E. Krasikov - updated : 3/8/2004
Victor A. McKusick - updated : 9/4/2003
Victor A. McKusick - updated : 3/4/2003
Victor A. McKusick - updated : 1/21/2003
Victor A. McKusick - updated : 10/14/2002
Victor A. McKusick - updated : 9/27/2002
Ada Hamosh - updated : 10/4/2001
Creation Date:
Victor A. McKusick : 8/18/1999
carol : 09/25/2022
alopez : 11/17/2021
alopez : 03/02/2020
mgross : 09/19/2019
mgross : 09/19/2019
carol : 08/11/2016
mgross : 04/04/2016
alopez : 4/23/2015
mcolton : 4/15/2015
mcolton : 1/24/2014
carol : 4/7/2011
mgross : 11/18/2010
terry : 11/15/2010
carol : 10/4/2010
carol : 10/29/2009
wwang : 7/20/2009
ckniffin : 6/24/2009
wwang : 7/14/2008
terry : 7/11/2008
carol : 6/20/2007
mgross : 4/30/2007
mgross : 4/30/2007
alopez : 11/10/2005
terry : 11/4/2005
tkritzer : 2/8/2005
terry : 1/31/2005
tkritzer : 1/6/2005
terry : 12/20/2004
terry : 11/3/2004
alopez : 10/22/2004
alopez : 4/22/2004
alopez : 4/22/2004
terry : 4/16/2004
carol : 3/8/2004
carol : 3/8/2004
ckniffin : 3/5/2004
tkritzer : 2/6/2004
cwells : 9/5/2003
terry : 9/4/2003
carol : 6/11/2003
cwells : 3/11/2003
terry : 3/4/2003
cwells : 1/24/2003
tkritzer : 1/21/2003
tkritzer : 10/28/2002
tkritzer : 10/18/2002
terry : 10/14/2002
carol : 10/1/2002
tkritzer : 9/27/2002
tkritzer : 9/27/2002
mgross : 10/5/2001
terry : 10/4/2001
carol : 9/27/2001
carol : 8/18/1999

* 604134

A DISINTEGRIN-LIKE AND METALLOPROTEASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 13; ADAMTS13


Alternative titles; symbols

VON WILLEBRAND FACTOR-CLEAVING PROTEASE; VWFCP


HGNC Approved Gene Symbol: ADAMTS13

SNOMEDCT: 373420004;  


Cytogenetic location: 9q34.2     Genomic coordinates (GRCh38): 9:133,414,337-133,459,386 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q34.2 Thrombotic thrombocytopenic purpura, hereditary 274150 Autosomal recessive 3

TEXT

Description

Von Willebrand factor (VWF; 613160) is a multimeric plasma glycoprotein that plays a critical role in platelet adhesion and aggregation on vascular lesions. ADAMTS13 is a multidomain protease that cleaves VWF in circulating blood and thereby limits platelet thrombosis (summary by Banno et al., 2009).

For general information on the ADAMTS family of zinc-dependent proteases, which includes ADAMTS13, see ADAMTS1 (605174).


Cloning and Expression

By cDNA library screening, RT-PCR, and genomic sequence analysis of the thrombotic thrombocytopenic purpura (TTP; 274150) interval on 9q34, Levy et al. (2001) isolated a full-length cDNA encoding ADAMTS13. ADAMTS13 encodes a predicted 1,427-amino acid protein. The ADAMTS13 protein has a signal peptide, followed by a short propeptide domain ending in a potential propeptide convertase cleavage site at amino acids 71 to 74 (RQRR), suggesting that proteolytic processing, either in the trans Golgi or the cell surface, is required for activation. The protease domain that follows has a perfect match for the HEXGHXXGXXHD (where X is any amino acid) consensus sequence of the extended catalytic site shared between snake venom metalloproteinases and the ADAM family members. The catalytic domain is followed by a thrombospondin-1-like (THBS1; 188060) domain and spacer domains characteristic of members of the ADAMTS family. An RGD sequence, present in only 1 other mature ADAMTS protein (ADAMTS2; 604539), is located immediately C terminal to the first THBS1 domain of ADAMTS13. The C terminus of ADAMTS13 contains 6 additional THBS1 repeats, followed by a segment homologous to the CUB domain of several developmentally regulated proteins (e.g., CUBN; 602997). The authors found evidence for alternative splicing of exon 17 due to a frameshift, predicting a truncated 842-amino acid form of the ADAMTS13 protein that lacks the 6 C-terminal THBS1 repeats. Northern blot analysis detected a 4.7-kb ADAMTS13 transcript specifically in liver, with an approximately 2.3-kb transcript faintly visible in placenta. These data suggested that the plasma VWF-cleaving protease may be derived primarily from ADAMTS13 expression in liver. A strong RT-PCR signal in ovary and variable expression in other tissues pointed to other potential functions for ADAMTS13.


Gene Structure

Levy et al. (2001) determined that the ADAMTS13 gene contains 29 exons and spans approximately 37 kb.


Mapping

By genomic sequence analysis, Levy et al. (2001) mapped the ADAMTS13 gene to chromosome 9q34.


Gene Function

Furlan et al. (1996) and Tsai (1996) independently reported that a metal-containing proteolytic enzyme (metalloprotease) in normal plasma cleaves the peptide bond between tyrosine at position 842 and methionine at position 843 in monomeric subunits of von Willebrand factor, thereby degrading the large multimers. Fujikawa et al. (2001) and Gerritsen et al. (2001) confirmed that the ADAMTS13 gene encodes the von Willebrand factor-cleaving protease (VWFCP).

Plaimauer et al. (2002) cloned the complete cDNA sequence of ADAMTS13 in a eukaryotic expression vector and transiently expressed the encoded recombinant ADAMTS13 in HEK293 cells. The expressed protein degraded VWF multimers and proteolytically cleaved VWF to the same fragments as those generated by plasma VWF-cleaving protease. Furthermore, recombinant ADAMTS13-mediated degradation of VWF multimers was entirely inhibited by the presence of plasma from a patient with acquired TTP. These data showed that ADAMTS13 is responsible for the physiologic proteolytic degradation of VWF multimers.

ADAMTS13 specifically cleaves a peptidyl bond between tyr1605 and met1606 in the A2 domain of VWF. Kokame et al. (2004) identified a 73-amino acid peptide, which they designated VWF73, as the minimal VWF substrate cleavable by ADAMTS13. VWF73 contains asp1596 to arg1668 of VWF.

Wu et al. (2006) cleaved VWF73 into shorter peptides and found that a 24-amino acid peptide encompassing pro1645 to lys1668 was the shortest peptide that could bind ADAMTS13 and competitively inhibit its cleavage of a VWF-derived substrate. This peptide and longer peptides containing this core sequence also inhibited cleavage of multimeric VWF by ADAMTS13. These results suggested the presence of a complementary extended binding site, or exosite, on ADAMTS13. Asp1653-to-ala and asp1663-to-ala mutations in the VWF-derived substrate significantly reduced the rate of cleavage of the substrate peptide by ADAMTS13, whereas a glu1655-to-ala mutation significantly enhanced the rate of cleavage. Wu et al. (2006) concluded that ionic interactions between the exosite on ADAMTS13 and a region of VWF spanning pro1645 to lys1668 play a significant role in substrate recognition.

Cao et al. (2008) showed that, under shear stress and at physiologic pH and ionic strength, coagulation factor VIII (300841) accelerated, by a factor of about 10, the rate of ADAMTS13-mediated cleavage of the tyr1605/met1606 bond in VWF. Multimer analysis revealed that factor VIII preferentially accelerated the cleavage of high molecular weight multimers. The ability of factor VIII to enhance VWF cleavage by ADAMTS13 was rapidly lost after pretreatment of factor VIII with thrombin (F2; 176930). Cao et al. (2008) concluded that factor VIII regulates proteolytic processing of VWF by ADAMTS13 under shear stress, which depends on the high-affinity interaction between factor VIII and VWF.

Using recombinant variants of ADAMTS13 and VWF for kinetic analysis, Gao et al. (2008) determined that segments between gln1624 and arg1668 in the VWF A2 domain interacted with the first thrombospondin-1 domain, the cys-rich domain, and the spacer domain of ADAMTS13. The individual interactions were relatively weak, but together they increased the rate of substrate cleavage. Internal deletion of gln1624 to arg1641 in the VWF A2 domain did not affect the cleavage rate, but short deletions on either side of the tyr1605-met1606 cleavage site abolished cleavage. Adding residues N-terminal to glu1554 in VWF reduced the rate of VWF cleavage by ADAMTS13.

Calcium and zinc are critical for the proteolysis of VWF by ADAMTS13. Gardner et al. (2009) found that Ca(2+) fully activated ADAMTS13 only after a 40-minute incubation. Calcium and zinc had independent roles in protease activity, with both ions absolutely required for expression of activity. Various in vitro kinetic and site-directed mutagenesis studies indicated that residues glu83 and asp173, in conjunction with cys281 and asp284, comprise a potential low-affinity Ca(2+)-binding site. Residues asp187 and glu212, in conjunction with asp182 or glu184, comprise a high-affinity Ca(2+)-binding site in the ADAMTS13 metalloprotease domain.

Tati et al. (2013) demonstrated deposition of complement C3 (120700) and C5b (120900)-C9 (120940) in renal cortex of 2 TTP patients using immunofluorescence microscopy and immunohistochemical analysis, respectively. Flow cytometric analysis showed that plasma from TTP patients contained significantly higher levels of complement-coated endothelial particles than control plasma. Histamine-stimulated glomerular endothelial cells exposed to patient platelet-rich plasma or patient platelet-poor plasma combined with normal platelets induced C3 deposition, via the alternative pathway, on VWF platelet strings and on endothelial cells in an in vitro perfusion system under shear conditions. No complement was detected when cells were exposed to control plasma or to patient plasma treated with EDTA or that had been heat inactivated. Tati et al. (2013) concluded that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and endothelium and may contribute to thrombotic microangiopathy.


Molecular Genetics

Bianchi et al. (2002) found that although ADAMTS13 activity is decreased in a 'substantial proportion of patients with thrombocytopenia of various causes,' severe deficiency with levels less than 5% of normal were specific for thrombotic thrombocytopenic purpura (TTP).

Hereditary Thrombotic Thrombocytopenic Purpura

Furlan et al. (1997) found that the von Willebrand factor-cleaving protease was deficient in 4 patients with chronic relapsing thrombotic thrombocytopenic purpura, 2 of whom were brothers. Because no inhibitor of the enzyme was detected in plasma, the deficiency was ascribed to an abnormality in the production, survival, or function of the protease. Furlan et al. (1998) found that 6 patients with familial thrombocytopenic purpura (TTP; 274150) lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was found to function normally in all 12 patients.

Levy et al. (2001) identified mutations in ADAMTS13 (604134.0001-604134.0012) in 7 pedigrees with congenital TTP, also known as Schulman-Upshaw syndrome. The 12 mutations identified accounted for all but 1 of the 15 disease alleles expected in this set of patients. No recurrent mutation was observed, except in family A. All 3 affected individuals of this family were homozygous for the same mutation carried on the same extended haplotype, suggesting recent common ancestry. Although there was no known consanguinity, the parents of affected individuals AIII-2, AIII-3, and AIII-8 were all from the same small village where the families had lived for several generations. Two of the 12 identified mutations resulted in frameshifts, 1 was a splice site mutation, and 9 were nonconservative amino acid substitutions at positions perfectly conserved between the human and murine genes. Levy et al. (2001) suggested that the absence of null alleles was notable and that perhaps complete deficiency of ADAMTS13 is lethal, consistent with the low levels of residual VWF-cleaving protease activity observed in all 10 deficient patients they studied.

In 2 Japanese families with Upshaw-Schulman syndrome, characterized by congenital TTP with neonatal onset and frequent relapses, Kokame et al. (2002) reported 4 novel mutations in the ADAMTS13 gene: 3 missense and 1 nonsense. Comparison of individual ADAMTS13 genotypes and plasma VWFCP activities indicated that 3 of the mutations, arg268 to pro (R268P; 604134.0014), gln449 to ter (Q449X; 604134.0013), and cys508 to tyr (C508Y; 604134.0015), abrogated activity of the enzyme, whereas the fourth, pro475 to ser (P475S; 604134.0016), retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWFCP containing either of the mutations R268P or C508Y was not secreted from cells; in contrast, VWFCP containing either Q449X or P475S was normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that the P475S mutation was heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWFCP activity. Thus, the mutation represents a SNP associated with alterations in VWFCP activity that may be a risk factor for thrombotic disorders.

Peyvandi et al. (2004) investigated the mechanisms of TTP in 100 patients diagnosed on the basis of the presence of at least 3 of the following: thrombocytopenia, hemolytic anemia, elevated serum levels of lactate dehydrogenase, and neurologic symptoms. Plasma levels of ADAMTS13 were severely reduced (less than 10% of normal) in 48%, moderately reduced (between 10% and 46%) in 24%, and normal (more than 46%) in 28%. A neutralizing antibody was the cause of the deficiency in 38% of the cases, with a higher prevalence of this mechanism (87%) in the 48 patients with severely reduced ADAMTS13. Three different mutations of the ADAMTS13 gene were identified in 2 patients with chronic recurrent TTP and no family history of the disease (see 604134.0022-604134.0024).

Van Dorland et al. (2019) presented data on 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017. Disease onset ranged from birth to 70 years of age. All patients were considered biallelic for mutated ADAMTS13; a table listed 47 homozygotes and 76 compound heterozygotes, but in the text it was stated that in 1 patient, whose phenotype was confirmed by a plasma infusion trial, only 1 mutation could be found. The most frequent mutation was c.4143_4144dupA (604134.0023), present on 60 of 246 alleles, followed by R1060W (604134.0025) on 13 of 246 alleles.

Acquired Thrombotic Thrombocytopenic Purpura

Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, Furlan et al. (1998) found that 20 had severe and 4 had moderate von Willebrand factor-cleaving protease deficiency during an acute event. An inhibitor of VWFCP found in 20 of the 24 patients (in all 5 plasma samples tested) was shown to be an IgG antibody to the protease.

Tsai and Lian (1998) likewise found severe deficiency of von Willebrand factor-cleaving protease in 37 patients with acute thrombotic thrombocytopenic purpura. No deficiency was detected in 16 samples of plasma from patients in remission. Inhibitory activity against the protease was detected in 26 of 39 plasma samples obtained during the acute phase of the disease. The inhibitors were IgG antibodies.

Atypical Hemolytic-Uremic Syndrome

Furlan et al. (1998) found that all 10 patients with familial hemolytic-uremic syndrome (HUS; 235400) had normal VWF-cleaving protease activity.

Remuzzi et al. (2002) studied ADAMTS13 activity, VWF antigen, and multimeric pattern in 20 patients with recurrent and familial TTP and in 29 patients with HUS. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted after remission. Remuzzi et al. (2002) found complete ADAMTS13 deficiency in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with heterozygous carrier state. In patients with TTP and HUS, there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. Remuzzi et al. (2002) concluded that ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and that it is not the only determinant of VWF abnormalities in these conditions.

In 41 children with diarrhea-positive HUS (D+HUS) and 23 children with diarrhea-negative or atypical HUS (D-HUS), Veyradier et al. (2003) found that von Willebrand factor-cleaving protease activity was normal in over 50% of patients, but was undetectable in 1 D+HUS and 6 D-HUS children. After a 3-month remission, the D+HUS patient recovered 100% VWFCP activity, whereas the 6 D-HUS patients kept an undetectable level. In these 6 D-HUS patients, the disease was characterized by a neonatal onset and several relapses of hemolytic anemia, thrombocytopenia, acute renal failure, and cerebral ischemia. Arterial hypertension and end-stage renal failure sometimes occurred. Veyradier et al. (2003) concluded that a subgroup of patients with D-HUS is related to VWFCP and may actually correspond to Upshaw-Schulman syndrome.


Animal Model

Motto et al. (2005) generated AdamtS13-deficient mice, which were viable and exhibited normal survival. Introduction of a genetic background from a mouse strain with elevated plasma vWF resulted in the appearance of spontaneous thrombocytopenia in a subset of Adamts13-deficient mice and significantly decreased survival. Challenge of these mice with Shiga toxin (derived from bacterial pathogens associated with the related human disease hemolytic uremic syndrome) resulted in a striking syndrome closely resembling human TTP. The data suggested that microbe-derived toxins, or possibly other sources of endothelial injury, together with additional genetic susceptibility factors, are required to trigger TTP in the setting of ADAMTS13 deficiency.

Banno et al. (2009) created a strain of mice harboring an intracisternal A-particle (IAP) retrotransposon in intron 23 of the Adamts13 gene, resulting in expression of a truncated Adamts13 protein that lacked the last 2 Tsp1 domains and the 2 C-terminal CUB domains. Mice expressing the truncated protein displayed a normal size distribution of plasma VWF multimers under steady-state conditions. However, compared with full-length Adamts13, truncated Adamts13 showed inefficient VWF cleavage under high shear stress in vitro and in vivo, with exacerbated platelet thrombosis after thrombogenic stimulation. Banno et al. (2009) concluded that the C-terminal domains of ADAMTS13 may play a role in efficient processing of VWF multimers during platelet thrombus growth.

Tati et al. (2013) observed complement deposits in kidney glomeruli and tubules of mice lacking Adamts13 and treated with Shiga toxin-2 (Stx2). Wildtype and heterozygous kidneys did not show complement deposition after Stx2 challenge.


ALLELIC VARIANTS 25 Selected Examples):

.0001   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, HIS96ASP
SNP: rs121908467, ClinVar: RCV000006154

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-G transversion at nucleotide 286 of the ADAMTS13 gene, resulting in a his96-to-asp (H96D) substitution. This mutation was found in compound heterozygosity with the cys951-to-gly mutation (C951G; 604134.0002) in this family. The H96D mutation was not identified in 180 normal control chromosomes.


.0002   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS951GLY
SNP: rs121908468, ClinVar: RCV000006155

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a T-to-G transversion at nucleotide 2851 in exon 22 of the ADAMTS13 gene, resulting in a cys951-to-gly (C951G) substitution. This mutation was not identified in 180 control normal chromosomes. It was found in compound heterozygosity with the H96D mutation (604134.0001) in affected family members.


.0003   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG102CYS
SNP: rs121908469, gnomAD: rs121908469, ClinVar: RCV000006156

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 304 of the ADAMTS13 gene, resulting in an arg102-to-cys (R102C) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals of this family were compound heterozygous for this mutation and the thr196-to-ile mutation (T196I; 604134.0004).


.0004   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, THR196ILE
SNP: rs121908470, gnomAD: rs121908470, ClinVar: RCV000006157, RCV001507764

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 587 of the ADAMTS13 gene, resulting in a thr196-to-ile substitution (T196I). This mutation was not identified in 180 normal control chromosomes. Affected family members were compound heterozygotes for this mutation and the R102C mutation (604134.0003).

Pimanda et al. (2004) described a patient with congenital thrombotic thrombocytopenic purpura who was a compound heterozygote for the T196I mutation in the metalloproteinase domain of ADAMTS13 and a frameshift mutation (4143-4144insA; 604134.0018).


.0005   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG398HIS
SNP: rs121908471, gnomAD: rs121908471, ClinVar: RCV000006158

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a G-to-A transition at nucleotide 1193 in exon 10 of the ADAMTS13 gene, resulting in an arg398-to-his (R398H) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals of this family were compound heterozygous for this mutation and the C1024G mutation (604134.0006).


.0006   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS1024GLY
SNP: rs121908472, gnomAD: rs121908472, ClinVar: RCV000006159, RCV002512821

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a T-to-G transversion at nucleotide 3070 in exon 24 of the ADAMTS13 gene, resulting in a cys1024-to-gly (C1024G) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals in this family were compound heterozygotes for this mutation and the R398H mutation (604134.0005).


.0007   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG528GLY
SNP: rs121908473, gnomAD: rs121908473, ClinVar: RCV000006160, RCV003480021

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified an A-to-G transition at nucleotide 1582 in exon 13 of the ADAMTS13 gene, resulting in an arg528-to-gly (R528G) substitution. This mutation was not identified in 180 normal control chromosomes. Affected individuals in this family were compound heterozygous for this mutation and a frameshift mutation in exon 27 (604134.0008).


.0008   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP INS, 3769T
SNP: rs387906341, ClinVar: RCV000006161

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a frameshift mutation in exon 27 of the ADAMTS13 gene, the insertion of a thymidine after nucleotide 3769. Affected individuals in this family were compound heterozygotes for this mutation and the R528G mutation (604134.0007).


.0009   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 25-BP DEL, NT2376
SNP: rs387906342, ClinVar: RCV000006162

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a 25-bp deletion in exon 19 of the ADAMTS13 gene. This mutation was found in compound heterozygosity with the C1213Y mutation (604134.0010).


.0010   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, CYS1213TYR
SNP: rs121908474, gnomAD: rs121908474, ClinVar: RCV000006164

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a G-to-A transition at nucleotide 3638 in exon 26 of the ADAMTS13 gene, resulting in a cys1213-to-tyr (C1213Y) substitution. This mutation was found in compound heterozygosity with a frameshift in exon 19 (604134.0009).


.0011   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG692CYS
SNP: rs121908475, gnomAD: rs121908475, ClinVar: RCV000006165, RCV002512822

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a C-to-T transition at nucleotide 2074 in exon 17 of the ADAMTS13 gene, resulting in an arg692-to-cys (R692C) substitution. All 3 affected individuals were homozygous for the same mutation, suggesting recent common ancestry. Although there was no known consanguinity, the parents of affected individuals were all from the same small village, where the families had lived for several generations. This mutation was not identified in 180 control normal chromosomes.


.0012   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS13DS, G-A, +5
SNP: rs782235228, gnomAD: rs782235228, ClinVar: RCV000006166, RCV002512823

In a family segregating congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150), Levy et al. (2001) identified a splice site mutation, 1584G-A+5. The second allele in this family was not identified. This substitution markedly reduced or eliminated utilization of the normal intron 13 splice donor and activated a cryptic donor splice site at the +70 position, resulting in a 23-codon insertion. This mutation was not identified in 180 control normal chromosomes.


.0013   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, GLN449TER
SNP: rs121908476, gnomAD: rs121908476, ClinVar: RCV000006167

Kokame et al. (2002) described a patient from a Japanese family who had Schulman-Upshaw syndrome (TTP; 274150) and was homozygous for a gln449-to-ter (Q449X) mutation in the ADAMTS13 gene. The proband had less than 3% of normal VWFCP activity; the activities of the father and mother were moderately decreased to 45% and 60% of control levels, respectively, and did not contain inhibitors of VWFCP activity.


.0014   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ARG268PRO
SNP: rs121908477, ClinVar: RCV000006168

In the family of a Japanese male with Schulman-Upshaw syndrome (TTP; 274150), Kokame et al. (2002) identified 4 missense mutations in the ADAMTS13 gene. The proband had an arg268-to-pro (R268P) mutation on 1 allele and 2 mutations on the other allele: gln448 to glu (Q448E) and cys508 to tyr (C508Y) (604134.0015), the effects of which were indistinguishable from each other because of their location on a single allele. The R268P mutation completely abrogated VWFCP activity; the mother carried the Q448E/C508Y diplotype and had intermediate (36%) VWFCP activity. The father was compound heterozygous for the R268P and pro475-to-ser (P475S; 604134.0016) mutations. He had a VWF-cleaving protease activity level of 5.6% but was asymptomatic. The sister of the proband, who was heterozygous for the P475S mutation, had a VWFCP activity of 30%.


.0015   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, GLN448GLU AND CYS508TYR
SNP: rs2301612, rs281875305, gnomAD: rs2301612, rs281875305, ClinVar: RCV000006169, RCV000059755, RCV000241706, RCV000275338, RCV002055012

For discussion of the gln448-to-glu (Q448E) and cys508-to-tyr (C508Y) in cis mutations in the ADAMTS13 gene that were found in compound heterozygous state in a patient with Schulman-Upshaw syndrome (TTP; 274150) by Kokame et al. (2002), see 604134.0014.


.0016   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, PRO475SER
SNP: rs11575933, gnomAD: rs11575933, ClinVar: RCV000006170, RCV000251648, RCV000767050

Kokame et al. (2002) reported a Japanese family in which a pro475-to-ser (P475S) mutation of the ADAMTS13 gene caused reduction in VWFCP activity, although that activity was not completely abrogated. The proband, who had Schulman-Upshaw syndrome (TTP; 274150), had VWFCP activity below 3% of normal; VWFCP activity of the proband's mother and sister were 36% and 30% of normal, respectively, and the father had activity 5.6% of normal. The father and daughter were heterozygous for the P475S mutation. Studies in HeLa cells demonstrated that this mutant form of VWFCP, like the gln449-to-ter (Q449X; 604134.0013) form, was normally secreted but showed 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 VWFCP activity. Thus, this mutation represents a SNP associated with alterations in VWFCP activity that may be a risk factor for thrombotic disorders.


.0017   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 2-BP DEL, 1783TT
SNP: rs387906344, ClinVar: RCV000006171

Savasan et al. (2001) reported a patient who had thrombocytopenia and microangiopathic hemolysis in early infancy that was responsive to plasma infusion, but who was thought to have normal ADAMTS13 activity. Savasan et al. (2003) reinvestigated this case of reportedly normal levels of VWF-cleaving protease activity despite the presence of features that were characteristic of congenital thrombotic thrombocytopenic purpura, or Schulman-Upshaw syndrome (TTP; 274150). Using a different method for analyzing plasma VWF-cleaving protease activity, they found that the patient had less than 0.1 U/L ADAMTS13 protease activity, whereas the parents were both partially deficient. Sequence analysis showed that the patient was homozygous for a 2-nucleotide (TT) deletion at the end of exon 15 (corresponding to positions 1783-1784 of the ADAMTS13 cDNA), resulting in a frameshift after his594, followed by a predicted 18-amino acid extension and premature termination. Savasan et al. (2003) concluded that hereditary TTP always results from genetic deficiency of ADAMTS13, since gene mutations had been identified in all patients studied at the molecular level.


.0018   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP INS, 4143A
SNP: rs387906343, ClinVar: RCV000006163, RCV001851691

In a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Pimanda et al. (2004) found compound heterozygosity for a thr196-to-ile amino acid substitution (T196I; 604134.0004) in ADAMTS13 and a frameshift mutation, 4143-4144insA, in the second CUB domain that resulted in loss of the last 49 amino acids of the protein. The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wildtype enzyme but its secretion from transfected COS-7 cells was about 14% of wildtype.


.0019   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS4DS, G-A, +1
SNP: rs786205077, ClinVar: RCV000006173

In 2 Japanese families segregating Upshaw-Schulman syndrome (TTP; 274150), Matsumoto et al. (2004) found homozygosity for an ADAMTS13 splice mutation, 414+1G-A in the cDNA. In 1 family the parents were cousins; the proband was reported by Miura et al. (1984) when he was 12 years old. His father died of cerebral infarction at 63 years of age, and another brother died of melena soon after birth. The proband showed hyperbilirubinemia during the newborn period, and he received phototherapy for 3 days without exchange blood transfusion. Thereafter, he had repeated episodes of thrombocytopenia and hemolytic anemia; he had received prophylactic infusion of 2 units of fresh frozen plasma (FFP) every 2 to 4 weeks since the age of 8 years. However, he gradually developed chronic nephritis and required continuous ambulatory peritoneal dialysis, switching to hemodialysis 4 years later. The proband of the second family, a Japanese female, was reported at the age of 4 years by Shinohara et al. (1982). She had an episode of severe hyperbilirubinemia soon after birth that required 2 exchange blood transfusions. After the age of 4 years, she received 1 unit of FPP every 3 weeks until the age of 21 years, following which the dosage was increased to 5 units of FFP every 2 weeks because of worsening renal function.


.0020   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, ALA250VAL
SNP: rs121908478, ClinVar: RCV000006174

In a 51-year-old Japanese male with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Uchida et al. (2004) identified compound heterozygosity for mutations in the ADAMTS13 gene: an ala250-to-val (A250V) substitution in the metalloproteinase domain in exon 7, and a G-to-A transition at the 5-prime end of intron 3 (604134.0021). In vitro expression studies revealed that the A250V mutation markedly reduced ADAMTS13 activity and the intron 3 G-to-A transition caused abnormal mRNA synthesis. The patient had a past history of thrombocytopenia of unknown etiology; it was impossible to determine whether he had such episodes during early childhood. A diagnosis of TTP was made because of progressive renal failure and decreased platelet counts. Fresh frozen plasma (FFP) infusion was effective. Later, thrombotic microangiopathy with severe thrombocytopenia developed, which was refractory to FFP infusion. The patient died of gastrointestinal bleeding and renal failure.


.0021   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, IVS3DS, G-A
SNP: rs786205078, ClinVar: RCV000006175

For discussion of the G-to-A transition at the 5-prime end of intron 3 in the ADAMTS13 gene that was found in compound heterozygous state in a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150) by Uchida et al. (2004), see 604134.0020.


.0022   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 29-BP DEL, NT291
SNP: rs387906345, gnomAD: rs387906345, ClinVar: RCV000006176

In a 20-year-old man from Turkey with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Peyvandi et al. (2004) identified compound heterozygosity for 2 truncating mutations of the ADAMTS13 gene: a 29-bp deletion in exon 3 (291del29) and a 1-bp insertion in exon 29 (4143insA; 604134.0023). These 2 mutations led to premature stops at codons 368 and 1387, respectively. The 1-bp insertion had previously been described by Schneppenheim et al. (2003).


.0023   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 1-BP DUP, 4143A
ClinVar: RCV000006163, RCV001851691

For discussion of the 1-bp insertion in the ADAMTS13 gene (4143insA) that was found in compound heterozygous state in a patient with congenital thrombotic thrombocytopenic purpura (TTP; 274150) by Peyvandi et al. (2004), see 604134.0022.

Among 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017 studied by van Dorland et al. (2019), the most frequent mutation was c.4143_4144dupA, present on 60 of 246 alleles. Van Dorland et al. (2019) noted the effect of the mutation on the protein as Glu1382ArgfsTer6.


.0024   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY

ADAMTS13, 6-BP DEL, NT2930
SNP: rs387906346, gnomAD: rs387906346, ClinVar: RCV000006177

In a 21-year-old man from Iran with congenital thrombotic thrombocytopenic purpura (TTP; 274150), Peyvandi et al. (2004) identified a homozygous 6-bp deletion in exon 23 of the ADAMTS13 gene (2930del6), resulting in a cys977-to-trp (C977W) substitution and deletion of 2 amino acids, ala978 and arg979.


.0025   THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY, ADULT-ONSET

ADAMTS13, ARG1060TRP
SNP: rs142572218, gnomAD: rs142572218, ClinVar: RCV000059767, RCV000779576, RCV002469002, RCV003952487

In 6 of 53 (11%) patients with adult-onset hereditary thrombotic thrombocytopenic purpura (TTP; 274150), Camilleri et al. (2008) reported a C-to-T transition at nucleotide 3178 (c.3178C-T) in exon 24 of the ADAMTS13 gene, resulting in an arginine-to-tryptophan substitution in codon 1060 (R1060W) within the TSP1-7 domain. This change was not identified in 100 healthy controls. One homozygous and 5 heterozygous patients were identified. Three of the patients had pregnancy-associated TTP and 3 (including 1 female) had chronic relapsing TTP of unknown etiology. In vitro expression studies demonstrated that R1060W caused severe intracellular retention of ADAMTS13 (less than 5%) without affecting its metalloprotease activity. Camilleri et al. (2008) also identified 6 asymptomatic first-degree relatives of the probands who carried the mutation in heterozygosity; all but 1 had subnormal ADAMTS13 activity.

In Norway, von Krogh et al. (2016) found the R1060W allele in 0.3 to 1.0% of the population.

Joly et al. (2018) studied 56 patients from 51 families with TTP. In the 22 patients with adult-onset disease, 18 (82%) carried the R1060W variant (c. NM_139025.4), 15 in heterozygosity and 3 in homozygosity. In all 22 adult-onset patients, TTP had been triggered by pregnancy.

Among 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017 studied by Van Dorland et al. (2019), the second most frequent mutation was R1060W, present on 13 of 246 alleles.

Delmas et al. (2020) found the R1060W mutation in homozygosity in a 75-year-old man who had a history of 5 ischemic strokes from the age of 63 years. No thrombocytopenia had been observed in more than 50 platelet measurements in over 10 years of follow-up. His parents were first cousins. He had had prolonged neonatal jaundice.


REFERENCES

  1. Banno, F., Chauhan, A. K., Kokame, K., Yang, J., Miyata, S., Wagner, D. D., Miyata, T. The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 113: 5323-5329, 2009. [PubMed: 19109562] [Full Text: https://doi.org/10.1182/blood-2008-07-169359]

  2. Bianchi, V., Robles, R., Alberio, L., Furlan, M., Lammle, B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood 100: 710-713, 2002. [PubMed: 12091372] [Full Text: https://doi.org/10.1182/blood-2002-02-0344]

  3. Camilleri, R. S., Cohen, H., Mackie, I. J., Scully, M., Starke, R. D., Crawley, J. T. B., Lane, D. A., Machin, S. J. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 6: 331-338, 2008. [PubMed: 18031293] [Full Text: https://doi.org/10.1111/j.1538-7836.2008.02846.x]

  4. Cao, W., Krishnaswamy, S., Camire, R. M., Lenting, P. J., Zheng, X. L. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc. Nat. Acad. Sci. 105: 7416-7421, 2008. [PubMed: 18492805] [Full Text: https://doi.org/10.1073/pnas.0801735105]

  5. Delmas, Y., Renou, P., Sibon, I. Hereditary thrombotic thrombocytopenic purpura. New Eng. J. Med. 382: 393-394, 2020. [PubMed: 31971692] [Full Text: https://doi.org/10.1056/NEJMc1915670]

  6. Fujikawa, K., Suzuki, H., McMullen, B., Chung, D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 98: 1662-1666, 2001. [PubMed: 11535495] [Full Text: https://doi.org/10.1182/blood.v98.6.1662]

  7. Furlan, M., Robles, R., Galbusera, M., Remuzzi, G., Kyrle, P. A., Brenner, B., Krause, M., Scharrer, I., Aumann, V., Mittler, U., Solenthaler, M., Lammle, B. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. New Eng. J. Med. 339: 1578-1584, 1998. [PubMed: 9828245] [Full Text: https://doi.org/10.1056/NEJM199811263392202]

  8. Furlan, M., Robles, R., Lammle, B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 87: 4223-4234, 1996. [PubMed: 8639781]

  9. Furlan, M., Robles, R., Solenthaler, M., Wassmer, M., Sandoz, Pl, Lammle, B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89: 3097-3103, 1997. [PubMed: 9129011]

  10. Gao, W., Anderson, P. J., Sadler, J. E. Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity. Blood 112: 1713-1719, 2008. [PubMed: 18492952] [Full Text: https://doi.org/10.1182/blood-2008-04-148759]

  11. Gardner, M. D., Chion, C. K. N. K., de Groot, R., Shah, A., Crawley, J. T. B., Lane, D. A. A functional calcium-binding site in the metalloprotease domain of ADAMTS13. Blood 113: 1149-1157, 2009. [PubMed: 19047683] [Full Text: https://doi.org/10.1182/blood-2008-03-144683]

  12. Gerritsen, H. E., Robles, R., Lammle, B., Furlan, M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood 98: 1654-1661, 2001. [PubMed: 11535494] [Full Text: https://doi.org/10.1182/blood.v98.6.1654]

  13. Joly, B. S., Boisseau, P., Roose, E., Stepanian, A., Biebuyck, N., Hogan, J., Provot, F., Delmas, Y., Garrec, C., Vanhoorelbeke, K., Coppo, P., Veyradier, A. ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age-onset in the French cohort of Upshaw-Schulman syndrome. Thromb. Haemost. 118: 1902-1917, 2018. [PubMed: 30312976] [Full Text: https://doi.org/10.1055/s-0038-1673686]

  14. Kokame, K., Matsumoto, M., Fujimura, Y., Miyata, T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 103: 607-612, 2004. [PubMed: 14512308] [Full Text: https://doi.org/10.1182/blood-2003-08-2861]

  15. Kokame, K., Matsumoto, M., Soejima, K., Yagi, H., Ishizashi, H., Funato, M., Tamai, H., Konno, M., Kamide, K., Kawano, Y., Miyata, T., Fujimura, Y. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Nat. Acad. Sci. 99: 11902-11907, 2002. [PubMed: 12181489] [Full Text: https://doi.org/10.1073/pnas.172277399]

  16. Levy, G. G., Nichols, W. C., Lian, E. C., Foroud, T., McClintick, J. N., McGee, B. M., Yang, A. Y., Slemieniak, D. R., Stark, K. R., Gruppo, R., Sarode, R., Shurin, S. B., Chandrasekaran, V., Stabler, S. P., Sabio, H., Bouhassira, E. E., Upshaw, J. D., Jr., Ginsburg, D., Tsai, H.-M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413: 488-494, 2001. [PubMed: 11586351] [Full Text: https://doi.org/10.1038/35097008]

  17. Matsumoto, M., Kokame, K., Soejima, K., Miura, M., Hayashi, S., Fujii, Y., Iwai, A., Ito, E., Tsuji, Y., Takeda-Shitaka, M., Iwadate, M., Umeyama, H., Yagi, H., Ishizashi, H., Banno, F., Nakagaki, T., Miyata, T., Fujimura, Y. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103: 1305-1310, 2004. [PubMed: 14563640] [Full Text: https://doi.org/10.1182/blood-2003-06-1796]

  18. Miura, M., Koizumi, S., Nakamura, K., Ohno, T., Tachinami, T., Yamagami, M., Taniguchi, N., Kinoshita, S., Abildgaard, C. F. Efficacy of several plasma components in a young boy with chronic thrombocytopenia and hemolytic anemia who responds repeatedly to normal plasma infusions. Am. J. Hemat. 17: 307-319, 1984. [PubMed: 6433703] [Full Text: https://doi.org/10.1002/ajh.2830170311]

  19. Motto, D. G., Chauhan, A. K., Zhu, G., Homeister, J., Lamb, C. B., Desch, K. C., Zhang, W., Tsai, H.-M., Wagner, D. D., Ginsburg, D. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J. Clin. Invest. 115: 2752-2761, 2005. [PubMed: 16200209] [Full Text: https://doi.org/10.1172/JCI26007]

  20. Peyvandi, F., Ferrari, S., Lavoretano, S., Canciani, M. T., Mannucci, P. M. von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Brit. J. Haemat. 127: 433-439, 2004. [PubMed: 15521921] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.05217.x]

  21. Pimanda, J. E., Maekawa, A., Wind, T., Paxton, J., Chesterman, C. N., Hogg, P. J. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood 103: 627-629, 2004. [PubMed: 14512317] [Full Text: https://doi.org/10.1182/blood-2003-04-1346]

  22. Plaimauer, B., Zimmermann, K., Volkel, D., Antoine, G., Kerschbaumer, R., Jenab, P., Furlan, M., Gerritsen, H., Lammle, B., Schwarz, H. P., Scheiflinger, F. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 100: 3626-3632, 2002. [PubMed: 12393399] [Full Text: https://doi.org/10.1182/blood-2002-05-1397]

  23. Remuzzi, G., Galbusera, M., Noris, M., Canciani, M. T., Daina, E., Bresin, E., Contaretti, S., Caprioli, J., Gamba, S., Ruggenenti, P., Perico, N., Mannucci, P. M. van Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 100: 778-785, 2002. [PubMed: 12130486] [Full Text: https://doi.org/10.1182/blood-2001-12-0166]

  24. Savasan, S., Lee, S.-K., Ginsburg, D., Tsai, H.-M. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood 101: 4449-4451, 2003. [PubMed: 12576319] [Full Text: https://doi.org/10.1182/blood-2002-12-3796]

  25. Savasan, S., Taub, J. W., Buck, S., Botterill, M., Furlan, M., Ravindranath, Y. Congenital microangiopathic hemolytic anemia and thrombocytopenia with unusually large von Willebrand factor multimers and von Willebrand factor-cleaving protease. J. Pediat. Hemat. Oncol. 23: 364-367, 2001. [PubMed: 11563771] [Full Text: https://doi.org/10.1097/00043426-200108000-00008]

  26. Schneppenheim, R., Budde, U., Oyen, F., Angerhaus, D., Aumann, V., Drewke, E., Hassenpflug, W., Haberle, J., Kentouche, K., Kohne, E., Kurnik, K., Mueller-Wiefel, D., Obser, T., Santer, R., Sykora, K. W. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 101: 1845-1850, 2003. [PubMed: 12393505] [Full Text: https://doi.org/10.1182/blood-2002-08-2399]

  27. Shinohara, T., Miyamura, S., Suzuki, E., Kobayashi, K. Congenital microangiopathic hemolytic anemia: report of a Japanese girl. Europ. J. Pediat. 138: 191-193, 1982. [PubMed: 7094941] [Full Text: https://doi.org/10.1007/BF00441153]

  28. Tati, R., Kristoffersson, A.-C., Stahl, A., Rebetz, J., Wang, L., Licht, C., Motto, D., Karpman, D. Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy. J. Immun. 191: 2184-2193, 2013. Note: Erratum: J. Immun. 192: 1990 only, 2014. [PubMed: 23878316] [Full Text: https://doi.org/10.4049/jimmunol.1301221]

  29. Tsai, H.-M., Lian, E. C.-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. New Eng. J. Med. 339: 1585-1594, 1998. [PubMed: 9828246] [Full Text: https://doi.org/10.1056/NEJM199811263392203]

  30. Tsai, H.-M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87: 4235-4244, 1996. [PubMed: 8639782]

  31. Uchida, T., Wada, H., Mizutani, M., Iwashita, M., Ishihara, H., Shibano, T., Suzuki, M., Matsubara, Y., Soejima, K., Matsumoto, M., Fujimura, Y., Ikeda, Y., Murata, M. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood 104: 2081-2083, 2004. [PubMed: 15126318] [Full Text: https://doi.org/10.1182/blood-2004-02-0715]

  32. van Dorland, H. A., Taleghani, M. M., Sakai, K., Friedman, K. D., George, J. N., Hrachovinova, I., Knobl, P. N., von Krogh, A. S., Schneppenheim, R., Aebi-Huber, I., Butikofer, L., Largiader, C. R., and 11 others. The International Hereditary Thrombotic Thrombocytopenic Purpura registry: key findings at enrollment until 2017. Haematologica 104: 2107-2116, 2019. [PubMed: 30792199] [Full Text: https://doi.org/10.3324/haematol.2019.216796]

  33. Veyradier, A., Obert, B., Haddad, E., Cloarec, S., Nivet, H., Foulard, M., Lesure, F., Delattre, P., Lakhdari, M., Meyer, D., Girma, J.-PO., Loirat, C. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome. J. Pediat. 142: 310-317, 2003. Note: Erratum: J. Pediat. 142: 616 only, 2003. [PubMed: 12640381] [Full Text: https://doi.org/10.1067/mpd.2003.79]

  34. von Krogh, A. S., Quist-Paulsen, P., Waage, A., Langseth, O. O., Thorstensen, K., Brudevold, R., Tjonnfjord, G. E., Largiader, C. R., Lammle, B., Kremer Hovinga, J. A. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J. Thromb. Haemost. 14: 73-82, 2016. [PubMed: 26566785] [Full Text: https://doi.org/10.1111/jth.13186]

  35. Wu, J.-J., Fujikawa, K., McMullen, B. A., Chung, D. W. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc. Nat. Acad. Sci. 103: 18470-18474, 2006. [PubMed: 17121983] [Full Text: https://doi.org/10.1073/pnas.0609190103]


Contributors:
Ada Hamosh - updated : 03/02/2020
Bao Lige - updated : 09/19/2019
Paul J. Converse - updated : 04/04/2016
Patricia A. Hartz - updated : 11/15/2010
Cassandra L. Kniffin - updated : 6/24/2009
Patricia A. Hartz - updated : 7/11/2008
Matthew B. Gross - updated : 4/30/2007
Patricia A. Hartz - updated : 4/30/2007
Victor A. McKusick - updated : 11/4/2005
Victor A. McKusick - updated : 1/31/2005
Victor A. McKusick - updated : 12/20/2004
Victor A. McKusick - updated : 4/16/2004
Cassandra L. Kniffin - updated : 3/8/2004
Natalie E. Krasikov - updated : 3/8/2004
Victor A. McKusick - updated : 9/4/2003
Victor A. McKusick - updated : 3/4/2003
Victor A. McKusick - updated : 1/21/2003
Victor A. McKusick - updated : 10/14/2002
Victor A. McKusick - updated : 9/27/2002
Ada Hamosh - updated : 10/4/2001

Creation Date:
Victor A. McKusick : 8/18/1999

Edit History:
carol : 09/25/2022
alopez : 11/17/2021
alopez : 03/02/2020
mgross : 09/19/2019
mgross : 09/19/2019
carol : 08/11/2016
mgross : 04/04/2016
alopez : 4/23/2015
mcolton : 4/15/2015
mcolton : 1/24/2014
carol : 4/7/2011
mgross : 11/18/2010
terry : 11/15/2010
carol : 10/4/2010
carol : 10/29/2009
wwang : 7/20/2009
ckniffin : 6/24/2009
wwang : 7/14/2008
terry : 7/11/2008
carol : 6/20/2007
mgross : 4/30/2007
mgross : 4/30/2007
alopez : 11/10/2005
terry : 11/4/2005
tkritzer : 2/8/2005
terry : 1/31/2005
tkritzer : 1/6/2005
terry : 12/20/2004
terry : 11/3/2004
alopez : 10/22/2004
alopez : 4/22/2004
alopez : 4/22/2004
terry : 4/16/2004
carol : 3/8/2004
carol : 3/8/2004
ckniffin : 3/5/2004
tkritzer : 2/6/2004
cwells : 9/5/2003
terry : 9/4/2003
carol : 6/11/2003
cwells : 3/11/2003
terry : 3/4/2003
cwells : 1/24/2003
tkritzer : 1/21/2003
tkritzer : 10/28/2002
tkritzer : 10/18/2002
terry : 10/14/2002
carol : 10/1/2002
tkritzer : 9/27/2002
tkritzer : 9/27/2002
mgross : 10/5/2001
terry : 10/4/2001
carol : 9/27/2001
carol : 8/18/1999