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{{Infobox_gene}}
 
'''ADAMTS13''' ('''''a''' '''d'''isintegrin '''a'''nd '''m'''etalloproteinase with a '''t'''hrombo'''s'''pondin type 1 motif, member '''13''''')—also known as ''von Willebrand factor-cleaving protease'' (VWFCP)—is a [[zinc]]-containing [[metalloprotease]] [[enzyme]] that cleaves [[von Willebrand factor]] (vWf), a large protein involved in [[coagulation|blood clotting]]. It is secreted in [[blood]] and degrades large vWf multimers, decreasing their activity.<ref name=Levy2005>{{cite journal |vauthors=Levy GG, Motto DG, Ginsburg D |title=ADAMTS13 turns 3 |journal=Blood |volume=106 |issue=1 |pages=11–7 |year=2005 |pmid=15774620 |doi=10.1182/blood-2004-10-4097| url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/1/11}}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = ADAM metallopeptidase with thrombospondin type 1 motif, 13
| HGNCid = 1366
| Symbol = ADAMTS13
| AltSymbols =; TTP; C9orf8; DKFZp434C2322; FLJ42993; MGC118899; MGC118900; VWFCP; vWF-CP
| OMIM = 604134
| ECnumber = 
| Homologene = 16372
| MGIid = 2685556
| GeneAtlas_image1 = PBB_GE_ADAMTS13_220208_at_tn.png
| Function = {{GNF_GO|id=GO:0004222 |text = metalloendopeptidase activity}} {{GNF_GO|id=GO:0005178 |text = integrin binding}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008233 |text = peptidase activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}}
| Component = {{GNF_GO|id=GO:0005578 |text = proteinaceous extracellular matrix}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0009986 |text = cell surface}}
| Process = {{GNF_GO|id=GO:0006508 |text = proteolysis}} {{GNF_GO|id=GO:0007160 |text = cell-matrix adhesion}} {{GNF_GO|id=GO:0007229 |text = integrin-mediated signaling pathway}} {{GNF_GO|id=GO:0009100 |text = glycoprotein metabolic process}} {{GNF_GO|id=GO:0016485 |text = protein processing}} {{GNF_GO|id=GO:0030168 |text = platelet activation}} {{GNF_GO|id=GO:0043171 |text = peptide catabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 11093
    | Hs_Ensembl = ENSG00000160323
    | Hs_RefseqProtein = NP_620597
    | Hs_RefseqmRNA = NM_139028
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 135276941
    | Hs_GenLoc_end = 135314329
    | Hs_Uniprot = Q76LX8
    | Mm_EntrezGene = 279028
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = XM_914175
    | Mm_RefseqProtein = XP_919268
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
==Overview==
'''ADAMTS13''' (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) is a [[zinc]]-containing [[metalloprotease]] [[enzyme]] that cleaves [[von Willebrand factor]] (vWf), a large protein involved in [[coagulation|blood clotting]]. It is also known as ''von Willebrand factor-cleaving protease'' (VWFCP). It is secreted in [[blood]] and degrades large vWf multimers, decreasing their activity.


==Genetics==
==Genetics==
The ''ADAMTS13'' [[gene]] maps to the ninth [[chromosome]] (9q34).
The ''ADAMTS13'' [[gene]] maps to the ninth [[chromosome]] (9q34).<ref name=Levy2005/>


==Discovery and function==
==Discovery==
Since 1982 it had been known that [[thrombotic thrombocytopenic purpura]] (TTP), one of the [[microangiopathic hemolytic anemia]]s (see below), was characterised in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).  
Since 1982 it had been known that [[thrombotic thrombocytopenic purpura]] (TTP), one of the [[microangiopathic hemolytic anemia]]s (see below), was characterized in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).<ref name=Levy2005/>


In 1994, VWF was shown to be cleaved between a [[tyrosine]] at position 1605 and a [[methionine]] at 1606 by a plasma metalloprotease when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized the enzyme that cleaved VWF. In the next two years, the same two groups showed that the congenital deficiency of vWf-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that in majority of patients [[IgG]] [[antibody|antibodies]], directed against this enzyme, caused TTP in non-familial cases.
In 1994, vWF was shown to be cleaved between a [[tyrosine]] at position 1605 and a [[methionine]] at 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving [[protease]] was associated with formation of [[platelet]] [[Thrombus|microthrombi]] in the small blood vessels. In addition, they reported that [[IgG]] [[antibody|antibodies]] directed against this same enzyme caused TTP in a majority of non-familial cases.<ref name=Levy2005/>


==Proteomics==
==Proteomics==
Genomically, ADAMTS13 shares many properties with the 19 member [[ADAM protein|ADAMTS family]], all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent [[disintegrin]] domain and one or more [[thrombospondin]] domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.
Genomically, ADAMTS13 shares many properties with the 19 member [[ADAMTS|ADAMTS family]], all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent [[disintegrin]] domain and one or more [[thrombospondin]] domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.<ref name=Levy2005/>


==Role in disease==
==Role in disease==
Deficiency of ADAMTS13 was originally discovered in [[Upshaw-Shulman syndrome]], the recurring familial form of TTP. By that time it was already suspected that TTP occurred in the [[autoimmune]] form as well, owing to its response to [[plasmapheresis]] and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific [[epitope]]s on its surface have been shown to be the target of inhibitory antibodies.
Deficiency of ADAMTS13 was originally discovered in [[Upshaw Schulman Syndrome]], the recurring familial form of [[thrombotic thrombocytopenic purpura]]. By that time it was already suspected that TTP occurred in the [[autoimmune]] form as well, owing to its response to [[plasmapheresis]] and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific [[epitope]]s on its surface have been shown to be the target of inhibitory antibodies.<ref name=Levy2005/><ref>{{cite journal |author =Tsai HM |title=Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura |journal=J. Am. Soc. Nephrol. |volume=14 |issue=4 |pages=1072–81 |year=2003 |pmid=12660343 |url=http://jasn.asnjournals.org/cgi/content/full/14/4/1072 |doi=10.1097/01.ASN.0000060805.04118.4C}}</ref><ref>{{cite journal |vauthors=Furlan M, Lämmle B |title=Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease |journal=Best Pract Res Clin Haematol |volume=14 |issue=2 |pages=437–54 |year=2001 |pmid=11686108 |doi=10.1053/beha.2001.0142}}</ref>


Especially since the link between [[aortic valve stenosis]] and [[angiodysplasia]] was proven to be due to high [[shear stress]] ([[Heyde's syndrome]]), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to [[hemorrhage|bleeding]] by causing increased degradation of vWf. This phenomenon is characterised by a form of [[von Willebrand disease]] (type 2a).
Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis,<ref>{{cite journal|last1=Sonneveld|first1=MA|title=Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis|journal=Blood Reviews|date=2014|volume=28|issue=4|doi=10.1016/j.blre.2014.04.003|pmid=24825749}}</ref> including myocardial infarction<ref>{{cite journal|last1=Maino|first1=A|title=Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis|journal=Journal of thrombosis and haemostasis|date=2015|volume=13|issue=8|doi=10.1111/jth.13032|pmid=26073931}}</ref> and cerebrovascular disease.<ref>{{cite journal|last1=Sonneveld|first1=MA|title=Low ADAMTS13 activity is associated with an increased risk of ischemic stroke.|journal=Blood|date=2015|volume=126|issue=25|doi=10.1182/blood-2015-05-643338|pmid=26511134}}</ref><ref>{{cite journal|last1=Denorme|first1=F|title=Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease.|journal=PLoS ONE|date=2017|volume=12|issue=6|doi=10.1371/journal.pone.0179258|pmid=28591212}}</ref>
 
Finally, since the link between [[aortic valve stenosis]] and [[angiodysplasia]] was proven to be due to high [[shear stress]] ([[Heyde's syndrome]]), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to [[hemorrhage|bleeding]] by causing increased degradation of vWf. This phenomenon is characterised by a form of [[von Willebrand disease]] (type 2a).<ref name=Levy2005/>


==See also==
==See also==
Line 71: Line 24:


==References==
==References==
{{reflist|2}}
{{reflist}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
* Furlan M, Lammle B. ''Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.'' Best Pract Res Clin Haematol 2001;14:437-54. PMID 11686108.
* Furlan M, Lammle B. ''Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.'' Best Pract Res Clin Haematol 2001;14:437-54. {{PMID|11686108}}.
* Tsai HM. ''Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.'' J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
* Tsai HM. ''Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.'' J Am Soc Nephrol 2003;14:1072-81. {{PMID|12660343}}.
* Levy GG, Motto DG, Ginsburg D. ''ADAMTS13 turns 3.'' Blood 2005;106:11-7. PMID 15774620.
{{PBB_Further_reading
{{PBB_Further_reading  
| citations =
| citations =  
*{{cite journal  | author=Tang BL |title=ADAMTS: a novel family of extracellular matrix proteases. |journal=Int. J. Biochem. Cell Biol. |volume=33 |issue= 1 |pages= 33–44 |year= 2001 |pmid= 11167130 |doi=10.1016/S1357-2725(00)00061-3 }}
*{{cite journal  | author=Tang BL |title=ADAMTS: a novel family of extracellular matrix proteases. |journal=Int. J. Biochem. Cell Biol. |volume=33 |issue= 1 |pages= 33-44 |year= 2001 |pmid= 11167130 |doi=  }}
*{{cite journal  |vauthors=Fujimura Y, Matsumoto M, Yagi H |title=Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome. |journal=Int. J. Hematol. |volume=75 |issue= 1 |pages= 25–34 |year= 2002 |pmid= 11843286 |doi=10.1007/BF02981975 |display-authors=etal}}
*{{cite journal  | author=Fujimura Y, Matsumoto M, Yagi H, ''et al.'' |title=Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome. |journal=Int. J. Hematol. |volume=75 |issue= 1 |pages= 25-34 |year= 2002 |pmid= 11843286 |doi=  }}
*{{cite journal  |vauthors=Zheng X, Majerus EM, Sadler JE |title=ADAMTS13 and TTP. |journal=Curr. Opin. Hematol. |volume=9 |issue= 5 |pages= 389–94 |year= 2003 |pmid= 12172456 |doi=10.1097/00062752-200209000-00001 }}
*{{cite journal  | author=Zheng X, Majerus EM, Sadler JE |title=ADAMTS13 and TTP. |journal=Curr. Opin. Hematol. |volume=9 |issue= 5 |pages= 389-94 |year= 2003 |pmid= 12172456 |doi=  }}
*{{cite journal  | author=Tsai HM |title=Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. |journal=J. Mol. Med. |volume=80 |issue= 10 |pages= 639–47 |year= 2003 |pmid= 12395148 |doi= 10.1007/s00109-002-0369-8 }}
*{{cite journal  | author=Tsai HM |title=Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. |journal=J. Mol. Med. |volume=80 |issue= 10 |pages= 639-47 |year= 2003 |pmid= 12395148 |doi= 10.1007/s00109-002-0369-8 }}
*{{cite journal  | author=Tsai HM |title=Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=23 |issue= 3 |pages= 388–96 |year= 2003 |pmid= 12615692 |doi= 10.1161/01.ATV.0000058401.34021.D4 }}
*{{cite journal  | author=Tsai HM |title=Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=23 |issue= 3 |pages= 388-96 |year= 2003 |pmid= 12615692 |doi= 10.1161/01.ATV.0000058401.34021.D4 }}
*{{cite journal  | author=Tsai HM |title=Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. |journal=J. Thromb. Haemost. |volume=1 |issue= 4 |pages= 625–31 |year= 2003 |pmid= 12871390 |doi=10.1046/j.1538-7836.2003.00169.x }}
*{{cite journal  | author=Tsai HM |title=Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. |journal=J. Thromb. Haemost. |volume=1 |issue= 4 |pages= 625-31 |year= 2003 |pmid= 12871390 |doi=  }}
*{{cite journal  | author=Remuzzi G |title=Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No. |journal=J. Thromb. Haemost. |volume=1 |issue= 4 |pages= 632–4 |year= 2003 |pmid= 12871391 |doi=10.1046/j.1538-7836.2003.00170.x }}
*{{cite journal  | author=Remuzzi G |title=Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No. |journal=J. Thromb. Haemost. |volume=1 |issue= 4 |pages= 632-4 |year= 2003 |pmid= 12871391 |doi=  }}
*{{cite journal  | author=Moake JL |title=von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 4–14 |year= 2004 |pmid= 14727254 |doi=10.1053/j.seminhematol.2003.10.003 }}
*{{cite journal  | author=Moake JL |title=von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 4-14 |year= 2004 |pmid= 14727254 |doi=  }}
*{{cite journal  |vauthors=López JA, Dong JF |title=Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 15–23 |year= 2004 |pmid= 14727255 |doi=10.1053/j.seminhematol.2003.10.004 }}
*{{cite journal  | author=López JA, Dong JF |title=Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 15-23 |year= 2004 |pmid= 14727255 |doi=  }}
*{{cite journal  |vauthors=Plaimauer B, Scheiflinger F |title=Expression and characterization of recombinant human ADAMTS-13. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 24–33 |year= 2004 |pmid= 14727256 |doi=10.1053/j.seminhematol.2003.10.006 }}
*{{cite journal  | author=Plaimauer B, Scheiflinger F |title=Expression and characterization of recombinant human ADAMTS-13. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 24-33 |year= 2004 |pmid= 14727256 |doi=  }}
*{{cite journal  |vauthors=Kokame K, Miyata T |title=Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 34–40 |year= 2004 |pmid= 14727257 |doi=10.1053/j.seminhematol.2003.10.002 }}
*{{cite journal  | author=Kokame K, Miyata T |title=Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 34-40 |year= 2004 |pmid= 14727257 |doi=  }}
*{{cite journal  |vauthors=Schneppenheim R, Budde U, Hassenpflug W, Obser T |title=Severe ADAMTS-13 deficiency in childhood. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 83–9 |year= 2004 |pmid= 14727263 |doi=10.1053/j.seminhematol.2003.10.007 }}
*{{cite journal  | author=Schneppenheim R, Budde U, Hassenpflug W, Obser T |title=Severe ADAMTS-13 deficiency in childhood. |journal=Semin. Hematol. |volume=41 |issue= 1 |pages= 83-9 |year= 2004 |pmid= 14727263 |doi=  }}
*{{cite journal  |vauthors=Kremer Hovinga JA, Studt JD, Lämmle B |title=The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP). |journal=Pathophysiol. Haemost. Thromb. |volume=33 |issue= 5-6 |pages= 417–21 |year= 2005 |pmid= 15692254 |doi= 10.1159/000083839 }}
*{{cite journal  | author=Kremer Hovinga JA, Studt JD, Lämmle B |title=The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP). |journal=Pathophysiol. Haemost. Thromb. |volume=33 |issue= 5-6 |pages= 417-21 |year= 2005 |pmid= 15692254 |doi= 10.1159/000083839 }}
*{{cite journal  |vauthors=Levy GG, Motto DG, Ginsburg D |title=ADAMTS13 turns 3. |journal=Blood |volume=106 |issue= 1 |pages= 11–7 |year= 2005 |pmid= 15774620 |doi= 10.1182/blood-2004-10-4097 }}
*{{cite journal  | author=Levy GG, Motto DG, Ginsburg D |title=ADAMTS13 turns 3. |journal=Blood |volume=106 |issue= 1 |pages= 11-7 |year= 2005 |pmid= 15774620 |doi= 10.1182/blood-2004-10-4097 }}
*{{cite journal  | author=George JN |title=ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. |journal=Curr. Hematol. Rep. |volume=4 |issue= 3 |pages= 167–9 |year= 2005 |pmid= 15865866 |doi=  }}
*{{cite journal  | author=George JN |title=ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. |journal=Curr. Hematol. Rep. |volume=4 |issue= 3 |pages= 167-9 |year= 2005 |pmid= 15865866 |doi=  }}
*{{cite journal  | author=Dong JF |title=Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. |journal=J. Thromb. Haemost. |volume=3 |issue= 8 |pages= 1710–6 |year= 2005 |pmid= 16102037 |doi= 10.1111/j.1538-7836.2005.01360.x }}
*{{cite journal  | author=Dong JF |title=Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. |journal=J. Thromb. Haemost. |volume=3 |issue= 8 |pages= 1710-6 |year= 2005 |pmid= 16102037 |doi= 10.1111/j.1538-7836.2005.01360.x }}
*{{Cite journal | last1 = Matsukawa | first1 = M. | last2 = Kaikita | first2 = K. | last3 = Soejima | first3 = K. | last4 = Fuchigami | first4 = S. | last5 = Nakamura | first5 = Y. | last6 = Honda | first6 = T. | last7 = Tsujita | first7 = K. | last8 = Nagayoshi | first8 = Y. | last9 = Kojima | first9 = S. | last10 = Shimomura | first10 = H. | last11 = Sugiyama | first11 = S. | last12 = Fujimoto | first12 = K. | last13 = Yoshimura | first13 = M. | last14 = Nakagaki | first14 = T. | last15 = Ogawa | first15 = H. | title = Serial Changes in von Willebrand Factor-Cleaving Protease (ADAMTS13) and Prognosis After Acute Myocardial Infarction | doi = 10.1016/j.amjcard.2007.03.095 | journal = The American Journal of Cardiology | volume = 100 | issue = 5 | pages = 758–763 | year = 2007 | pmid =  17719316| pmc = }}
}}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M12.241 M12.241]
* {{OMIM|274150}}
* {{OMIM|274150}}
* [http://spd.cbi.pku.edu.cn/spd_pro.php?id=nm_139025 Secreted protein database] entry
* [http://spd.cbi.pku.edu.cn/spd_pro.php?id=nm_139025 Secreted protein database] entry
* {{UCSC gene info|ADAMTS13}}


{{Metalloproteinases}}
{{Metalloendopeptidases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


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ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted in blood and degrades large vWf multimers, decreasing their activity.[1]

Genetics

The ADAMTS13 gene maps to the ninth chromosome (9q34).[1]

Discovery

Since 1982 it had been known that thrombotic thrombocytopenic purpura (TTP), one of the microangiopathic hemolytic anemias (see below), was characterized in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).[1]

In 1994, vWF was shown to be cleaved between a tyrosine at position 1605 and a methionine at 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that IgG antibodies directed against this same enzyme caused TTP in a majority of non-familial cases.[1]

Proteomics

Genomically, ADAMTS13 shares many properties with the 19 member ADAMTS family, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin domain and one or more thrombospondin domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.[1]

Role in disease

Deficiency of ADAMTS13 was originally discovered in Upshaw Schulman Syndrome, the recurring familial form of thrombotic thrombocytopenic purpura. By that time it was already suspected that TTP occurred in the autoimmune form as well, owing to its response to plasmapheresis and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific epitopes on its surface have been shown to be the target of inhibitory antibodies.[1][2][3]

Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis,[4] including myocardial infarction[5] and cerebrovascular disease.[6][7]

Finally, since the link between aortic valve stenosis and angiodysplasia was proven to be due to high shear stress (Heyde's syndrome), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to bleeding by causing increased degradation of vWf. This phenomenon is characterised by a form of von Willebrand disease (type 2a).[1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Levy GG, Motto DG, Ginsburg D (2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
  2. ↑ Tsai HM (2003). "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura". J. Am. Soc. Nephrol. 14 (4): 1072–81. doi:10.1097/01.ASN.0000060805.04118.4C. PMID 12660343.
  3. ↑ Furlan M, Lämmle B (2001). "Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease". Best Pract Res Clin Haematol. 14 (2): 437–54. doi:10.1053/beha.2001.0142. PMID 11686108.
  4. ↑ Sonneveld, MA (2014). "Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis". Blood Reviews. 28 (4). doi:10.1016/j.blre.2014.04.003. PMID 24825749.
  5. ↑ Maino, A (2015). "Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis". Journal of thrombosis and haemostasis. 13 (8). doi:10.1111/jth.13032. PMID 26073931.
  6. ↑ Sonneveld, MA (2015). "Low ADAMTS13 activity is associated with an increased risk of ischemic stroke". Blood. 126 (25). doi:10.1182/blood-2015-05-643338. PMID 26511134.
  7. ↑ Denorme, F (2017). "Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease". PLoS ONE. 12 (6). doi:10.1371/journal.pone.0179258. PMID 28591212.

Further reading

  • Furlan M, Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001;14:437-54. PMID 11686108.
  • Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
  • Tang BL (2001). "ADAMTS: a novel family of extracellular matrix proteases". Int. J. Biochem. Cell Biol. 33 (1): 33–44. doi:10.1016/S1357-2725(00)00061-3. PMID 11167130.
  • Fujimura Y, Matsumoto M, Yagi H, et al. (2002). "Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome". Int. J. Hematol. 75 (1): 25–34. doi:10.1007/BF02981975. PMID 11843286.
  • Zheng X, Majerus EM, Sadler JE (2003). "ADAMTS13 and TTP". Curr. Opin. Hematol. 9 (5): 389–94. doi:10.1097/00062752-200209000-00001. PMID 12172456.
  • Tsai HM (2003). "Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura". J. Mol. Med. 80 (10): 639–47. doi:10.1007/s00109-002-0369-8. PMID 12395148.
  • Tsai HM (2003). "Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura". Arterioscler. Thromb. Vasc. Biol. 23 (3): 388–96. doi:10.1161/01.ATV.0000058401.34021.D4. PMID 12615692.
  • Tsai HM (2003). "Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes". J. Thromb. Haemost. 1 (4): 625–31. doi:10.1046/j.1538-7836.2003.00169.x. PMID 12871390.
  • Remuzzi G (2003). "Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No". J. Thromb. Haemost. 1 (4): 632–4. doi:10.1046/j.1538-7836.2003.00170.x. PMID 12871391.
  • Moake JL (2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Semin. Hematol. 41 (1): 4–14. doi:10.1053/j.seminhematol.2003.10.003. PMID 14727254.
  • López JA, Dong JF (2004). "Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells". Semin. Hematol. 41 (1): 15–23. doi:10.1053/j.seminhematol.2003.10.004. PMID 14727255.
  • Plaimauer B, Scheiflinger F (2004). "Expression and characterization of recombinant human ADAMTS-13". Semin. Hematol. 41 (1): 24–33. doi:10.1053/j.seminhematol.2003.10.006. PMID 14727256.
  • Kokame K, Miyata T (2004). "Genetic defects leading to hereditary thrombotic thrombocytopenic purpura". Semin. Hematol. 41 (1): 34–40. doi:10.1053/j.seminhematol.2003.10.002. PMID 14727257.
  • Schneppenheim R, Budde U, Hassenpflug W, Obser T (2004). "Severe ADAMTS-13 deficiency in childhood". Semin. Hematol. 41 (1): 83–9. doi:10.1053/j.seminhematol.2003.10.007. PMID 14727263.
  • Kremer Hovinga JA, Studt JD, Lämmle B (2005). "The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP)". Pathophysiol. Haemost. Thromb. 33 (5–6): 417–21. doi:10.1159/000083839. PMID 15692254.
  • Levy GG, Motto DG, Ginsburg D (2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
  • George JN (2005). "ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome". Curr. Hematol. Rep. 4 (3): 167–9. PMID 15865866.
  • Dong JF (2005). "Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions". J. Thromb. Haemost. 3 (8): 1710–6. doi:10.1111/j.1538-7836.2005.01360.x. PMID 16102037.
  • Matsukawa, M.; Kaikita, K.; Soejima, K.; Fuchigami, S.; Nakamura, Y.; Honda, T.; Tsujita, K.; Nagayoshi, Y.; Kojima, S.; Shimomura, H.; Sugiyama, S.; Fujimoto, K.; Yoshimura, M.; Nakagaki, T.; Ogawa, H. (2007). "Serial Changes in von Willebrand Factor-Cleaving Protease (ADAMTS13) and Prognosis After Acute Myocardial Infarction". The American Journal of Cardiology. 100 (5): 758–763. doi:10.1016/j.amjcard.2007.03.095. PMID 17719316.

External links

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