ADAMTS13 (adisintegrin 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.[5]
Genetics
The ADAMTS13 gene maps to the ninth chromosome (9q34).[5]
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).[5]
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.[5]
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.[5]
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.[5][6][7]
Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis,[8] including myocardial infarction[9] and cerebrovascular disease.[10][11]
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).[5]
^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.
^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.
^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.
^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" (PDF). Journal of Thrombosis and Haemostasis. 13 (8): 1396–404. doi:10.1111/jth.13032. hdl:10044/1/26935. PMID 26073931. S2CID 324472.
^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.
^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. Bibcode:2017PLoSO..1279258D. doi:10.1371/journal.pone.0179258. PMC 5462472. PMID 28591212.
Further reading
Tang BL (January 2001). "ADAMTS: a novel family of extracellular matrix proteases". The International Journal of Biochemistry & Cell Biology. 33 (1): 33–44. doi:10.1016/S1357-2725(00)00061-3. PMID 11167130.
Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K (January 2002). "Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome". International Journal of Hematology. 75 (1): 25–34. doi:10.1007/BF02981975. PMID 11843286. S2CID 19926816.
Zheng X, Majerus EM, Sadler JE (September 2002). "ADAMTS13 and TTP". Current Opinion in Hematology. 9 (5): 389–94. doi:10.1097/00062752-200209000-00001. PMID 12172456. S2CID 19457473.
Tsai HM (March 2003). "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. doi:10.1161/01.ATV.0000058401.34021.D4. PMID 12615692.
Tsai HM (April 2003). "Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes". Journal of Thrombosis and Haemostasis. 1 (4): 625–31. doi:10.1046/j.1538-7836.2003.00169.x. PMID 12871390. S2CID 26485194.
Remuzzi G (April 2003). "Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No". Journal of Thrombosis and Haemostasis. 1 (4): 632–4. doi:10.1046/j.1538-7836.2003.00170.x. PMID 12871391. S2CID 10742104.
López JA, Dong JF (January 2004). "Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells". Seminars in Hematology. 41 (1): 15–23. doi:10.1053/j.seminhematol.2003.10.004. PMID 14727255.
Plaimauer B, Scheiflinger F (January 2004). "Expression and characterization of recombinant human ADAMTS-13". Seminars in Hematology. 41 (1): 24–33. doi:10.1053/j.seminhematol.2003.10.006. PMID 14727256.
Kokame K, Miyata T (January 2004). "Genetic defects leading to hereditary thrombotic thrombocytopenic purpura". Seminars in Hematology. 41 (1): 34–40. doi:10.1053/j.seminhematol.2003.10.002. PMID 14727257.
Schneppenheim R, Budde U, Hassenpflug W, Obser T (January 2004). "Severe ADAMTS-13 deficiency in childhood". Seminars in Hematology. 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)". Pathophysiology of Haemostasis and Thrombosis. 33 (5–6): 417–21. doi:10.1159/000083839. PMID 15692254.
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. S2CID 25645477.
George JN (May 2005). "ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome". Current Hematology Reports. 4 (3): 167–9. PMID 15865866.
Dong JF (August 2005). "Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions". Journal of Thrombosis and Haemostasis. 3 (8): 1710–6. doi:10.1111/j.1538-7836.2005.01360.x. PMID 16102037. S2CID 33464866.
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 (September 2007). "Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction". The American Journal of Cardiology. 100 (5): 758–63. doi:10.1016/j.amjcard.2007.03.095. PMID 17719316.
External links
The MEROPS online database for peptidases and their inhibitors: M12.241
Online Mendelian Inheritance in Man (OMIM): 274150
Secreted protein database entry
Human ADAMTS13 genome location and ADAMTS13 gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: Q76LX8 (A disintegrin and metalloproteinase with thrombospondin motifs 13) at the PDBe-KB.
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This research aimed to explore the significance of low activity of ADAMTS-13 in acute myeloid leukemia (AML) after bone morrow transplantation (BMT), and to evaluate the disease progress and prognosis of the patients with low or normal activity of ADAMTS-13 after BMT. 46 AML patients were included i
Thrombotic microangiopathy (TMA) is an uncommon and severe complication of snakebites, and is similar, in general, to hemolytic-uremic syndrome (HUS). We describe a case of TMA following envenomation by Bothrops jararaca. A 56-y-old-woman with controlled hypertension was transferred from a primary h
Biology
