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ADAMTS13: more than a regulator of thrombosis

  • Review Article
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Abstract

ADAMTS13, a plasma reprolysin-like metalloprotease, proteolyzes von Willebrand factor (VWF). ADAMTS13 is primarily synthesized by hepatic stellate cells (HSCs), and mainly regulates thrombogenesis by cleaving VWF. Recent studies demonstrate that ADAMTS13 also plays a role in the down-regulation of inflammation, regulation angiogenesis, and degradation of extracellular matrix. The purpose of this review is to introduce the state of progress with respect to some of the theorized roles of ADAMTS13.

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References

  1. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339(22):1578–84.

    Article  CAS  PubMed  Google Scholar 

  2. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339(22):1585–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Uemura M, Tatsumi K, Matsumoto M, Fujimoto M, Matsuyama T, Ishikawa M, Iwamoto TA, Mori T, Wanaka A, Fukui H, et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood. 2005;106(3):922–4.

    Article  CAS  PubMed  Google Scholar 

  4. Wang A, Duan Q, Wu J, Liu X, Sun Z. The expression of ADAMTS13 in human microvascular endothelial cells. Blood Coagul Fibrinolysis. 2015;11:11.

    Google Scholar 

  5. Shang D, Zheng XW, Niiya M, Zheng XL. Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts. Blood. 2006;108(7):2207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Manea M, Tati R, Karlsson J, Bekassy ZD, Karpman D. Biologically active ADAMTS13 is expressed in renal tubular epithelial cells. Pediatr Nephrol. 2010;25(1):87–96.

    Article  PubMed  Google Scholar 

  7. Tati R, Kristoffersson AC, Stahl AL, Morgelin M, Motto D, Satchell S, Mathieson P, Manea-Hedstrom M, Karpman D. Phenotypic expression of ADAMTS13 in glomerular endothelial cells. PLoS One. 2011;6(6):24.

    Article  Google Scholar 

  8. Manea M, Kristoffersson A, Schneppenheim R, Saleem MA, Mathieson PW, Morgelin M, Bjork P, Holmberg L, Karpman D. Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2007;138(5):651–62.

    Article  CAS  PubMed  Google Scholar 

  9. Suzuki M, Murata M, Matsubara Y, Uchida T, Ishihara H, Shibano T, Ashida S, Soejima K, Okada Y, Ikeda Y. Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. Biochem Biophys Res Commun. 2004;313(1):212–6.

    Article  CAS  PubMed  Google Scholar 

  10. Liu L, Choi H, Bernardo A, Bergeron AL, Nolasco L, Ruan C, Moake JL, Dong JF. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J Thromb Haemost. 2005;3(11):2536–44.

    Article  CAS  PubMed  Google Scholar 

  11. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589–600.

    Article  CAS  PubMed  Google Scholar 

  12. Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K. Von Willebrand factor-cleaving protease and Upshaw–Schulman syndrome. Int J Hematol. 2002;75(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  13. Epperla N, Hemauer K, Friedman KD, George JN, Foy P. Congenital thrombotic thrombocytopenic purpura related to a novel mutation in ADAMTS13 gene and management during pregnancy. Am J Hematol. 2016;28(10):24311.

    Google Scholar 

  14. Krabbe JG, Kemna EW, Strunk AL, Jobse PA, Kramer PA, Dikkeschei LD, van den Heuvel LP, Fijnheer R, Verdonck LF. Adult-onset congenital thrombotic thrombocytopenic purpura caused by a novel compound heterozygous mutation of the ADAMTS13 gene. Int J Hematol. 2015;102(4):477–81.

    Article  CAS  PubMed  Google Scholar 

  15. Kim HY, Lee KO, Yoo KH, Kim SH, Oh D, Kim HJ. Congenital thrombotic thrombocytopenic purpura (Upshaw–Schulman syndrome) caused by novel ADAMTS13 mutations. Br J Haematol. 2015. doi:10.1111/bjh.13564.

    Google Scholar 

  16. Ferrari B, Cairo A, Pontiggia S, Mancini I, Masini L, Peyvandi F. Congenital and acquired ADAMTS13 deficiency: two mechanisms, one patient. J Clin Apher. 2015;30(4):252–6.

    Article  PubMed  Google Scholar 

  17. Benevides TC, Orsi FA, Colella MP, Percout Pde O, Moura MS, Dias MA, Lins BD, Paula EV, Vassallo J, Annichino-Bizzachi J. Acquired thrombotic thrombocytopenic purpura due to antibody-mediated ADAMTS13 deficiency precipitated by a localized Castleman’s disease: a case report. Platelets. 2015;26(3):263–6.

    Article  CAS  PubMed  Google Scholar 

  18. Reuken PA, Kussmann A, Kiehntopf M, Budde U, Stallmach A, Claus RA, Bruns T. Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis. Liver Int. 2015;35(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  19. Ikeda H, Tateishi R, Enooku K, Yoshida H, Nakagawa H, Masuzaki R, Kondo Y, Goto T, Shiina S, Kume Y, et al. Prediction of hepatocellular carcinoma development by plasma ADAMTS13 in chronic hepatitis B and C. Cancer Epidemiol Biomark Prev. 2011;20(10):2204–11.

    Article  CAS  Google Scholar 

  20. Huang Y, Zhang SD, McCrudden C, Chan KW, Lin Y, Kwok HF. The prognostic significance of PD-L1 in bladder cancer. Oncol Rep. 2015;33(6):3075–84.

    PubMed  Google Scholar 

  21. Hugenholtz GC, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT, Lisman T. An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology. 2013;58(2):752–61.

    Article  CAS  PubMed  Google Scholar 

  22. Lee M, Rodansky ES, Smith JK, Rodgers GM. ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis. Microvasc Res. 2012;84(2):109–15.

    Article  CAS  PubMed  Google Scholar 

  23. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488–94.

    Article  CAS  PubMed  Google Scholar 

  24. Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276(44):41059–63.

    Article  CAS  PubMed  Google Scholar 

  25. Plaimauer B, Zimmermann K, Volkel D, Antoine G, Kerschbaumer R, Jenab P, Furlan M, Gerritsen H, Lammle B, Schwarz HP, et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood. 2002;100(10):3626–32.

    Article  CAS  PubMed  Google Scholar 

  26. Okano E, Ko S, Kanehiro H, Matsumoto M, Fujimura Y, Nakajima Y. ADAMTS13 activity decreases after hepatectomy, reflecting a postoperative liver dysfunction. Hepatogastroenterology. 2010;57(98):316–20.

    CAS  PubMed  Google Scholar 

  27. Kume Y, Ikeda H, Inoue M, Tejima K, Tomiya T, Nishikawa T, Watanabe N, Ichikawa T, Kaneko M, Okubo S, et al. Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats. FEBS Lett. 2007;581(8):1631–4.

    Article  CAS  PubMed  Google Scholar 

  28. Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell. 1986;46(2):185–90.

    Article  CAS  PubMed  Google Scholar 

  29. Dong JF, Moake JL, Nolasco L, Bernardo A, Arceneaux W, Shrimpton CN, Schade AJ, McIntire LV, Fujikawa K, Lopez JA. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100(12):4033–9.

    Article  CAS  PubMed  Google Scholar 

  30. Chauhan AK, Goerge T, Schneider SW, Wagner DD. Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin. J Thromb Haemost. 2007;5(3):583–9.

    Article  CAS  PubMed  Google Scholar 

  31. Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D, Wagner DD. Systemic antithrombotic effects of ADAMTS13. J Exp Med. 2006;203(3):767–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res. 2015;107(3):331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fan Z, Ley K. Leukocyte arrest: biomechanics and molecular mechanisms of beta2 integrin activation. Biorheology. 2015;52(5–6):353–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Thomas MR, Storey RF. The role of platelets in inflammation. Thromb Haemost. 2015;114(3):449–58.

    Article  PubMed  Google Scholar 

  35. Rabinovich A, Cohen JM, Kahn SR. Predictive value of markers of inflammation in the postthrombotic syndrome: a systematic review: inflammatory biomarkers and PTS. Thromb Res. 2015;136(2):289–97.

    Article  CAS  PubMed  Google Scholar 

  36. Sudoyo AW, Rachman A, Harimurti K. Angiogenesis, inflammation, platelets count, and metastatic status as a predictor for thrombosis risk in nasopharyngeal carcinoma patients. Acta Med Indones. 2015;47(1):11–5.

    PubMed  Google Scholar 

  37. Ghasemzadeh M, Hosseini E. Platelet-leukocyte crosstalk: linking proinflammatory responses to procoagulant state. Thromb Res. 2013;131(3):191–7.

    Article  CAS  PubMed  Google Scholar 

  38. Chauhan AK, Kisucka J, Brill A, Walsh MT, Scheiflinger F, Wagner DD. ADAMTS13: a new link between thrombosis and inflammation. J Exp Med. 2008;205(9):2065–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Motto DG, Chauhan AK, Zhu G, Homeister J, Lamb CB, Desch KC, Zhang W, Tsai HM, Wagner DD, Ginsburg D. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Investig. 2005;115(10):2752–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Habe K, Wada H, Ito-Habe N, Hatada T, Matsumoto T, Ohishi K, Maruyama K, Imai H, Mizutani H, Nobori T. Plasma ADAMTS13, von Willebrand factor (VWF) and VWF propeptide profiles in patients with DIC and related diseases. Thromb Res. 2012;129(5):598–602.

    Article  CAS  PubMed  Google Scholar 

  41. Fukushima H, Nishio K, Asai H, Watanabe T, Seki T, Matsui H, Sugimoto M, Matsumoto M, Fujimura Y, Okuchi K. Ratio of von Willebrand factor propeptide to ADAMTS13 is associated with severity of sepsis. Shock. 2013;39(5):409–14.

    Article  CAS  PubMed  Google Scholar 

  42. Ota M, Mochizuki S, Shimoda M, Abe H, Miyamae Y, Ishii K, Kimura H, Okada Y. ADAM23 is down-regulated in side population and suppresses lung metastasis of lung carcinoma cells. Cancer Sci. 2016;22(10):12895.

    Google Scholar 

  43. Martin AC, Cardoso AC, Selistre-de-Araujo HS, Cominetti MR. Recombinant disintegrin domain of human ADAM9 inhibits migration and invasion of DU145 prostate tumor cells. Cell Adhes Migr. 2015;9(4):293–9.

    Article  CAS  Google Scholar 

  44. Wagstaff L, Kelwick R, Decock J, Edwards DR. The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis. Front Biosci. 2011;16:1861–72.

    Article  CAS  Google Scholar 

  45. Rodriguez-Manzaneque JC, Fernandez-Rodriguez R, Rodriguez-Baena FJ, Iruela-Arispe ML. ADAMTS proteases in vascular biology. Matrix Biol. 2015;46:38–45.

    Article  Google Scholar 

  46. Stanton H, Melrose J, Little CB, Fosang AJ. Proteoglycan degradation by the ADAMTS family of proteinases. Biochim Biophys Acta. 2011;12(29):2.

    Google Scholar 

  47. Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol. 2007;42(3):113–85.

    Article  CAS  PubMed  Google Scholar 

  48. Luque A, Carpizo DR, Iruela-Arispe ML. ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165. J Biol Chem. 2003;278(26):23656–65.

    Article  CAS  PubMed  Google Scholar 

  49. Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA. 2001;98(22):12485–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee M, Keener J, Xiao J, Long Zheng X, Rodgers GM. ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2. Cell Mol Life Sci. 2015;72(2):349–56.

    Article  CAS  PubMed  Google Scholar 

  51. Ruggeri ZM. The role of von Willebrand factor in thrombus formation. Thromb Res. 2007;120(1):9.

    Google Scholar 

  52. Jung J, Lee HJ, Lee JM, Na KH, Hwang SG, Kim GJ. Placenta extract promote liver regeneration in CCl4-injured liver rat model. Int Immunopharmacol. 2011;11(8):976–84.

    Article  CAS  PubMed  Google Scholar 

  53. Ali SO, Darwish HA, Ismail NA. Modulatory effects of curcumin, silybin-phytosome and alpha-R-lipoic acid against thioacetamide-induced liver cirrhosis in rats. Chem Biol Interact. 2014;216:26–33.

    Article  CAS  PubMed  Google Scholar 

  54. Duarte S, Shen XD, Fondevila C, Busuttil RW, Coito AJ. Fibronectin-alpha4beta1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway. Am J Transplant. 2012;12(10):2689–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang K, Gao Y, Zhong M, Xu Y, Li J, Chen Y, Duan X, Zhu H. Hepatoprotective effects of Dicliptera chinensis polysaccharides on dimethylnitrosamine-induced hepatic fibrosis rats and its underlying mechanism. J Ethnopharmacol. 2016;179:38–44.

    Article  CAS  PubMed  Google Scholar 

  56. Peng Y, Chen Q, Yang T, Tao Y, Lu X, Liu C. Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice. Mol Biol Rep. 2014;41(3):1815–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim TH, Mars WM, Stolz DB, Petersen BE, Michalopoulos GK. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology. 1997;26(4):896–904.

    Article  CAS  PubMed  Google Scholar 

  58. Kim TH, Mars WM, Stolz DB, Michalopoulos GK. Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology. 2000;31(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  59. Bockmeyer CL, Kern DS, Forstmeier V, Lovric S, Modde F, Agustian PA, Steffens S, Birschmann I, Traeder J, Dammrich ME, et al. Arteriolar vascular smooth muscle cell differentiation in benign nephrosclerosis. Nephrol Dial Transplant. 2012;27(9):3493–501.

    Article  CAS  PubMed  Google Scholar 

  60. Gardner SE, Humphry M, Bennett MR, Clarke MC. Senescent vascular smooth muscle cells drive inflammation through an interleukin-1alpha-dependent senescence-associated secretory phenotype. Arterioscler Thromb Vasc Biol. 2015;35(9):1963–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu Y, Liu G, Chen W, Yang M, Zhu C. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside reduces intimal hyperplasia of tissue engineering blood vessel by inhibiting phenotype switch of vascular smooth muscle cell. J Biomed Mater Res B Appl Biomater. 2016;7(10):33585.

    Google Scholar 

  62. Belo VA, Guimaraes DA, Castro MM. Matrix metalloproteinase 2 as a potential mediator of vascular smooth muscle cell migration and chronic vascular remodeling in hypertension. J Vasc Res. 2015;52(4):221–31.

    Article  CAS  PubMed  Google Scholar 

  63. Bockmeyer CL, Forstmeier V, Modde F, Lovric S, Claus RA, Schiffer M, Agustian PA, Grothusen C, Grote K, Birschmann I, et al. ADAMTS13–marker of contractile phenotype of arterial smooth muscle cells lost in benign nephrosclerosis. Nephrol Dial Transplant. 2011;26(6):1871–81.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The work presented in the review article was supported by grants from the National Natural Science Foundation of China (Nos. 30672243, 81200354), the Population and Family Planning Committee of Hubei Province (No. JS-20130017), Huazhong University of Science and Technology (No. 2013YGYL016).

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

    Yun Feng, Juan Xiao, Wei Li, Jing Liu, Xue Zeng, Xi Chen & Suhua Chen

  2. Department of Urology, Zhengzhou First People’s Hospital, Zhengzhou, China

    Xueyin Li

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  1. Yun Feng
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  2. Xueyin Li
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  3. Juan Xiao
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  4. Wei Li
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  7. Xi Chen
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  8. Suhua Chen
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Correspondence to Suhua Chen.

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Feng, Y., Li, X., Xiao, J. et al. ADAMTS13: more than a regulator of thrombosis. Int J Hematol 104, 534–539 (2016). https://doi.org/10.1007/s12185-016-2091-2

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