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 metalloproteaseenzyme 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]
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 plateletmicrothrombi in the small blood vessels. In addition, they reported that IgGantibodies 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]
↑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. PMID11686108.
↑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. PMID24825749.
↑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. PMID26073931.
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. PMID11686108.
Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81. PMID12660343.
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. PMID11843286.
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. PMID12395148.
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. PMID12615692.
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. PMID12871390.
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. PMID15692254.