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The role of von Willebrand factor in thrombotic microangiopathy

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Abstract

Thrombotic microangiopathy (TMA) is caused by thrombus formation in the microvasculature. The disease spectrum of TMA includes, amongst others, thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS). TTP is caused by defective cleavage of von Willebrand factor (VWF), whereas aHUS is caused by overshooting complement activation and subsequent endothelial cell (EC) injury. Despite their distinct pathophysiology, the clinical manifestation of TTP and aHUS consisting of microangiopathic haemolytic anaemia and thrombocytopenia is often similar and difficult to distinguish. Recent evidence hints at both a genetic and functional link between TTP and aHUS, especially between VWF and the complement system. There is novel in vitro evidence that complement activation not only results in VWF release from ECs, but that VWF also functions as a negative complement regulator, thus protecting the EC surface from ongoing complement attack. Although contrary to previous experimental work suggesting that complement can be activated on VWF multimers, there may be an explanation in vivo that rationalizes these apparently contradictory findings, whereby a system primarily meant to regulate becomes overwhelmed or pathologic in the disease state. The importance of unravelling these recent findings for our understanding of TMA pathology becomes even more evident considering that glomerular ECs express VWF in a heterogeneous pattern with an overall decreased expression level, thus potentially leaving the glomerular ECs vulnerable to complement-mediated injury. Taken together, these findings support the concept that TTP and aHUS represent two extreme ends of a TMA disease spectrum rather than isolated disease entities.

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References

  1. Kwaan HC (2011) Microvascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 37:961–978

    Article  PubMed  Google Scholar 

  2. George JN, Nester CM (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371:654–666

    Article  PubMed  CAS  Google Scholar 

  3. Cataland SR, Wu HM (2014) Diagnosis and management of complement mediated thrombotic microangiopathies. Blood Rev 28:67–74

    Article  PubMed  CAS  Google Scholar 

  4. Deford CC, Reese JA, Schwartz LH, Perdue JJ, Kremer Hovinga JA, Lammle B, Terrell DR, Vesely SK, George JN (2013) Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood 122:2023–2029, quiz 2142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Clark WF (2012) Thrombotic microangiopathy: current knowledge and outcomes with plasma exchange. Semin Dial 25:214–219

    Article  PubMed  Google Scholar 

  6. Radhi M, Carpenter SL (2012) Thrombotic microangiopathies. ISRN Hematol 2012:310596

    Article  PubMed  PubMed Central  Google Scholar 

  7. Riedl M, Orth-Holler D, Wurzner R (2014) An update on the thrombotic microangiopathies hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Semin Thromb Hemost 40:413–415

    Article  PubMed  Google Scholar 

  8. Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC, Fremeaux-Bacchi V, Licht C (2014) Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin Thromb Hemost 40:444–464

    Article  PubMed  CAS  Google Scholar 

  9. Van Hove JL, Van Damme-Lombaerts R, Grunewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B (2002) Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 111:195–201

    Article  PubMed  Google Scholar 

  10. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531–536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Miller BW, Hmiel SP, Schnitzler MA, Brennan DC (1997) Cyclosporine as cause of thrombotic microangiopathy after renal transplantation. Am J Kidney Dis 29:813–814

    Article  PubMed  CAS  Google Scholar 

  13. Kojouri K, Vesely SK, George JN (2001) Quinine-associated thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes. Ann Intern Med 135:1047–1051

  14. D’Angelo A, Fattorini A, Crippa L (2009) Thrombotic microangiopathy in pregnancy. Thromb Res 123[Suppl 2]:S56–S62

    Article  PubMed  Google Scholar 

  15. Noone D, Al-Matrafi J, Tinckam K, Zipfel PF, Herzenberg AM, Thorner PS, Pluthero FG, Kahr WH, Filler G, Hebert D, Harvey E, Licht C (2012) Antibody mediated rejection associated with complement factor H-related protein 3/1 deficiency successfully treated with eculizumab. Am J Transplant 12:2546–2553

    Article  PubMed  CAS  Google Scholar 

  16. Satoskar AA, Pelletier R, Adams P, Nadasdy GM, Brodsky S, Pesavento T, Henry M, Nadasdy T (2010) De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection. Am J Transplant 10:1804–1811

    Article  PubMed  CAS  Google Scholar 

  17. Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA, Davies SM, Pluthero FG, Lu L, Laskin BL (2013) Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood 122:2003–2007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jodele S, Fukuda T, Vinks A, Mizuno K, Laskin BL, Goebel J, Dixon BP, Teusink A, Pluthero FG, Lu L, Licht C, Davies SM (2014) Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant 20:518–525

    Article  PubMed  CAS  Google Scholar 

  19. Symmers WS (1952) Thrombotic microangiopathic haemolytic anaemia (thrombotic microangiopathy). Br Med J 2:897–903

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Moschcowitz E (1924) Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc NY Pathol Soc 24:21–24

    Google Scholar 

  21. Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, Seder RH, Hong SL, Deykin D (1982) Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 307:1432–1435

    Article  PubMed  CAS  Google Scholar 

  22. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lammle B (1998) Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339:1578–1584

    Article  PubMed  CAS  Google Scholar 

  23. Tsai HM, Lian EC (1998) Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 339:1585–1594

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Rennard S, Abe S (1979) Decreased cold-insoluble globulin in congenital thrombocytopenia (Upshaw-Schulman syndrome). N Engl J Med 300:368

    PubMed  CAS  Google Scholar 

  25. Taguchi F, Yagi H, Matsumoto M, Sadamura S, Isonishi A, Soejima K, Fujimura Y (2012) The homozygous p.C1024R- ADAMTS13 gene mutation links to a late-onset phenotype of Upshaw-Schulman syndrome in Japan. Thromb Haemost 107:1003–1005

    Article  PubMed  CAS  Google Scholar 

  26. Moatti-Cohen M, Garrec C, Wolf M, Boisseau P, Galicier L, Azoulay E, Stepanian A, Delmas Y, Rondeau E, Bezieau S, Coppo P, Veyradier A (2012) Unexpected frequency of Upshaw–Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 119:5888–5897

  27. Tsai HM (2013) Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome. Am J Med 126:200–209

    Article  PubMed  Google Scholar 

  28. Kinoshita S, Yoshioka A, Park YD, Ishizashi H, Konno M, Funato M, Matsui T, Titani K, Yagi H, Matsumoto M, Fujimura Y (2001) Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int J Hematol 74:101–108

    Article  PubMed  CAS  Google Scholar 

  29. Sasahara Y, Kumaki S, Ohashi Y, Minegishi M, Kano H, Bessho F, Tsuchiya S (2001) Deficient activity of von Willebrand factor-cleaving protease in patients with Upshaw-Schulman syndrome. Int J Hematol 74:109–114

    Article  PubMed  CAS  Google Scholar 

  30. Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K (2001) Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 276:41059–41063

    Article  PubMed  CAS  Google Scholar 

  31. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM (2001) Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413:488–494

    Article  PubMed  CAS  Google Scholar 

  32. Knobl P (2014) Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. Semin Thromb Hemost 40:493–502

    Article  PubMed  CAS  Google Scholar 

  33. Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086

    PubMed  CAS  Google Scholar 

  34. Karmali MA, Steele BT, Petric M, Lim C (1983) Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet 1:619–620

    Article  PubMed  CAS  Google Scholar 

  35. Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R (1955) Hemolytic–uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 20:905–909

    Google Scholar 

  36. Scheiring J, Andreoli SP, Zimmerhackl LB (2008) Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 23:1749–1760

    Article  PubMed  Google Scholar 

  37. Kaplan BS (1977) Hemolytic uremic syndrome with recurrent episodes: an important subset. Clin Nephrol 8:495–498

    PubMed  CAS  Google Scholar 

  38. Brain MC (1969) The haemolytic-uraemic syndrome. Semin Hematol 6:162–180

    PubMed  CAS  Google Scholar 

  39. Hagge WW, Holley KE, Burke EC, Stickler GB (1967) Hemolytic–uremic syndrome in two siblings. N Engl J Med 277:138–139

  40. Kaplan BS, Chesney RW, Drummond KN (1975) Hemolytic uremic syndrome in families. N Engl J Med 292:1090–1093

    Article  PubMed  CAS  Google Scholar 

  41. Carreras L, Romero R, Requesens C, Oliver AJ, Carrera M, Clavo M, Alsina J (1981) Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype. JAMA 245:602–604

    Article  PubMed  CAS  Google Scholar 

  42. Drukker A, Winterborn M, Bennett B, Churg J, Spitzer A, Greifer I (1975) Recurrent hemolytic-uremic syndrome: a case report. Clin Nephrol 4:68–72

    PubMed  CAS  Google Scholar 

  43. Barre P, Kaplan BS, de Chadarevian JP, Drummond KN (1977) Hemolytic uremic syndrome with hypocomplementemia, serum C3NeF, and glomerular deposits of C3. Arch Pathol Lab Med 101:357–361

    PubMed  CAS  Google Scholar 

  44. Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46:110–119

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Pichette V, Querin S, Schurch W, Brun G, Lehner-Netsch G, Delage JM (1994) Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 24:936–941

    Article  PubMed  CAS  Google Scholar 

  46. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844

    Article  PubMed  CAS  Google Scholar 

  47. Warwicker P, Donne RL, Goodship JA, Goodship TH, Howie AJ, Kumararatne DS, Thompson RA, Taylor CM (1999) Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency. Nephrol Dial Transplant 14:1229–1233

    Article  PubMed  CAS  Google Scholar 

  48. Warwicker P, Goodship JA, Goodship TH (1998) Factor H—US? Nephrol Dial Transplant 13:1921–1923

    Article  PubMed  CAS  Google Scholar 

  49. Noone D, Waters A, Pluthero FG, Geary DF, Kirschfink M, Zipfel PF, Licht C (2014) Successful treatment of DEAP-HUS with eculizumab. Pediatr Nephrol 29:841–851

    Article  PubMed  Google Scholar 

  50. Zafrani L, Mariotte E, Darmon M, Canet E, Merceron S, Boutboul D, Veyradier A, Galicier L, Azoulay E (2015) Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity. J Thromb Haemost 13:380–389

    Article  PubMed  CAS  Google Scholar 

  51. Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN (2010) Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 115:1500–1511, quiz 1662

    Article  PubMed  Google Scholar 

  52. Zafrani L, Azoulay E (2015) Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity: reply. J Thromb Haemost 13:1526–1527

    Article  PubMed  CAS  Google Scholar 

  53. Vesely SK, George JN, Lammle B, Studt JD, Alberio L, El-Harake MA, Raskob GE (2003) ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102:60–68

    Article  PubMed  CAS  Google Scholar 

  54. Sadler JE (2015) What’s new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematol Am Soc Hematol Educ Program 2015:631–636

    Google Scholar 

  55. Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T (2005) FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 129:93–100

    Article  PubMed  CAS  Google Scholar 

  56. Kato S, Matsumoto M, Matsuyama T, Isonishi A, Hiura H, Fujimura Y (2006) Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion 46:1444–1452

    Article  PubMed  CAS  Google Scholar 

  57. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V, HUS International (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31:15–39

    Article  PubMed  Google Scholar 

  58. De Ceunynck K, De Meyer SF, Vanhoorelbeke K (2013) Unwinding the von Willebrand factor strings puzzle. Blood 121:270–277

    Article  PubMed  CAS  Google Scholar 

  59. Nightingale T, Cutler D (2013) The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. J Thromb Haemost 11[Suppl 1]:192–201

    Article  PubMed  PubMed Central  Google Scholar 

  60. Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ, Carter T (2008) Selective release of molecules from Weibel-Palade bodies during a lingering kiss. Blood 111:5282–5290

    Article  PubMed  CAS  Google Scholar 

  61. De Ceunynck K, Rocha S, Feys HB, De Meyer SF, Uji-i H, Deckmyn H, Hofkens J, Vanhoorelbeke K (2011) Local elongation of endothelial cell-anchored von Willebrand factor strings precedes ADAMTS13 protein-mediated proteolysis. J Biol Chem 286:36361–36367

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Turner N, Nolasco L, Moake J (2012) Generation and breakdown of soluble ultralarge von Willebrand factor multimers. Semin Thromb Hemost 38:38–46

    Article  PubMed  CAS  Google Scholar 

  63. Turner N, Nolasco L, Dong JF, Moake J (2009) 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 7:229–232

    Article  PubMed  CAS  Google Scholar 

  64. Schneider SW, Nuschele S, Wixforth A, Gorzelanny C, Alexander-Katz A, Netz RR, Schneider MF (2007) Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci USA 104:7899–7903

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Ruggeri ZM (2007) The role of von Willebrand factor in thrombus formation. Thromb Res 120[Suppl 1]:S5–S9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Valentijn KM, Eikenboom J (2013) Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost 11:581–592

    Article  PubMed  CAS  Google Scholar 

  67. Tsai HM (1996) Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87:4235–4244

    PubMed  CAS  Google Scholar 

  68. Furlan M, Robles R, Lammle B (1996) Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 87:4223–4234

    PubMed  CAS  Google Scholar 

  69. Dong JF (2005) Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 3:1710–1716

    Article  PubMed  CAS  Google Scholar 

  70. Dong JF, Moake JL, Bernardo A, Fujikawa K, Ball C, Nolasco L, Lopez JA, Cruz MA (2003) ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem 278:29633–29639

    Article  PubMed  CAS  Google Scholar 

  71. Lopez JA, Dong JF (2004) Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells. Semin Hematol 41:15–23

    Article  PubMed  CAS  Google Scholar 

  72. Lancellotti S, De Cristofaro R (2011) Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies. Prog Mol Biol Transl Sci 99:105–144

    Article  PubMed  CAS  Google Scholar 

  73. Tsai HM (2010) Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 91:1–19

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tsai HM, Raoufi M, Zhou W, Guinto E, Grafos N, Ranzurmal S, Greenfield RS, Rand JH (2006) ADAMTS13-binding IgG are present in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 95:886–892

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Delvaeye M, Conway EM (2009) Coagulation and innate immune responses: can we view them separately? Blood 114:2367–2374

    Article  PubMed  CAS  Google Scholar 

  76. Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD (2012) Interactions between coagulation and complement—their role in inflammation. Semin Immunopathol 34:151–165

    Article  PubMed  CAS  Google Scholar 

  77. Markiewski MM, Nilsson B, Nilsson Ekdahl K, Mollnes TE, Lambris JD (2007) Complement and coagulation: strangers or partners in crime? Trends Immunol 28:184–192

    Article  PubMed  CAS  Google Scholar 

  78. Conway EM (2015) Reincarnation of ancient links between coagulation and complement. J Thromb Haemost 13[Suppl 1]:S121–S132

    Article  PubMed  CAS  Google Scholar 

  79. Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12:682–687

    Article  PubMed  CAS  Google Scholar 

  80. Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, Lambris JD, Huber-Lang M (2008) Interaction between the coagulation and complement system. Adv Exp Med Biol 632:71–79

    PubMed  PubMed Central  CAS  Google Scholar 

  81. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185:5628–5636

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Zipfel PF, Wolf G, John U, Kentouche K, Skerka C (2011) Novel developments in thrombotic microangiopathies: is there a common link between hemolytic uremic syndrome and thrombotic thrombocytic purpura? Pediatr Nephrol 26:1947–1956

    Article  PubMed  Google Scholar 

  83. Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622–633

    Article  PubMed  CAS  Google Scholar 

  84. Ruiz-Torres MP, Casiraghi F, Galbusera M, Macconi D, Gastoldi S, Todeschini M, Porrati F, Belotti D, Pogliani EM, Noris M, Remuzzi G (2005) Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies. Thromb Haemost 93:443–452

    PubMed  CAS  Google Scholar 

  85. Reti M, Farkas P, Csuka D, Razso K, Schlammadinger A, Udvardy ML, Madach K, Domjan G, Bereczki C, Reusz GS, Szabo AJ, Prohaszka Z (2012) Complement activation in thrombotic thrombocytopenic purpura. J Thromb Haemost 10:791–798

    Article  PubMed  CAS  Google Scholar 

  86. Wu TC, Yang S, Haven S, Holers VM, Lundberg AS, Wu H, Cataland SR (2013) Complement activation and mortality during an acute episode of thrombotic thrombocytopenic purpura. J Thromb Haemost 11:1925–1927

    PubMed  CAS  Google Scholar 

  87. Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH, Smith RJ, Afshar-Kharghan V (2013) Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood 122:1487–1493

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Turner NA, Moake J (2013) Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis. PLoS One 8:e59372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Tati R, Kristoffersson AC, Stahl AL, Rebetz J, Wang L, Licht C, Motto D, Karpman D (2013) Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy. J Immunol 191:2184–2193

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Turner N, Nolasco L, Nolasco J, Sartain S, Moake J (2014) Thrombotic Microangiopathies and the linkage between von Willebrand factor and the alternative complement pathway. Semin Thromb Hemost 40:544–550

    Article  PubMed  CAS  Google Scholar 

  91. Nolasco L, Nolasco J, Feng S, Afshar-Kharghan V, Moake J (2013) Human complement factor H is a reductase for large soluble von Willebrand factor multimers—brief report. Arterioscler Thromb Vasc Biol 33:2524–2528

    Article  PubMed  CAS  Google Scholar 

  92. Feng S, Liang X, Cruz MA, Vu H, Zhou Z, Pemmaraju N, Dong JF, Kroll MH, Afshar-Kharghan V (2013) The interaction between factor H and von Willebrand factor. PLoS One 8:e73715

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Rayes J, Roumenina LT, Dimitrov JD, Repesse Y, Ing M, Christophe O, Jokiranta TS, Halbwachs-Mecarelli L, Borel-Derlon A, Kaveri SV, Fremeaux-Bacchi V, Lacroix-Desmazes S (2014) The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status. Blood 123:121–125

    Article  PubMed  CAS  Google Scholar 

  94. Noone DG, Riedl M, Pluthero FG, Bowman ML, Liszewski MK, Lu L, Quan Y, Balgobin S, Schneppenheim R, Schneppenheim S, Budde U, James P, Atkinson JP, Palaniyar N, Kahr WH, Licht C (2016) Von Willebrand factor regulates complement on endothelial cells. Kidney Int 90:123–134

    Article  PubMed  CAS  Google Scholar 

  95. Martin-Ramirez J, Hofman M, van den Biggelaar M, Hebbel RP, Voorberg J (2012) Establishment of outgrowth endothelial cells from peripheral blood. Nat Protoc 7:1709–1715

    Article  PubMed  CAS  Google Scholar 

  96. Othman M, Chirinian Y, Brown C, Notley C, Hickson N, Hampshire D, Buckley S, Waddington S, Parker AL, Baker A, James P, Lillicrap D (2010) Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease. Blood 116:3645–3652

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wang JW, Bouwens EA, Pintao MC, Voorberg J, Safdar H, Valentijn KM, de Boer HC, Mertens K, Reitsma PH, Eikenboom J (2013) Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease. Blood 121:2762–2772

    Article  PubMed  CAS  Google Scholar 

  98. Nakashima S, Qian Z, Rahimi S, Wasowska BA, Baldwin WM 3rd (2002) Membrane attack complex contributes to destruction of vascular integrity in acute lung allograft rejection. J Immunol 169:4620–4627

    Article  PubMed  CAS  Google Scholar 

  99. Ota H, Fox-Talbot K, Hu W, Qian Z, Sanfilippo F, Hruban RH, Baldwin WM 3rd (2005) Terminal complement components mediate release of von Willebrand factor and adhesion of platelets in arteries of allografts. Transplantation 79:276–281

    Article  PubMed  CAS  Google Scholar 

  100. Hattori R, Hamilton KK, McEver RP, Sims PJ (1989) Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface. J Biol Chem 264:9053–9060

    PubMed  CAS  Google Scholar 

  101. Aird WC (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100:158–173

    Article  PubMed  CAS  Google Scholar 

  102. Aird WC (2007) Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100:174–190

    Article  PubMed  CAS  Google Scholar 

  103. Kawanami O, Jin E, Ghazizadeh M, Fujiwara M, Jiang L, Nagashima M, Shimizu H, Takemura T, Ohaki Y, Arai S, Gomibuchi M, Takeda K, Yu ZX, Ferrans VJ (2000) Heterogeneous distribution of thrombomodulin and von Willebrand factor in endothelial cells in the human pulmonary microvessels. J Nippon Med Sch 67:118–125

    Article  PubMed  CAS  Google Scholar 

  104. Muller AM, Skrzynski C, Skipka G, Muller KM (2002) Expression of von Willebrand factor by human pulmonary endothelial cells in vivo. Respiration 69:526–533

    Article  PubMed  Google Scholar 

  105. Pusztaszeri MP, Seelentag W, Bosman FT (2006) Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 54:385–395

    Article  PubMed  CAS  Google Scholar 

  106. Sayani FA, Abrams CS (2015) How I treat refractory thrombotic thrombocytopenic purpura. Blood 125:3860–3867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Eskazan AE (2016) Bortezomib therapy in patients with relapsed/refractory acquired thrombotic thrombocytopenic purpura. Ann Hematol 95:1751–1756

    Article  PubMed  CAS  Google Scholar 

  108. Tersteeg C, Schiviz A, De Meyer SF, Plaimauer B, Scheiflinger F, Rottensteiner H, Vanhoorelbeke K (2015) Potential for recombinant ADAMTS13 as an effective therapy for acquired thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol 35:2336–2342

    Article  PubMed  CAS  Google Scholar 

  109. Schiviz A, Wuersch K, Piskernik C, Dietrich B, Hoellriegl W, Rottensteiner H, Scheiflinger F, Schwarz HP, Muchitsch EM (2012) A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13. Blood 119:6128–6135

    Article  PubMed  CAS  Google Scholar 

  110. Tersteeg C, de Maat S, De Meyer SF, Smeets MW, Barendrecht AD, Roest M, Pasterkamp G, Fijnheer R, Vanhoorelbeke K, de Groot PG, Maas C (2014) Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy. Circulation 129:1320–1331

    Article  PubMed  CAS  Google Scholar 

  111. Tersteeg C, Fijnheer R, Pasterkamp G, de Groot PG, Vanhoorelbeke K, de Maat S, Maas C (2016) Keeping von Willebrand factor under control: alternatives for ADAMTS13. Semin Thromb Hemost 42:9–17

    Article  PubMed  CAS  Google Scholar 

  112. Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, Smith RJ (2014) Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 25:55–64

    Article  PubMed  CAS  Google Scholar 

  113. Chen J, Reheman A, Gushiken FC, Nolasco L, Fu X, Moake JL, Ni H, Lopez JA (2011) N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 121:593–603

  114. George JN, Lopez JA, Konkle BA (2014) N-acetylcysteine: an old drug, a new insight, a potentially effective treatment for thrombotic thrombocytopenic purpura. Transfusion 54:1205–1207

    Article  PubMed  CAS  Google Scholar 

  115. Cabanillas G, Popescu-Martinez A (2016) N-acetylcysteine for relapsing thrombotic thrombocytopenic purpura: more evidence of a promising drug. Am J Ther 23:e1277–e1279

    Article  PubMed  Google Scholar 

  116. Li GW, Rambally S, Kamboj J, Reilly S, Moake JL, Udden MM, Mims MP (2014) Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report. Transfusion 54:1221–1224

  117. Shortt J, Opat SS, Wood EM (2014) N-acetylcysteine for thrombotic thrombocytopenic purpura: is a von Willebrand factor-inhibitory dose feasible in vivo? Transfusion 54:2362–2363

    Article  PubMed  CAS  Google Scholar 

  118. Callewaert F, Roodt J, Ulrichts H, Stohr T, van Rensburg WJ, Lamprecht S, Rossenu S, Priem S, Willems W, Holz JB (2012) Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura. Blood 120:3603–3610

    Article  PubMed  CAS  Google Scholar 

  119. Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knobl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D, Investigators TITAN (2016) Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 374:511–522

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada

    Damien G. Noone & Christoph Licht

  2. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    Damien G. Noone & Christoph Licht

  3. Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

    Magdalena Riedl & Christoph Licht

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Christoph Licht

  5. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Christoph Licht

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  1. Damien G. Noone
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  2. Magdalena Riedl
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Correspondence to Damien G. Noone.

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DN, MR or CL have no conflicts of interest to delare that are relevant to this review.

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Noone, D.G., Riedl, M. & Licht, C. The role of von Willebrand factor in thrombotic microangiopathy. Pediatr Nephrol 33, 1297–1307 (2018). https://doi.org/10.1007/s00467-017-3744-y

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  • DOI: https://doi.org/10.1007/s00467-017-3744-y

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