International Journal of Hematology

, Volume 91, Issue 1, pp 1–19 | Cite as

Pathophysiology of thrombotic thrombocytopenic purpura

  • Han-Mou TsaiEmail author
Progress in Hematology Recent advance in thrombotic thrombocytopenic purpura


Thrombotic thrombocytopenic purpura (TTP) is a disorder with characteristic von Willebrand factor (VWF)-rich microthrombi affecting the arterioles and capillaries of multiple organs. The disorder frequently leads to early death unless the patients are treated with plasma exchange or infusion. Studies in the last decade have provided ample evidence to support that TTP is caused by deficiency of a plasma metalloprotease, ADAMTS13. When exposed to high shear stress in the microcirculation, VWF and platelets are prone to form aggregates. This propensity of VWF and platelet to form microvascular thrombosis is mitigated by ADAMTS13, which cleaves VWF before it is activated by shear stress to cause platelet aggregation in the circulation. Deficiency of ADAMTS13, due to autoimmune inhibitors in patients with acquired TTP and mutations of the ADAMTS13 gene in hereditary cases, leads to VWF–platelet aggregation and microvascular thrombosis of TTP. In this review, we discuss the current knowledge on the pathogenesis, diagnosis and management of TTP, address the ongoing controversies, and indicate the directions of future investigations.


TTP von Willebrand factor ADAMTS13 Shear stress Microvascular thrombosis 



This work is supported in part by a grant (R01 HL62136) from the National Heart Lung and Blood Institute of the National Institutes of Health.


  1. 1.
    Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb Res. 1985;38:469–79.PubMedGoogle Scholar
  2. 2.
    Tsai HM, Chandler WL, Sarode R, et al. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res. 2001;49:653–9.PubMedGoogle Scholar
  3. 3.
    Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. 2003;127:834–9.PubMedGoogle Scholar
  4. 4.
    Sadler JE. New concepts in von Willebrand disease. Annu Rev Med. 2005;56:173–91.PubMedGoogle Scholar
  5. 5.
    Tsai HM, Nagel RL, Hatcher VB, Sussman II. Multimeric composition of endothelial cell-derived von Willebrand factor. Blood. 1989;73:2074–6.PubMedGoogle Scholar
  6. 6.
    Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM, Fay PJ, Marder VJ. Topology and order of formation of interchain disulfide bonds in von Willebrand factor. Blood. 1987;69:27–32.PubMedGoogle Scholar
  7. 7.
    Handin RI, Wagner DD. Molecular and cellular biology of von Willebrand factor. Prog Hemost Thromb. 1989;9:233–59.PubMedGoogle Scholar
  8. 8.
    Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood. 1994;83:2171–9.PubMedGoogle Scholar
  9. 9.
    Furlan M, Robles R, Lamie B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood. 1996;87:4223–34.PubMedGoogle Scholar
  10. 10.
    Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood. 1996;87:4235–44.PubMedGoogle Scholar
  11. 11.
    Furlan M, Robles R, Solenthaler M, et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood. 1997;89:3097–103.PubMedGoogle Scholar
  12. 12.
    Tsai HM, Sussman II, Ginsburg D, et al. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1. Blood. 1997;89:1954–62.PubMedGoogle Scholar
  13. 13.
    Furlan M, Robles R, Solenthaler M, Lammle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood. 1998;91:2839–46.PubMedGoogle Scholar
  14. 14.
    Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–94.PubMedGoogle Scholar
  15. 15.
    Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578–84.PubMedGoogle Scholar
  16. 16.
    Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood. 2001;98:1662–6.PubMedGoogle Scholar
  17. 17.
    Gerritsen HE, Robles R, Lammle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood. 2001;98:1654–61.PubMedGoogle Scholar
  18. 18.
    Soejima K, Mimura N, Hirashima M, et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? J Biochem (Tokyo). 2001;130:475–80.Google Scholar
  19. 19.
    Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94.PubMedGoogle Scholar
  20. 20.
    Rick ME, Moll S, Taylor MA, et al. Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura. Thromb Haemost. 2002;88:598–604.PubMedGoogle Scholar
  21. 21.
    Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood. 2001;98:1765–72.PubMedGoogle Scholar
  22. 22.
    Remuzzi G, Galbusera M, Noris M, et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood. 2002;100:778–85.PubMedGoogle Scholar
  23. 23.
    Bohm M, Vigh T, Scharrer I. Evaluation and clinical application of a new method for measuring activity of von Willebrand factor-cleaving metalloprotease (ADAMTS13). Ann Hematol. 2002;81:430–5.PubMedGoogle Scholar
  24. 24.
    Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102:60–8.PubMedGoogle Scholar
  25. 25.
    Coppo P, Bengoufa D, Veyradier A, et al. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. Medicine (Baltimore). 2004;83:233–44.Google Scholar
  26. 26.
    Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004;103:4043–9.PubMedGoogle Scholar
  27. 27.
    Studt JD, Kremer Hovinga JA, Alberio L, Bianchi V, Lammle B. Von Willebrand factor-cleaving protease (ADAMTS-13) activity in thrombotic microangiopathies: diagnostic experience 2001/2002 of a single research laboratory. Swiss Med Wkly. 2003;133:325–32.PubMedGoogle Scholar
  28. 28.
    Peyvandi F, Ferrari S, Lavoretano S, Canciani MT, Mannucci PM. von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2004;127:433–9.PubMedGoogle Scholar
  29. 29.
    Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA. 2002;99:11902–7.PubMedGoogle Scholar
  30. 30.
    Kentouche K, Budde U, Furlan M, et al. Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor-cleaving protease by infusion of solvent/detergent plasma. Acta Paediatr. 2002;91:1056–9.PubMedGoogle Scholar
  31. 31.
    Bestetti G, Stellari A, Lattuada A, et al. ADAMTS 13 genotype and vWF protease activity in an Italian family with TTP. Thromb Haemost. 2003;90:955–6.PubMedGoogle Scholar
  32. 32.
    Assink K, Schiphorst R, Allford S, et al. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int. 2003;63:1995–9.PubMedGoogle Scholar
  33. 33.
    Antoine G, Zimmermann K, Plaimauer B, et al. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13. Br J Haematol. 2003;120:821–4.PubMedGoogle Scholar
  34. 34.
    Schneppenheim R, Budde U, Oyen F, et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood. 2003;101:1845–50.PubMedGoogle Scholar
  35. 35.
    Savasan S, Lee SK, Ginsburg D, Tsai HM. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood. 2003;101:4449–51.PubMedGoogle Scholar
  36. 36.
    Matsumoto M, Kokame K, Soejima K, et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood. 2004;103:1305–10.PubMedGoogle Scholar
  37. 37.
    Pimanda JE, Maekawa A, Wind T, et al. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood. 2004;103:627–9.PubMedGoogle Scholar
  38. 38.
    Uchida T, Wada H, Mizutani M, et al. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood. 2004;104:2081–3.PubMedGoogle Scholar
  39. 39.
    Veyradier A, Lavergne JM, Ribba AS, et al. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J Thromb Haemost. 2004;2:424–9.PubMedGoogle Scholar
  40. 40.
    Studt JD, Hovinga JA, Antoine G, et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood. 2005;105:542–4.PubMedGoogle Scholar
  41. 41.
    Licht C, Stapenhorst L, Simon T, et al. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Kidney Int. 2004;66:955–8.PubMedGoogle Scholar
  42. 42.
    Snider CE, Moore JC, Warkentin TE, et al. Dissociation between the level of von Willebrand factor-cleaving protease activity and disease in a patient with congenital thrombotic thrombocytopenic purpura. Am J Hematol. 2004;77:387–90.PubMedGoogle Scholar
  43. 43.
    Camilleri RS, Cohen H, MacKie IJ, et al. Prevalence of the ADAMTS-13 missense mutation R1060 W in late onset adult thrombotic thrombocytopenic purpura. J Thromb Haemost. 2008;6:331–8.PubMedGoogle Scholar
  44. 44.
    Noris M, Bucchioni S, Galbusera M, et al. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol. 2005;16:1177–83.PubMedGoogle Scholar
  45. 45.
    Liu F, Jin J, Dong NZ, Wang YG, Ruan CG. Identification of two novel mutations in ADAMTS13 gene in a patient with hereditary thrombotic thrombocytopenic purpura. Zhonghua Xue.Ye.Xue.Za Zhi. 2005;26:521–4.PubMedGoogle Scholar
  46. 46.
    Donadelli R, Banterla F, Galbusera M, et al. In vitro and in vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura. Thromb Haemost. 2006;96:454–64.PubMedGoogle Scholar
  47. 47.
    Peyvandi F, Lavoretano S, Palla R, et al. Mechanisms of the interaction between two ADAMTS13 gene mutations leading to severe deficiency of enzymatic activity. Hum Mutat. 2006;27:330–6.PubMedGoogle Scholar
  48. 48.
    Plaimauer B, Fuhrmann J, Mohr G, et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood. 2006;107:118–25.PubMedGoogle Scholar
  49. 49.
    Schneppenheim R, Kremer Hovinga JA, Becker T, et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006;96:3–6.PubMedGoogle Scholar
  50. 50.
    Shibagaki Y, Matsumoto M, Kokame K, et al. Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw-Schulman syndrome showing predominant episodes of repeated acute renal failure. Nephrol Dial Transplant. 2006;21:1289–92.PubMedGoogle Scholar
  51. 51.
    Tao Z, Anthony K, Peng Y, et al. Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. J Thromb Haemost. 2006;4:1931–5.PubMedGoogle Scholar
  52. 52.
    Hommais A, Rayes J, Houllier A, et al. Molecular characterization of four ADAMTS13 mutations responsible for congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). Thromb Haemost. 2007;98:593–9.PubMedGoogle Scholar
  53. 53.
    Meyer SC, Jeddi R, Meddeb B, et al. A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13. Ann Hematol. 2008;87:663–6.PubMedGoogle Scholar
  54. 54.
    Palla R, Lavoretano S, Lombardi R, et al. The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura. Haematologica. 2009;94:289–93.PubMedGoogle Scholar
  55. 55.
    Kokame K, Aoyama Y, Matsumoto M, Fujimura Y, Miyata T. Inherited and de novo mutations of ADAMTS13 in a patient with Upshaw-Schulman syndrome. J Thromb Haemost. 2008;6:213–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Garagiola I, Valsecchi C, Lavoretano S, et al. Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion. Haematologica. 2008;93:1678–85.PubMedGoogle Scholar
  57. 57.
    Fujimura Y, Matsumoto M, Kokame K, et al. Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients. Br J Haematol. 2009;144:742–54.PubMedGoogle Scholar
  58. 58.
    Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest. 2005;85:780–8.PubMedGoogle Scholar
  59. 59.
    Uemura M, Tatsumi K, Matsumoto M, et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood. 2005;106:922–4.PubMedGoogle Scholar
  60. 60.
    Manea M, Tati R, Karlsson J, Bekassy ZD, Karpman D. Biologically active ADAMTS13 is expressed in renal tubular epithelial cells. Pediatr. Nephrol. 2009 [Epub ahead of print].Google Scholar
  61. 61.
    Manea M, Kristoffersson A, Schneppenheim R, et al. Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2007;138:651–62.PubMedGoogle Scholar
  62. 62.
    Turner N, Nolasco L, Tao Z, Dong JF, Moake J. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost. 2006;4:1396–404.PubMedGoogle Scholar
  63. 63.
    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;108:2207–15.PubMedGoogle Scholar
  64. 64.
    Suzuki M, Murata M, Matsubara Y, et al. Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. Biochem Biophys Res Commun. 2004;313:212–6.PubMedGoogle Scholar
  65. 65.
    Liu L, Choi H, Bernardo A, et al. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J Thromb Haemost. 2005;3:2536–44.PubMedGoogle Scholar
  66. 66.
    Crawley JT, Lam JK, Rance JB, et al. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood. 2005;105:1085–93.PubMedGoogle Scholar
  67. 67.
    Cao WJ, Niiya M, Zheng XW, Shang DZ, Zheng XL. Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost. 2008;6:1233–5.PubMedGoogle Scholar
  68. 68.
    Ricketts LM, Dlugosz M, Luther KB, Haltiwanger RS, Majerus EM. O-fucosylation is required for ADAMTS13 secretion. J. Biol. Chem. 2007;282:17014–23.PubMedGoogle Scholar
  69. 69.
    Zhou W, Tsai HM. N-Glycans of ADAMTS13 modulate its secretion and von Willebrand factor cleaving activity. Blood. 2009;113:929–35.PubMedGoogle Scholar
  70. 70.
    McKinnon TA, Chion AC, Millington AJ, Lane DA, Laffan MA. N-linked glycosylation of VWF modulates its interaction with ADAMTS13. Blood. 2008;111:3042–9.PubMedGoogle Scholar
  71. 71.
    Zhou W, Bouhassira EE, Tsai HM. An IAP retrotransposon in the mouse ADAMTS13 gene creates ADAMTS13 variant proteins that are less effective in cleaving von Willebrand factor multimers. Blood. 2007;110:886–93.PubMedGoogle Scholar
  72. 72.
    Tao Z, Peng Y, Nolasco L, et al. Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions. Blood. 2005;106:4139–45.PubMedGoogle Scholar
  73. 73.
    Niiya M, Endo M, Shang D, et al. Correction of ADAMTS13 deficiency by in utero gene transfer of lentiviral vector encoding ADAMTS13 genes. Mol Ther. 2009;17:34–41.PubMedGoogle Scholar
  74. 74.
    Zanardelli S, Chion AC, Groot E, et al. A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF. Blood. 2009.Google Scholar
  75. 75.
    Banno F, Kaminaka K, Soejima K, Kokame K, Miyata T. Identification of strain-specific variants of mouse Adamts13 gene encoding von Willebrand factor-cleaving protease. J Biol. Chem. 2004;279:30896–903.PubMedGoogle Scholar
  76. 76.
    Banno F, Chauhan AK, Kokame K, et al. The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood. 2009;113:5323–9.PubMedGoogle Scholar
  77. 77.
    Gao W, Anderson PJ, Majerus EM, Tuley EA, Sadler JE. Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc Natl Acad Sci USA. 2006;103:19099–104.PubMedGoogle Scholar
  78. 78.
    Soejima K, Matsumoto M, Kokame K, et al. ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood. 2003;102:3232–7.PubMedGoogle Scholar
  79. 79.
    Zheng X, Nishio K, Majerus EM, Sadler JE. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J Biol Chem. 2003;278:30136–41.PubMedGoogle Scholar
  80. 80.
    Wu JJ, Fujikawa K, McMullen BA, Chung DW. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc Natl Acad Sci USA. 2006;103:18470–4.PubMedGoogle Scholar
  81. 81.
    de Groot R, Bardhan A, Ramroop N, Lane DA, Crawley JT. Essential role of the disintegrin-like domain in ADAMTS13 function. Blood. 2009;113:5609–16.PubMedGoogle Scholar
  82. 82.
    Kokame K, Matsumoto M, Fujimura Y, Miyata T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood. 2004;103:607–12.PubMedGoogle Scholar
  83. 83.
    Zhang Q, Zhou YF, Zhang CZ, et al. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci USA. 2009;106:9226–31.PubMedGoogle Scholar
  84. 84.
    Phillips MD, Vu C, Nolasco L, Moake JL. Granulocyte proteases do not process endothelial cell-derived unusually large von Willebrand factor multimers to plasma VWF in vivo. Am J Hematol. 1991;37:80–3.PubMedGoogle Scholar
  85. 85.
    Siedlecki CA, Lestini BJ, Kottke-Marchant KK, et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood. 1996;88:2939–50.PubMedGoogle Scholar
  86. 86.
    Reininger AJ, Heijnen HF, Schumann H, et al. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood. 2006;107:3537–45.PubMedGoogle Scholar
  87. 87.
    Schneider SW, Nuschele S, Wixforth A, et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci USA. 2007;104:7899–903.PubMedGoogle Scholar
  88. 88.
    Singh I, Themistou E, Porcar L, Neelamegham S. Fluid shear induces conformation change in human blood protein von Willebrand factor in solution. Biophys J. 2009;96:2313–20.PubMedGoogle Scholar
  89. 89.
    Singh I, Shankaran H, Beauharnois ME, et al. Solution structure of human von Willebrand factor studied using small angle neutron scattering. J. Biol. Chem. 2006;281:38266–75.PubMedGoogle Scholar
  90. 90.
    Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science. 2009;324:1330–4.PubMedGoogle Scholar
  91. 91.
    Schneppenheim R, Budde U, Obser T, et al. Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease. Blood. 2001;97:2059–66.PubMedGoogle Scholar
  92. 92.
    Dong JF, Moake JL, Nolasco L, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100:4033–9.PubMedGoogle Scholar
  93. 93.
    Turner N, Nolasco L, Dong JF, Moake J. ADAMTS-13 cleaves long von Willebrand factor multimeric strings anchored to endothelial cells in the absence of flow, platelets or conformation-altering chemicals. J Thromb Haemost. 2009;7:229–32.PubMedGoogle Scholar
  94. 94.
    Vincentelli A, Susen S, Le TT, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med. 2003;349:343–9.PubMedGoogle Scholar
  95. 95.
    Veyradier A, Nishikubo T, Humbert M, et al. Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arterial hypertension. Circulation. 2000;102:2460–2.PubMedGoogle Scholar
  96. 96.
    Donadelli R, Orje JN, Capoferri C, Remuzzi G, Ruggeri ZM. Size regulation of von Willebrand factor-mediated platelet thrombi by ADAMTS13 in flowing blood. Blood. 2006;107:1943–50.PubMedGoogle Scholar
  97. 97.
    Bonnefoy A, Daenens K, Feys HB, et al. Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13. Blood. 2006;107:955–64.PubMedGoogle Scholar
  98. 98.
    Motto DG, Chauhan AK, Zhu G, et al. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Invest. 2005;115:2752–61.PubMedGoogle Scholar
  99. 99.
    Banno F, Kokame K, Okuda T, et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood. 2006;107:3161–6.PubMedGoogle Scholar
  100. 100.
    Nolasco LH, Turner NA, Bernardo A, et al. Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood. 2005;106:4199–209.PubMedGoogle Scholar
  101. 101.
    Romani DW, Fijnheer R, Brinkman HJ, et al. Endothelial cell activation in thrombotic thrombocytopenic purpura (TTP): a prospective analysis. Br J Haematol. 2003;123:522–7.Google Scholar
  102. 102.
    Hunt BJ, Lammle B, Nevard CH, Haycock GB, Furlan M. von Willebrand factor-cleaving protease in childhood diarrhoea-associated haemolytic uraemic syndrome. Thromb Haemost. 2001;85:975–8.PubMedGoogle Scholar
  103. 103.
    Kwaan HC. The role of fibrinolysis in disease processes. Semin Thromb Hemost. 1984;10:71–9.PubMedGoogle Scholar
  104. 104.
    Tsai AL, Manner CE, Rudersdorf T, Wu KK. Quantitation of serum prostacyclin-binding in thrombotic thrombocytopenic purpura. Thromb Res. 1988;51:583–92.PubMedGoogle Scholar
  105. 105.
    Wada H, Kaneko T, Ohiwa M, et al. Increased levels of vascular endothelial cell markers in thrombotic thrombocytopenic purpura. Am J Hematol. 1993;44:101–5.PubMedGoogle Scholar
  106. 106.
    Burns ER, Zucker-Franklin D. Pathologic effects of plasma from patients with thrombotic thrombocytopenic purpura on platelets and cultured vascular endothelial cells. Blood. 1982;60:1030–7.PubMedGoogle Scholar
  107. 107.
    Leung DY, Moake JL, Havens PL, Kim M, Pober JS. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet. 1988;2:183–6.PubMedGoogle Scholar
  108. 108.
    Praprotnik S, Blank M, Levy Y, et al. Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells. Int Immunol. 2001;13:203–10.PubMedGoogle Scholar
  109. 109.
    Neame PB, Hirsh J. Circulating immune complexes in thrombotic thrombocytopenic purpura (TTP). Blood. 1978;51:559–60.PubMedGoogle Scholar
  110. 110.
    Siddiqui FA, Lian EC. Characterization of platelet agglutinating protein p37 purified from the plasma of a patient with thrombotic thrombocytopenic purpura. Biochem Mol Biol Int. 1993;30:385–95.PubMedGoogle Scholar
  111. 111.
    Tandon NN, Rock G, Jamieson GA. Anti-CD36 antibodies in thrombotic thrombocytopenic purpura. Br J Haematol. 1994;88:816–25.PubMedGoogle Scholar
  112. 112.
    Kelton JG, Moore JC, Murphy WG. The platelet aggregating factor(s) of thrombotic thrombocytopenic purpura. Prog Clin Biol Res. 1990;337:141–9.PubMedGoogle Scholar
  113. 113.
    Mauro M, Kim J, Costello C, Laurence J. Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Am J Hematol. 2001;66:12–22.PubMedGoogle Scholar
  114. 114.
    Joseph G, Smith KJ, Hadley TJ, et al. HLA-DR53 protects against thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome. Am J Hematol. 1994;47:189–93.PubMedGoogle Scholar
  115. 115.
    Zeigler Z, Kelton J, Moore J, et al. Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura. Bone Marrow Transplant. 1999;24:641–5.PubMedGoogle Scholar
  116. 116.
    Rock G, Chauhan K, Jamieson GA, Tandon NN. Anti-CD36 antibodies in patients with lupus anticoagulant and thrombotic complications. Br J Haematol. 1994;88:878–80.PubMedGoogle Scholar
  117. 117.
    Schultz DR, Arnold PI, Jy W, et al. Anti-CD36 autoantibodies in thrombotic thrombocytopenic purpura and other thrombotic disorders: identification of an 85 kD form of CD36 as a target antigen. Br J Haematol. 1998;103:849–57.PubMedGoogle Scholar
  118. 118.
    Rock G, Clark W, Sternbach M, Kolajova M, McLaine P. Haemolytic uraemic syndrome is an immune-mediated disease: role of anti-CD36 antibodies. Br J Haematol. 2005;131:247–52.PubMedGoogle Scholar
  119. 119.
    Hori Y, Wada H, Mori Y, et al. Plasma sFas and sFas ligand levels in patients with thrombotic thrombocytopenic purpura and in those with disseminated intravascular coagulation. Am J Hematol. 1999;61:21–5.PubMedGoogle Scholar
  120. 120.
    Manea M, Kristoffersson A, Tsai HM, et al. ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura. Eur J Pediatr. 2007;166:249–57.PubMedGoogle Scholar
  121. 121.
    Schneppenheim R, Kremer Hovinga JA, Becker T, et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006;96:3–6.PubMedGoogle Scholar
  122. 122.
    Jang MJ, Kim NK, Chong SY, et al. Frequency of Pro475Ser polymorphism of ADAMTS13 gene and its association with ADAMTS-13 activity in the Korean population. Yonsei Med J. 2008;49:405–8.PubMedGoogle Scholar
  123. 123.
    Akiyama M, Kokame K, Miyata T. ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea lability in vitro. J Thromb Haemost. 2008;6:1830–2.PubMedGoogle Scholar
  124. 124.
    Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000;132:794–9.PubMedGoogle Scholar
  125. 125.
    Sugio Y, Okamura T, Shimoda K, et al. Ticlopidine-Associated thrombotic thrombocytopenic purpura with an IgG-type inhibitor to von Willebrand factor-cleaving protease activity. Int J Hematol. 2001;74:347–51.PubMedGoogle Scholar
  126. 126.
    Terrell DR, Williams LA, Vesely SK, et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost. 2005;3:1432–6.PubMedGoogle Scholar
  127. 127.
    Zhou W, Dong L, Ginsburg D, Bouhassira EE, Tsai HM. Enzymatically active ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies: a novel therapeutic strategy? J Biol. Chem. 2005;280:39934–41.PubMedGoogle Scholar
  128. 128.
    Luken BM, Turenhout EA, Hulstein JJ, et al. The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Thromb Haemost. 2005;93:267–74.PubMedGoogle Scholar
  129. 129.
    Luken BM, Turenhout EA, Kaijen PH, et al. Amino acid regions 572–579 and 657–666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP. Thromb Haemost. 2006;96:295–301.PubMedGoogle Scholar
  130. 130.
    Tsai HM, Li A, Rock G. Inhibitors of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura. Clin. Lab. 2001;47:387–92.PubMedGoogle Scholar
  131. 131.
    Tsai HM. High titers of inhibitors of von Willebrand factor-cleaving metalloproteinase in a fatal case of acute thrombotic thrombocytopenic purpura. Am J Hematol. 2000;65:251–5.PubMedGoogle Scholar
  132. 132.
    Dong L, Chandrasekaran V, Zhou W, Tsai HM. Evolution of ADAMTS13 antibodies in a fatal case of thrombotic thrombocytopenic purpura. Am J Hematol. 2008;83:815–7.PubMedGoogle Scholar
  133. 133.
    Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai HM. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. Br J Haematol. 2004;124:787–95.PubMedGoogle Scholar
  134. 134.
    Mannucci PM, Canciani MT, Forza I, et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood. 2002;98:2730–5.Google Scholar
  135. 135.
    Park YD, Yoshioka A, Kawa K, et al. Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation. Bone Marrow Transplant. 2002;29:789–94.PubMedGoogle Scholar
  136. 136.
    Uemura M, Matsuyama T, Ishikawa M, et al. Decreased activity of plasma ADAMTS13 may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol Clin Exp Res. 2005;29:264S–71S.PubMedGoogle Scholar
  137. 137.
    Ono T, Mimuro J, Madoiwa S, et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood. 2006;107:528–34.PubMedGoogle Scholar
  138. 138.
    Nguyen TC, Liu A, Liu L, et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica. 2007;92:121–4.PubMedGoogle Scholar
  139. 139.
    Kremer Hovinga JA, Zeerleder S, Kessler P, et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost. 2007;5:2284–90.PubMedGoogle Scholar
  140. 140.
    Martin K, Borgel D, Lerolle N, et al. Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med. 2007;35:2375–82.PubMedGoogle Scholar
  141. 141.
    Bianchi V, Robles R, Alberio L, Furlan M, Lammle B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100:710–3.PubMedGoogle Scholar
  142. 142.
    Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53–61.PubMedGoogle Scholar
  143. 143.
    Moake JL, McPherson PD. Abnormalities of von Willebrand factor multimers in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Am J Med. 1989;87:9N–15N.PubMedGoogle Scholar
  144. 144.
    Jin M, Cataland S, Bissell M, Wu HM. A rapid test for the diagnosis of thrombotic thrombocytopenic purpura using surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF)-mass spectrometry. J Thromb Haemost. 2006;4:333–8.PubMedGoogle Scholar
  145. 145.
    Wu JJ, Fujikawa K, Lian EC, et al. A rapid enzyme-linked assay for ADAMTS-13. J Thromb Haemost. 2006;4:129–36.PubMedGoogle Scholar
  146. 146.
    Kato S, Matsumoto M, Matsuyama T, et al. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion. 2006;46:1444–52.PubMedGoogle Scholar
  147. 147.
    Cao W, Krishnaswamy S, Camire RM, Lenting PJ, Zheng XL. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc Natl Acad Sci USA. 2008;105:7416–21.PubMedGoogle Scholar
  148. 148.
    Shim K, Anderson PJ, Tuley EA, Wiswall E, Sadler JE. Platelet–VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood. 2008;111:651–7.PubMedGoogle Scholar
  149. 149.
    Jin M, Casper TC, Cataland SR, et al. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse. Br J Haematol. 2008;141:651–8.PubMedGoogle Scholar
  150. 150.
    Eckmann CM, De Laaf RT, Van Keulen JM, van Mourik JA, De Laat B. Bilirubin oxidase as a solution for the interference of hyperbilirubinemia with ADAMTS-13 activity measurement by FRETS-VWF73 assay. J Thromb Haemost. 2007;5:1330–1.PubMedGoogle Scholar
  151. 151.
    Gutterman LA, Kloster B, Tsai HM. Rituximab therapy for refractory thrombotic thrombocytopenic purpura. Blood Cells Mol Dis. 2002;28:385–91.PubMedGoogle Scholar
  152. 152.
    Downes KA, Yomtovian R, Tsai HM, et al. Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident. J Clin Apheresis. 2004;19:86–9.PubMedGoogle Scholar
  153. 153.
    Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, et al. Where next with atypical hemolytic uremic syndrome? Mol Immunol. 2007;44:3889–900.PubMedGoogle Scholar
  154. 154.
    Delvaeye M, Noris M, De VA, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–57.PubMedGoogle Scholar
  155. 155.
    Cataland SR, Jin M, Lin S, et al. Effect of prophylactic cyclosporine therapy on ADAMTS13 biomarkers in patients with idiopathic thrombotic thrombocytopenic purpura. Am J Hematol. 2008;83:911–5.PubMedGoogle Scholar
  156. 156.
    Elliott MA, Heit JA, Pruthi RK, et al. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol. 2009.Google Scholar
  157. 157.
    Vesely SK, Li X, McMinn JR, Terrell DR, George JN. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion. 2004;44:1149–58.PubMedGoogle Scholar
  158. 158.
    Sanchez-Luceros A, Farias CE, Amaral MM, et al. von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost. 2004;92:1320–6.PubMedGoogle Scholar
  159. 159.
    Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci PM. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica. 2003;88:1029–34.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  1. 1.Section of Thrombosis and Hemostasis, Division of Hematology and Oncology, H046Pennsylvania State University, Milton S. Hershey College of Medicine, Pennsylvania State Cancer InstituteHersheyUSA

Personalised recommendations