ADAMTS13 explained

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 into the blood and degrades large vWf multimers, decreasing their activity, hence ADAMTS13 acts to reduce thrombus formation.^[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]

Further reading

• Tang BL . ADAMTS: a novel family of extracellular matrix proteases . The International Journal of Biochemistry & Cell Biology . 33 . 1 . 33–44 . January 2001 . 11167130 . 10.1016/S1357-2725(00)00061-3 .
• Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K . Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome . International Journal of Hematology . 75 . 1 . 25–34 . January 2002 . 11843286 . 10.1007/BF02981975 . 19926816 .
• J. Evan Sadler. Zheng X, Majerus EM, Sadler JE . ADAMTS13 and TTP . Current Opinion in Hematology . 9 . 5 . 389–94 . September 2002 . 12172456 . 10.1097/00062752-200209000-00001 . 19457473 .
• Tsai HM . Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura . Journal of Molecular Medicine . 80 . 10 . 639–47 . October 2002 . 12395148 . 10.1007/s00109-002-0369-8 . 24992893 .
• Tsai HM . Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura . Arteriosclerosis, Thrombosis, and Vascular Biology . 23 . 3 . 388–96 . March 2003 . 12615692 . 10.1161/01.ATV.0000058401.34021.D4 . free .
• Tsai HM . Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes . Journal of Thrombosis and Haemostasis . 1 . 4 . 625–31 . April 2003 . 12871390 . 10.1046/j.1538-7836.2003.00169.x . 26485194 . free .
• Remuzzi G . Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No . Journal of Thrombosis and Haemostasis . 1 . 4 . 632–4 . April 2003 . 12871391 . 10.1046/j.1538-7836.2003.00170.x . 10742104 . free .
• Moake JL . von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura . Seminars in Hematology . 41 . 1 . 4–14 . January 2004 . 14727254 . 10.1053/j.seminhematol.2003.10.003 .
• López JA, Dong JF . Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells . Seminars in Hematology . 41 . 1 . 15–23 . January 2004 . 14727255 . 10.1053/j.seminhematol.2003.10.004 .
• Plaimauer B, Scheiflinger F . Expression and characterization of recombinant human ADAMTS-13 . Seminars in Hematology . 41 . 1 . 24–33 . January 2004 . 14727256 . 10.1053/j.seminhematol.2003.10.006 .
• Kokame K, Miyata T . Genetic defects leading to hereditary thrombotic thrombocytopenic purpura . Seminars in Hematology . 41 . 1 . 34–40 . January 2004 . 14727257 . 10.1053/j.seminhematol.2003.10.002 .
• Schneppenheim R, Budde U, Hassenpflug W, Obser T . Severe ADAMTS-13 deficiency in childhood . Seminars in Hematology . 41 . 1 . 83–9 . January 2004 . 14727263 . 10.1053/j.seminhematol.2003.10.007 .
• Kremer Hovinga JA, Studt JD, Lämmle B . The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP) . Pathophysiology of Haemostasis and Thrombosis . 33 . 5–6 . 417–21 . 2005 . 15692254 . 10.1159/000083839 . free .
• Levy GG, Motto DG, Ginsburg D . ADAMTS13 turns 3 . Blood . 106 . 1 . 11–7 . July 2005 . 15774620 . 10.1182/blood-2004-10-4097 . 25645477 . free .
• George JN . ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome . Current Hematology Reports . 4 . 3 . 167–9 . May 2005 . 15865866 .
• Dong JF . Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions . Journal of Thrombosis and Haemostasis . 3 . 8 . 1710–6 . August 2005 . 16102037 . 10.1111/j.1538-7836.2005.01360.x . 33464866 . free .
• 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 . Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction . The American Journal of Cardiology . 100 . 5 . 758–63 . September 2007 . 17719316 . 10.1016/j.amjcard.2007.03.095 .

External links

• The MEROPS online database for peptidases and their inhibitors: M12.241
  • Secreted protein database entry

Notes and References

1. Levy GG, Motto DG, Ginsburg D . ADAMTS13 turns 3 . Blood . 106 . 1 . 11–7 . July 2005 . 15774620 . 10.1182/blood-2004-10-4097 . 25645477 . free .
2. Tsai HM . Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura . Journal of the American Society of Nephrology . 14 . 4 . 1072–81 . April 2003 . 12660343 . 10.1097/01.ASN.0000060805.04118.4C . free .
3. Furlan M, Lämmle B . 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 . June 2001 . 11686108 . 10.1053/beha.2001.0142 .
4. Sonneveld MA, de Maat MP, Leebeek FW . Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis . Blood Reviews . 28 . 4 . 167–78 . July 2014 . 24825749 . 10.1016/j.blre.2014.04.003 .
5. Maino A, Siegerink B, Lotta LA, Crawley JT, le Cessie S, Leebeek FW, Lane DA, Lowe GD, Peyvandi F, Rosendaal FR . 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 . August 2015 . 26073931 . 10.1111/jth.13032 . 10044/1/26935 . 324472 . free .
6. Sonneveld MA, de Maat MP, Portegies ML, Kavousi M, Hofman A, Turecek PL, Rottensteiner H, Scheiflinger F, Koudstaal PJ, Ikram MA, Leebeek FW . Low ADAMTS13 activity is associated with an increased risk of ischemic stroke . Blood . 126 . 25 . 2739–46 . December 2015 . 26511134 . 10.1182/blood-2015-05-643338 . free .
7. Denorme F, Kraft P, Pareyn I, Drechsler C, Deckmyn H, Vanhoorelbeke K, Kleinschnitz C, De Meyer SF . Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease . PLOS ONE . 12 . 6 . e0179258 . 2017 . 28591212 . 10.1371/journal.pone.0179258 . 5462472. 2017PLoSO..1279258D . free .