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'''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 | date = July 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 is 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 | vauthors = Tsai HM | title = Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura | journal = Journal of the American Society of Nephrology | volume = 14 | issue = 4 | pages = 1072–81 | date = April 2003 | pmid = 12660343 | doi = 10.1097/01.ASN.0000060805.04118.4C | url = http://jasn.asnjournals.org/cgi/content/full/14/4/1072 }}</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 Practice & Research. Clinical Haematology | volume = 14 | issue = 2 | pages = 437–54 | date = June 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 | vauthors = Sonneveld MA, de Maat MP, Leebeek FW | title = Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis | journal = Blood Reviews | volume = 28 | issue = 4 | pages = 167–78 | date = July 2014 | pmid = 24825749 | doi = 10.1016/j.blre.2014.04.003 }}</ref> including myocardial infarction<ref>{{cite journal | vauthors = Maino A, Siegerink B, Lotta LA, Crawley JT, le Cessie S, Leebeek FW, Lane DA, Lowe GD, Peyvandi F, Rosendaal FR | title = Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis | journal = Journal of Thrombosis and Haemostasis | volume = 13 | issue = 8 | pages = 1396–404 | date = August 2015 | pmid = 26073931 | doi = 10.1111/jth.13032 }}</ref> and cerebrovascular disease.<ref>{{cite journal | vauthors = Sonneveld MA, de Maat MP, Portegies ML, Kavousi M, Hofman A, Turecek PL, Rottensteiner H, Scheiflinger F, Koudstaal PJ, Ikram MA, Leebeek FW | title = Low ADAMTS13 activity is associated with an increased risk of ischemic stroke | journal = Blood | volume = 126 | issue = 25 | pages = 2739–46 | date = December 2015 | pmid = 26511134 | doi = 10.1182/blood-2015-05-643338 }}</ref><ref>{{cite journal | vauthors = Denorme F, Kraft P, Pareyn I, Drechsler C, Deckmyn H, Vanhoorelbeke K, Kleinschnitz C, De Meyer SF | title = Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease | journal = PLOS One | volume = 12 | issue = 6 | pages = e0179258 | date = 2017 | pmid = 28591212 | doi = 10.1371/journal.pone.0179258 | pmc=5462472}}</ref>


==See also==
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 ==
* [[ADAMTS5]] <!--another ADAMTS with a wiki page-->
* [[ADAMTS5]] <!--another ADAMTS with a wiki page-->


==References==
== References ==
{{reflist}}
{{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.
* {{cite journal | vauthors = Tang BL | title = ADAMTS: a novel family of extracellular matrix proteases | journal = The International Journal of Biochemistry & Cell Biology | volume = 33 | issue = 1 | pages = 33–44 | date = January 2001 | pmid = 11167130 | doi = 10.1016/S1357-2725(00)00061-3 }}
* Tsai HM. ''Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.'' J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
* {{cite journal | vauthors = Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K | title = Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome | journal = International Journal of Hematology | volume = 75 | issue = 1 | pages = 25–34 | date = January 2002 | pmid = 11843286 | doi = 10.1007/BF02981975 }}
* Levy GG, Motto DG, Ginsburg D. ''ADAMTS13 turns 3.'' Blood 2005;106:11-7. PMID 15774620.
* {{cite journal |authorlink3=J. Evan Sadler| vauthors = Zheng X, Majerus EM, Sadler JE | title = ADAMTS13 and TTP | journal = Current Opinion in Hematology | volume = 9 | issue = 5 | pages = 389–94 | date = September 2002 | pmid = 12172456 | doi = 10.1097/00062752-200209000-00001 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Tsai HM | title = Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura | journal = Journal of Molecular Medicine | volume = 80 | issue = 10 | pages = 639–47 | date = October 2002 | pmid = 12395148 | doi = 10.1007/s00109-002-0369-8 | pmc = 2435681 }}
| citations =
* {{cite journal | vauthors = Tsai HM | title = Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 3 | pages = 388–96 | date = March 2003 | pmid = 12615692 | doi = 10.1161/01.ATV.0000058401.34021.D4 }}
*{{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 = Tsai HM | title = Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 4 | pages = 625–31 | date = April 2003 | pmid = 12871390 | doi = 10.1046/j.1538-7836.2003.00169.x }}
*{{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 = Remuzzi G | title = Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 4 | pages = 632–4 | date = April 2003 | pmid = 12871391 | doi = 10.1046/j.1538-7836.2003.00170.x }}
*{{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 | vauthors = Moake JL | title = von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 4–14 | date = January 2004 | pmid = 14727254 | doi = 10.1053/j.seminhematol.2003.10.003 }}
*{{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 | vauthors = López JA, Dong JF | title = Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 15–23 | date = January 2004 | pmid = 14727255 | doi = 10.1053/j.seminhematol.2003.10.004 }}
*{{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 | vauthors = Plaimauer B, Scheiflinger F | title = Expression and characterization of recombinant human ADAMTS-13 | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 24–33 | date = January 2004 | pmid = 14727256 | doi = 10.1053/j.seminhematol.2003.10.006 }}
*{{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 | vauthors = Kokame K, Miyata T | title = Genetic defects leading to hereditary thrombotic thrombocytopenic purpura | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 34–40 | date = January 2004 | pmid = 14727257 | doi = 10.1053/j.seminhematol.2003.10.002 }}
*{{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 | vauthors = Schneppenheim R, Budde U, Hassenpflug W, Obser T | title = Severe ADAMTS-13 deficiency in childhood | journal = Seminars in Hematology | volume = 41 | issue = 1 | pages = 83–9 | date = January 2004 | pmid = 14727263 | doi = 10.1053/j.seminhematol.2003.10.007 }}
*{{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 = 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 = Pathophysiology of Haemostasis and Thrombosis | volume = 33 | issue = 5–6 | pages = 417–21 | year = 2005 | pmid = 15692254 | doi = 10.1159/000083839 }}
*{{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 = Levy GG, Motto DG, Ginsburg D | title = ADAMTS13 turns 3 | journal = Blood | volume = 106 | issue = 1 | pages = 11–7 | date = July 2005 | pmid = 15774620 | doi = 10.1182/blood-2004-10-4097 }}
*{{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 = George JN | title = ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome | journal = Current Hematology Reports | volume = 4 | issue = 3 | pages = 167–9 | date = May 2005 | pmid = 15865866 | doi =  }}
*{{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 = Dong JF | title = Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions | journal = Journal of Thrombosis and Haemostasis | volume = 3 | issue = 8 | pages = 1710–6 | date = August 2005 | pmid = 16102037 | doi = 10.1111/j.1538-7836.2005.01360.x }}
*{{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 = 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 | title = Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction | journal = The American Journal of Cardiology | volume = 100 | issue = 5 | pages = 758–63 | date = September 2007 | pmid = 17719316 | pmc =  | doi = 10.1016/j.amjcard.2007.03.095 }}
*{{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 | 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=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 }}
}}
{{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
* [https://web.archive.org/web/20041127134912/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}}


{{DEFAULTSORT:Adamts13}}
[[Category:EC 3.4.24]]
[[Category:EC 3.4.24]]
 
[[Category:ADAMTS]]
 
{{WikiDoc Sources}}

Latest revision as of 07:30, 10 January 2019

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Orthologs
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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 is 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 (July 2005). "ADAMTS13 turns 3". Blood. 106 (1): 11–7. doi:10.1182/blood-2004-10-4097. PMID 15774620.
  2. ↑ Tsai HM (April 2003). "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura". Journal of the American Society of Nephrology. 14 (4): 1072–81. doi:10.1097/01.ASN.0000060805.04118.4C. PMID 12660343.
  3. ↑ Furlan M, Lämmle B (June 2001). "Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease". Best Practice & Research. Clinical Haematology. 14 (2): 437–54. doi:10.1053/beha.2001.0142. PMID 11686108.
  4. ↑ Sonneveld MA, de Maat MP, Leebeek FW (July 2014). "Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis". Blood Reviews. 28 (4): 167–78. doi:10.1016/j.blre.2014.04.003. PMID 24825749.
  5. ↑ Maino A, Siegerink B, Lotta LA, Crawley JT, le Cessie S, Leebeek FW, Lane DA, Lowe GD, Peyvandi F, Rosendaal FR (August 2015). "Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis". Journal of Thrombosis and Haemostasis. 13 (8): 1396–404. doi:10.1111/jth.13032. PMID 26073931.
  6. ↑ Sonneveld MA, de Maat MP, Portegies ML, Kavousi M, Hofman A, Turecek PL, Rottensteiner H, Scheiflinger F, Koudstaal PJ, Ikram MA, Leebeek FW (December 2015). "Low ADAMTS13 activity is associated with an increased risk of ischemic stroke". Blood. 126 (25): 2739–46. doi:10.1182/blood-2015-05-643338. PMID 26511134.
  7. ↑ Denorme F, Kraft P, Pareyn I, Drechsler C, Deckmyn H, Vanhoorelbeke K, Kleinschnitz C, De Meyer SF (2017). "Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease". PLOS One. 12 (6): e0179258. doi:10.1371/journal.pone.0179258. PMC 5462472. PMID 28591212.

Further reading

External links

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