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Gene Review

ADAMTS13  -  ADAM metallopeptidase with thrombospondin...

Homo sapiens

Synonyms: A disintegrin and metalloproteinase with thrombospondin motifs 13, ADAM-TS 13, ADAM-TS13, ADAMTS-13, C9orf8, ...
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Disease relevance of ADAMTS13


Psychiatry related information on ADAMTS13

  • Prompt identification of absent or impaired ADAMTS13 activity could prove invaluable to clinical decision-making regarding diagnosis and treatment of suspected TTP patients [5].

High impact information on ADAMTS13

  • We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis [6].
  • A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13) [6].
  • Absence of ADAMTS13 did not promote thrombi formation in alphaIIbbeta3 integrin-inhibited blood [1].
  • Recombinant ADAMTS13 reduced platelet adhesion and aggregation in histamine-activated venules and promoted thrombus dissolution in injured arterioles [1].
  • An inhibitory antibody to ADAMTS13 infused in wild-type mice prolonged adhesion of platelets to endothelium and induced thrombi formation with embolization in the activated microvenules [1].

Chemical compound and disease context of ADAMTS13

  • RESULTS: Discontinuation of cyclosporine and daily plasma exchange increased the ADAMTS13 activity, which was followed by resolution of the microangiopathic hemolysis and improvement of the graft function [7].
  • The presence of a consumptive coagulopathy in the setting of thrombocytopenia supports a diagnosis of DIC, not TTP-HUS, and is demonstrated by decreasing serum fibrinogen levels, and increasing TTs, PTs, aPTTs, and fibrin degradation products [8].
  • Among secondary alterations in hemostasis, thrombocytopenia, platelet function abnormalities, or factor consumption contribute to the risk of ICH in patients with ITP, TTP, disseminated intravascular coagulation, myeloproliferative or myelodysplastic disorders, and exposure to certain medications [9].

Biological context of ADAMTS13

  • The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity [10].
  • Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis [11].
  • Considerable progress has also been realized toward understanding the role of ADAMTS13 in normal hemostasis, as well as the mechanisms by which ADAMTS13 deficiency contributes to TTP pathogenesis [12].
  • Mutation analysis of the ADAMTS13 gene in the patients deficient in VWF-CP by direct sequencing of all 29 exons identified 8 different mutations, suggesting the hereditary form of TTP in 1 patient with ITP, in the patient with Evans syndrome, and in 5 of the 8 patients with TTP [13].
  • In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state [3].

Anatomical context of ADAMTS13

  • We found that recombinant CUB-1 and CUB-1+2 polypeptides and synthetic peptides derived from CUB-1 partially blocked the cleavage of ULVWF by ADAMTS13 on the surface of endothelial cells under flow [14].
  • ADAMTS13 activity was similar in all 4 type I VWD cryodepleted plasmas and comparable to a normal control plasma [15].
  • ADAMTS13, the specific von Willebrand factor (VWF)-cleaving metalloprotease, prevents the spontaneous formation of platelet thrombi in the microcirculation by degrading the highly adhesive ultralarge VWF multimers into smaller forms [16].
  • In expression experiments using HeLa cells, all mutants showed no or a marginal secretion of ADAMTS13 [17].
  • Furthermore, ADAMTS13 was detected immunohistochemically in perisinusoidal cells, whereas no staining was observed in hepatocytes [18].

Associations of ADAMTS13 with chemical compounds


Physical interactions of ADAMTS13


Enzymatic interactions of ADAMTS13

  • ADAMTS13 cleaved VWF and FRETS-VWF73 with roughly comparable catalytic efficiency of 55 microM(-1) min(-1) and 18 microM(-1) min(-1), respectively [20].

Regulatory relationships of ADAMTS13


Other interactions of ADAMTS13


Analytical, diagnostic and therapeutic context of ADAMTS13

  • Surface plasmon resonance demonstrated appreciable reduction in binding affinity between ADAMTS13 and VWF115 mutants (KD up to approximately 1.3 microM), compared with VWF115 (KD 20 nM) [29].
  • Using high pressure liquid chromatography analysis, the initial rates of VWF115 cleavage by ADAMTS13 at different substrate concentrations were determined, and from this the kinetic constants were derived (Km 1.61 microM; kcat 0.14 s(-1)), from which the specificity constant kcat/Km was calculated, 8.70 x 10(4) m(-1) s(-1) [29].
  • By using real-time RT-PCR, we confirmed that in mice the liver had the highest level of the ADAMTS13 transcript [21].
  • Northern blot analysis has shown that ADAMTS13 is expressed primarily in the liver [21].
  • The ELISA was more sensitive than the standard functional inhibitor assay for detecting antibodies against ADAMTS13 [30].


  1. Systemic antithrombotic effects of ADAMTS13. Chauhan, A.K., Motto, D.G., Lamb, C.B., Bergmeier, W., Dockal, M., Plaimauer, B., Scheiflinger, F., Ginsburg, D., Wagner, D.D. J. Exp. Med. (2006) [Pubmed]
  2. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Bianchi, V., Robles, R., Alberio, L., Furlan, M., Lämmle, B. Blood (2002) [Pubmed]
  3. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Remuzzi, G., Galbusera, M., Noris, M., Canciani, M.T., Daina, E., Bresin, E., Contaretti, S., Caprioli, J., Gamba, S., Ruggenenti, P., Perico, N., Mannucci, P.M. Blood (2002) [Pubmed]
  4. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Hulstein, J.J., de Groot, P.G., Silence, K., Veyradier, A., Fijnheer, R., Lenting, P.J. Blood (2005) [Pubmed]
  5. Simplified assay for VWF cleaving protease (ADAMTS13) activity and inhibitor in plasma. Knovich, M.A., Craver, K., Matulis, M.D., Lawson, H., Owen, J. Am. J. Hematol. (2004) [Pubmed]
  6. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Levy, G.G., Nichols, W.C., Lian, E.C., Foroud, T., McClintick, J.N., McGee, B.M., Yang, A.Y., Siemieniak, D.R., Stark, K.R., Gruppo, R., Sarode, R., Shurin, S.B., Chandrasekaran, V., Stabler, S.P., Sabio, H., Bouhassira, E.E., Upshaw, J.D., Ginsburg, D., Tsai, H.M. Nature (2001) [Pubmed]
  7. Inhibitors of ADAMTS13: a potential factor in the cause of thrombotic microangiopathy in a renal allograft recipient. Pham, P.T., Danovitch, G.M., Wilkinson, A.H., Gritsch, H.A., Pham, P.C., Eric, T.M., Kendrick, E., Charles, L.R., Tsai, H.M. Transplantation (2002) [Pubmed]
  8. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Drews, R.E. Clin. Chest Med. (2003) [Pubmed]
  9. Hematologic causes of intracerebral hemorrhage and their treatment. del Zoppo, G.J., Mori, E. Neurosurg. Clin. N. Am. (1992) [Pubmed]
  10. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Kokame, K., Matsumoto, M., Soejima, K., Yagi, H., Ishizashi, H., Funato, M., Tamai, H., Konno, M., Kamide, K., Kawano, Y., Miyata, T., Fujimura, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis. O'Donnell, J.S., McKinnon, T.A., Crawley, J.T., Lane, D.A., Laffan, M.A. Blood (2005) [Pubmed]
  12. ADAMTS13 turns 3. Levy, G.G., Motto, D.G., Ginsburg, D. Blood (2005) [Pubmed]
  13. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Schneppenheim, R., Budde, U., Oyen, F., Angerhaus, D., Aumann, V., Drewke, E., Hassenpflug, W., Häberle, J., Kentouche, K., Kohne, E., Kurnik, K., Mueller-Wiefel, D., Obser, T., Santer, R., Sykora, K.W. Blood (2003) [Pubmed]
  14. Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions. Tao, Z., Peng, Y., Nolasco, L., Cal, S., Lopez-Otin, C., Li, R., Moake, J.L., López, J.A., Dong, J.F. Blood (2005) [Pubmed]
  15. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Bowen, D.J., Collins, P.W. Blood (2004) [Pubmed]
  16. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). Veyradier, A., Lavergne, J.M., Ribba, A.S., Obert, B., Loirat, C., Meyer, D., Girma, J.P. J. Thromb. Haemost. (2004) [Pubmed]
  17. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Matsumoto, M., Kokame, K., Soejima, K., Miura, M., Hayashi, S., Fujii, Y., Iwai, A., Ito, E., Tsuji, Y., Takeda-Shitaka, M., Iwadate, M., Umeyama, H., Yagi, H., Ishizashi, H., Banno, F., Nakagaki, T., Miyata, T., Fujimura, Y. Blood (2004) [Pubmed]
  18. Localization of ADAMTS13 to the stellate cells of human liver. Uemura, M., Tatsumi, K., Matsumoto, M., Fujimoto, M., Matsuyama, T., Ishikawa, M., Iwamoto, T.A., Mori, T., Wanaka, A., Fukui, H., Fujimura, Y. Blood (2005) [Pubmed]
  19. Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Nishio, K., Anderson, P.J., Zheng, X.L., Sadler, J.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  20. Zinc and calcium ions cooperatively modulate ADAMTS13 activity. Anderson, P.J., Kokame, K., Sadler, J.E. J. Biol. Chem. (2006) [Pubmed]
  21. ADAMTS13 is expressed in hepatic stellate cells. Zhou, W., Inada, M., Lee, T.P., Benten, D., Lyubsky, S., Bouhassira, E.E., Gupta, S., Tsai, H.M. Lab. Invest. (2005) [Pubmed]
  22. O-fucosylation is required for ADAMTS13 secretion. Ricketts, L.M., Dlugosz, M., Luther, K.B., Haltiwanger, R.S., Majerus, E.M. J. Biol. Chem. (2007) [Pubmed]
  23. Binding of ADAMTS13 to von Willebrand factor. Majerus, E.M., Anderson, P.J., Sadler, J.E. J. Biol. Chem. (2005) [Pubmed]
  24. Von Willebrand factor cleaving protease (ADAMTS-13) in 123 patients with connective tissue diseases (systemic lupus erythematosus and systemic sclerosis). Mannucci, P.M., Vanoli, M., Forza, I., Canciani, M.T., Scorza, R. Haematologica (2003) [Pubmed]
  25. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Cal, S., Obaya, A.J., Llamazares, M., Garabaya, C., Quesada, V., López-Otín, C. Gene (2002) [Pubmed]
  26. The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Luken, B.M., Turenhout, E.A., Hulstein, J.J., Van Mourik, J.A., Fijnheer, R., Voorberg, J. Thromb. Haemost. (2005) [Pubmed]
  27. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Pimanda, J.E., Maekawa, A., Wind, T., Paxton, J., Chesterman, C.N., Hogg, P.J. Blood (2004) [Pubmed]
  28. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Crawley, J.T., Lam, J.K., Rance, J.B., Mollica, L.R., O'Donnell, J.S., Lane, D.A. Blood (2005) [Pubmed]
  29. ADAMTS13 substrate recognition of von Willebrand factor A2 domain. Zanardelli, S., Crawley, J.T., Chion, C.K., Lam, J.K., Preston, R.J., Lane, D.A. J. Biol. Chem. (2006) [Pubmed]
  30. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Rieger, M., Mannucci, P.M., Kremer Hovinga, J.A., Herzog, A., Gerstenbauer, G., Konetschny, C., Zimmermann, K., Scharrer, I., Peyvandi, F., Galbusera, M., Remuzzi, G., Böhm, M., Plaimauer, B., Lämmle, B., Scheiflinger, F. Blood (2005) [Pubmed]
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