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Pathophysiology of thrombotic thrombocytopenic purpura

  • Progress in Hematology
  • Recent advance in thrombotic thrombocytopenic purpura
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Abstract

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.

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References

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  4. Sadler JE. New concepts in von Willebrand disease. Annu Rev Med. 2005;56:173–91.

    CAS  PubMed  Google Scholar 

  5. Tsai HM, Nagel RL, Hatcher VB, Sussman II. Multimeric composition of endothelial cell-derived von Willebrand factor. Blood. 1989;73:2074–6.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  7. Handin RI, Wagner DD. Molecular and cellular biology of von Willebrand factor. Prog Hemost Thromb. 1989;9:233–59.

    CAS  PubMed  Google Scholar 

  8. Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood. 1994;83:2171–9.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  49. Schneppenheim R, Kremer Hovinga JA, Becker T, et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006;96:3–6.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  58. Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest. 2005;85:780–8.

    CAS  PubMed  Google Scholar 

  59. Uemura M, Tatsumi K, Matsumoto M, et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood. 2005;106:922–4.

    CAS  PubMed  Google Scholar 

  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].

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  65. Liu L, Choi H, Bernardo A, et al. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J Thromb Haemost. 2005;3:2536–44.

    CAS  PubMed  Google Scholar 

  66. Crawley JT, Lam JK, Rance JB, et al. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood. 2005;105:1085–93.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  69. Zhou W, Tsai HM. N-Glycans of ADAMTS13 modulate its secretion and von Willebrand factor cleaving activity. Blood. 2009;113:929–35.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  94. Vincentelli A, Susen S, Le TT, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med. 2003;349:343–9.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  103. Kwaan HC. The role of fibrinolysis in disease processes. Semin Thromb Hemost. 1984;10:71–9.

    CAS  PubMed  Google Scholar 

  104. Tsai AL, Manner CE, Rudersdorf T, Wu KK. Quantitation of serum prostacyclin-binding in thrombotic thrombocytopenic purpura. Thromb Res. 1988;51:583–92.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  109. Neame PB, Hirsh J. Circulating immune complexes in thrombotic thrombocytopenic purpura (TTP). Blood. 1978;51:559–60.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  111. Tandon NN, Rock G, Jamieson GA. Anti-CD36 antibodies in thrombotic thrombocytopenic purpura. Br J Haematol. 1994;88:816–25.

    CAS  PubMed  Google Scholar 

  112. Kelton JG, Moore JC, Murphy WG. The platelet aggregating factor(s) of thrombotic thrombocytopenic purpura. Prog Clin Biol Res. 1990;337:141–9.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  121. Schneppenheim R, Kremer Hovinga JA, Becker T, et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006;96:3–6.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  130. Tsai HM, Li A, Rock G. Inhibitors of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura. Clin. Lab. 2001;47:387–92.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. 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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  138. Nguyen TC, Liu A, Liu L, et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica. 2007;92:121–4.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  145. Wu JJ, Fujikawa K, Lian EC, et al. A rapid enzyme-linked assay for ADAMTS-13. J Thromb Haemost. 2006;4:129–36.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  151. Gutterman LA, Kloster B, Tsai HM. Rituximab therapy for refractory thrombotic thrombocytopenic purpura. Blood Cells Mol Dis. 2002;28:385–91.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  153. Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, et al. Where next with atypical hemolytic uremic syndrome? Mol Immunol. 2007;44:3889–900.

    CAS  PubMed  Google Scholar 

  154. Delvaeye M, Noris M, De VA, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–57.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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Correspondence to Han-Mou Tsai.

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Tsai, HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 91, 1–19 (2010). https://doi.org/10.1007/s12185-009-0476-1

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