Pathogenesis of thrombotic microangiopathies

Annual Review of Pathology: Mechanisms of Disease

Volumn 3, Issue , 2008, Pages 249-277

  Zheng, X Long ^a   Sadler, J Evan ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

ADAMTS13; Complement dysregulation; Hemolytic uremic syndrome; Thrombotic thrombocytopenic purpura; Von Willebrand factor cleaving metalloprotease

Indexed keywords

ALTERNATIVE COMPLEMENT PATHWAY C3 C5 CONVERTASE; AUTOANTIBODY; COMPLEMENT FACTOR H; COMPLEMENT FACTOR I; MEMBRANE COFACTOR PROTEIN; SHIGA TOXIN; VON WILLEBRAND FACTOR; VON WILLEBRAND FACTOR CLEAVING PROTEINASE;

ADAMTS13 GENE; AUTOIMMUNITY; COMPLEMENT SYSTEM; ESCHERICHIA COLI O157; GENE; GENE MUTATION; HEMOLYTIC UREMIC SYNDROME; HISTOPATHOLOGY; HUMAN; IMMUNOPATHOGENESIS; IMMUNOREGULATION; MOLECULAR CLONING; NONHUMAN; PENETRANCE; PRIORITY JOURNAL; REGULATOR GENE; REVIEW; RISK FACTOR; THROMBOTIC THROMBOCYTOPENIC PURPURA;

ADAM PROTEINS; DIARRHEA; HEMOLYTIC-UREMIC SYNDROME; HUMANS; KIDNEY FAILURE, ACUTE; MICROCIRCULATION; POINT MUTATION; PURPURA, THROMBOTIC THROMBOCYTOPENIC; VON WILLEBRAND FACTOR;

EID: 41749101957     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev.pathmechdis.3.121806.154311     Document Type: Review

References (170)

1. Moschcowitz E. 1924. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc. NY Pathol. Soc. 24:21-24
2. Amorosi EL, Ultmann JE. 1966. Thrombocytopic purpura: report of 16 cases and review of the literature. Medicine 45:139-59
3. George JN, Gilcher RO, Smith JW, Chandler L, Duvall D, et al. 1998. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: diagnosis and management. J. Clin. Apher. 13:120-25
4. George JN. 2000. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 96:1223-29
5. Bell WR, Braine HG, Ness PM, Kickler TS. 1991. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N. Engl. J. Med. 325:398-403
6. 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. 85:905-9
7. Vesely SK, George JN, Lammle B, Studt JD, Alberio L, et al. 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
8. Zheng X, Sadler JE. 2006. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. In Clinical Hematology, ed. NS Young, SL Gerson, KA High, pp. 802-13. Philadelphia: Mosby Elsevier
9. Thompson CE, Damon LE, Ries CA, Linker CA. 1992. Thrombotic microangiopathies in the 1980s: clinical features, response to treatment, and the impact of the human immunodeficiency virus epidemic. Blood 80:1890-95
10. Bueno D Jr, Sevigny J, Kaplan AA. 1999. Extracorporeal treatment of thrombotic microangiopathy: a ten year experience. Ther. Apher. 3:294-97
11. Cleary TG. 1988. Cytotoxin-producing Escherichia coli and the hemolytic uremic syndrome. Pediatr. Clin. N. Am. 35:485-501
12. Tarr PI, Neill MA, Clausen CR, Watkins SL, Christie DL, et al. 1990. Escherichia coli O157:H7 and the hemolytic uremic syndrome: importance of early cultures in establishing the etiology. J. Infect. Dis. 162:553-56
13. 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. 101:357-61
14. Roodhooft AM, McLean RH, Eist E, Van Acker KJ. 1990. Recurrent hemolytic uraemic syndrome and acquired hypomorphic variant of the third component of complement. Pediatr. Nephrol. 4:597-99
15. Pichette V, Querin S, Schurch W, Brun G, Lehner-Netsch G, et al. 1994. Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am. J. Kidney Dis. 24:936-41
16. Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lammle B. 1997. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89:3097-103
17. Furlan M, Lammle B. 1998. Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura. Baillieres Clin. Haematol. 11:509-14
18. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, et al. 1998. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N. Engl. J. Med. 339:1578-84
19. Furlan M, Robles R, Morselli B, Sandoz P, Lammle B. 1999. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura. Thromb. Haemost. 81:8-13
20. Furlan M, Robles R, Solenthaler M, Lammle B. 1998. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 91:2839-46
21. Tsai HM, Lian EC. 1998. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N. Engl. J. Med. 339:1585-94
22. Elliott MA, Nichols WL Jr, Plumhoff EA, Ansell SM, Dispenzieri A, et al. 2003. Post-transplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin. Proc. 78:421-30
23. George JN, Selby GB. 2004. Thrombotic microangiopathy after allogeneic bone marrow transplantation: a pathologic abnormality associated with diverse clinical syndromes. Bone Marrow Transplant. 33:1073-74
24. Gharpure VS, Devine SM, Holland HK, Geller RB, O'Toole K, et al. 1995. Thrombotic thrombocytopenic purpura associated with FK506 following bone marrow transplantation. Bone Marrow Transplant. 16:715-16
25. Moake JL, Byrnes JJ. 1996. Thrombotic microangiopathies associated with drugs and bone marrow transplantation. Hematol. Oncol. Clin. N. Am. 10:485-97
26. Medina PJ, Sipols JM, George JN. 2001. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr. Opin. Hematol. 8:286-93
27. Pisoni R, Ruggenenti P, Remuzzi G. 2001. Drug-induced thrombotic microangiopathy: incidence, prevention and management. Drug Saf. 24:491-501
28. Fontana S, Gerritsen HE, Kremer Hovinga J, Furlan M, Lammle B. 2001. Microangiopathic hemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease. Br. J. Haematol. 113:100-2
29. Mannucci PM, Karimi M, Mosalaei A, Canciani MT, Peyvandi F. 2003. Patients with localized and disseminated tumors have reduced but measurable levels of ADAMTS-13 (von Willebrand factor cleaving protease). Haematologica 88:454-58
30. May HV Jr, Harbert GM Jr, Thornton WN Jr. 1976. Thrombotic thrombocytopenic purpura associated with pregnancy. Am. J. Obstet. Gynecol. 126:452-58
31. Atlas M, Barkai G, Menczer J, Houlu N, Lieberman P. 1982. Thrombotic thrombocytopenic purpura in pregnancy. Br. J. Obstet. Gynaecol. 89:476-79
32. McCrae KR, Cines DB. 1997. Thrombotic microangiopathy during pregnancy. Semin. Hematol. 34:148-58
33. Terrell DR, Williams LA, Vesely SK, Lammle B, Hovinga JA, George JN. 2005. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J. Thromb. Haemost. 3:1432-36
34. Torok TJ, Holman RC, Chorba TL. 1995. Increasing mortality from thrombotic thrombocytopenic purpura in the United States: analysis of national mortality data, 1968-1991. Am. J. Hematol. 50:84-90
35. Lohrmann HP, Adam W, Heymer B, Kubanek B. 1973. Microangiopathic hemolytic anemia in metastatic carcinoma. Report of eight cases. Ann. Intern. Med. 79:368-75
36. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. 2004. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 44:294-304
37. Leaf AN, Laubenstein LJ, Raphael B, Höchster H, Baez L, et al. 1988. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus type 1 (HIV-1) infection. Ann. Intern. Med. 109:194-97
38. Becker S, Fusco G, Fusco J, Balu R, Gangjee S, et al. 2004. HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: an observational study. Clin. Infect. Dis. 39(Suppl. 5):S267-75
39. Esplin MS, Branch DW. 1999. Diagnosis and management of thrombotic microangiopathies during pregnancy. Clin. Obstet. Gynecol. 42:360-67
40. George JN. 2003. The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr. Opin. Hematol. 10:339-44
41. Dashe JS, Ramin SM, Cunningham FG. 1998. The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet. Gynecol. 91:662-68
42. Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. 2001. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 98:2730-35
43. Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. 2000. 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. 132:794-99
44. Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, et al. 2000. Thrombotic thrombocytopenic purpura associated with clopidogrel. N. Engl. J. Med. 342:1773-77
45. Jonas S, Grieco G. 2004. Editorial comment-an approach to the estimation of the risk of TTP during clopidogrel therapy. Stroke 35:537-38
46. Zakarija A, Bandarenko N, Pandey DK, Auerbach A, Raisch DW, et al. 2004. Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration. Stroke 35:533-37
47. Hosier GA, Cusumano AM, Hutchins GM. 2003. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch. Pathol. Lab. Med. 127:834-39
48. Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. 1985. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb. Res. 38:469-79
49. Katoh M, Shigematsu H. 1999. Renal involvement of thrombotic thrombocytopenic purpura: special reference to the glomeruloid structures. Pathol. Int. 49:638-42
50. Padilla A, Moake JL, Bernardo A, Ball C, Wang Y, et al. 2004. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 103:2150-56
51. Tsai HM. 1996. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87:4235-44
52. Sadler JE. 1991. von Willebrand factor. J. Biol. Chem. 266:22777-80
53. Tsai HM, Sussman I, Nagel RL. 1994. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood 83:2171-79
54. 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 87:4223-34
55. Tsai HM, Sussman II, Ginsburg D, Lankhof H, Sixma JJ, Nagel RL. 1997. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1. Blood 89:1954-62
56. Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, et al. 1982. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N. Engl. J. Med. 307:1432-35
57. Hulstein JJ, de Groot PG, Silence K, Veyradier A, Fijnheer R, Lenting PJ. 2005. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Blood 106:3035-42
58. Fujikawa K, Suzuki H, McMullen B, Chung D. 2001. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 98:1662-66
59. Gerritsen HE, Robles R, Lammle B, Furlan M. 2001. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood 98:1654-61
60. Plaimauer B, Zimmermann K, Volkel D, Antoine G, Kerschbaumer R, et al. 2002. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 100:3626-32
61. Soejima K, Mimura N, Hirashima M, Maeda H, Hamamoto T, et al. 2001. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? J. Biochem. 130:475-80
62. 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. 276:41059-63
63. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, et al. 2001. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413:488-94
64. Bork P, Beckmann G. 1993. The CUB domain. A widespread module in developmentally regulated proteins. J. Mol. Biol. 231:539-45
65. Shang D, Zheng XW, Niiya M, Zheng XL. 2006. 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 108:2207-15
66. Turner N, Nolasco L, Tao Z, Dong JF, Moake J. 2006. Human endothelial cells synthesize and release ADAMTS-13. J. Thromb. Haemost. 4:1396-404
67. Liu L, Choi H, Bernardo A, Bergeron AL, Nolasco L, et al. 2005. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J. Thromb. Haemost. 3:2536-44
68. Suzuki M, Murata M, Matsubara Y, Uchida T, Ishihara H, et al. 2004. Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. Biochem. Biophys. Res. Commun. 313:212-16
69. Zheng XW, Niiya M, Zheng X, Pollak E. 2006. Isolation and characterization of human ADAMTS13 gene promoter region-control of ADAMTS13 gene expression by hepatic transcription factors and inflammatory cytokines. Blood 108:459a
70. Soejima K, Nakamura H, Hirashima M, Morikawa W, Nozaki C, et al. 2006. Analysis on the molecular species and concentration of circulating ADAMTS13 in blood. J. Biochem. 139:147-54
71. Crawley JT, Lam JK, Ranee JB, Mollica LR, O'Donnell JS, Lane DA. 2005. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 105:1085-93
72. Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura Y, et al. 2006. 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 107:528-34
73. Zhou W, Inada M, Lee TP, Benten D, Lyubsky S, et al. 2005. ADAMTS13 is expressed in hepatic stellate cells. Lab. Invest. 85:780-88
74. Uemura M, Tatsumi K, Matsumoto M, Fujimoto M, Matsuyama T, et al. 2005. Localization of ADAMTS13 to the stellate cells of human liver. Blood 106:922-24
75. Niiya M, Uemura M, Zheng XW, Pollak ES, Dockal M, et al. 2006. Increased ADAMTS13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J. Thromb. Haemost. 4:1063-70
76. Soejima K, Matsumoto M, Kokame K, Yagi H, Ishizashi H, et al. 2003. ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood 102:3232-37
77. Zheng X, Nishio K, Majerus EM, Sadler JE. 2003. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J. Biol. Chem. 278:30136-41
78. Anderson PJ, Kokame K, Sadler JE. 2006. Zinc and calcium ions cooperatively modulate ADAMTS13 activity. J. Biol. Chem. 281:850-57
79. Ai J, Smith P, Wang S, Zhang P, Zheng XL. 2005. The proximal carboxyl-terminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor. J. Biol. Chem. 280:29428-34
80. Gao W, Anderson PJ, Majerus EM, Tuley EA, Sadler JE. 2006. Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc. Natl. Acad. Sci. USA 103:19099-104
81. Kokame K, Matsumoto M, Fujimura Y, Miyata T. 2003. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 103:607-12
82. Zhou W, Tsai HM. 2004. An enzyme immunoassay of ADAMTS13 distinguishes patients with thrombotic thrombocytopenic purpura from normal individuals and carriers of ADAMTS13 mutations. Thromb. Haemost. 91:806-11
83. Wu JJ, Fujikawa K, McMullen BA, Chung DW. 2006. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc. Natl. Acad. Sci. USA 103:18470-74
84. Tao Z, Wang Y, Choi H, Bernardo A, Nishio K, et al. 2005. Cleavage of ultralarge multimers of von Willebrand factor by C-terminal-truncated mutants of ADAMTS-13 under flow. Blood 106:141-43
85. Pimanda JE, Maekawa A, Wind T, Paxton J, Chesterman CN, et al. 2004. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood 103:627-29
86. Shelat SG, Ai J, Zheng XL. 2005. Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Semin. Thromb. Hemost. 31:659-72
87. Klaus C, Plaimauer B, Studt JD, Dorner F, Lammle B, et al. 2004. Epitope mapping of ADAMTS 13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood 103:4514-19
88. Bernardo A, Nolasco L, Wang Y, Ball C, Moake J, et al. 2003. Peptides from the C-terminal regions of ADAMTS-13 specifically block cleavage of ultralarge von Willebrand factor multimers on the endothelial surface under flow. J. Thromb. Haemost. 1:405a
89. Tao Z, Peng Y, Nolasco L, Cal S, Lopez-Otin C, et al. 2005. Role of the CUB-1 domain in docking ADAMTS-13 to unusually large von Willebrand factor in flowing blood. Blood 106:4139-45
90. Zhang P, Pan W, Rux AH, Sachais BS, Zheng X. 2007. The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow. Blood 110:1887-94
91. Majerus EM, Anderson PJ, Sadler JE. 2005. Binding of ADAMTS13 to von Willebrand factor. J. Biol. Chem. 280:71773-78
92. Dong JF, Moake JL, Bernardo A, Fujikawa K, Ball C, et al. 2003. ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultralarge von Willebrand factor. J. Biol. Chem. 278:29633-39
93. Jenkins PV, Pasi KJ, Perkins SJ. 1998. Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand's disease. Blood 91:2032-44
94. Tsai HM. 2003. Shear stress and von Willebrand factor in health and disease. Semin. Thromb. Hemost. 29:479-88
95. Nishio K, Anderson PJ, Zheng XL, Sadler JE. 2004. Binding of platelet glycoprotein Ibα to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc. Natl. Acad. Sci. USA 101:10578-83
96. De Cristofaro R, Peyvandi F, Palla R, Lavoretano S, Lombardi R, et al. 2005. Role of chloride ions in the modulation of the interaction between von Willebrand factor and ADAMTS-3. J. Biol. Chem. 280:23295-302
97. Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. 2004. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 104:100-6
98. Studt JD, Hovinga JA, Antoine G, Hermann M, Rieger M, et al. 2005. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood 105:542-44
99. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, et al. 2002. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Natl. Acad. Sci. USA 99:11902-7
100. Antoine G, Zimmermann K, Plaimauer B, Grillowitzer M, Studt JD, et al. 2003. 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. 120:821-24
101. Assink K, Schiphorst R, Allford S, Karpman D, Etzioni A, et al. 2003. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int. 63:1995-99
102. Matsumoto M, Kokame K, Soejima K, Miura M, Hayashi S, et al. 2003. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103:1305-10
103. Savasan S, Lee SK, Ginsburg D, Tsai HM. 2003. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood 101:4449-51
104. Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, et al. 2003. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 101:1845-50
105. Licht C, Stapenhorst L, Simon T, Budde U, Schneppenheim R, et al. 2004. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Kidney Int. 66:955-58
106. Uchida T, Wada H, Mizutani M, Iwashita M, Ishihara H, et al. 2004. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood 104:2081-83
107. Noris M, Bucchioni S, Galbusera M, Donadelli R, Bresin E, et al. 2005. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J. Am. Soc. Nephrol. 16:1177-83
108. Furlan M, Lammle B. 2001. Aetiology and pa thogenesis of thrombotic thrombocytopenic purpura and hemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract. Res. Clin. Haematol. 14:437-54
109. Kokame K, Miyata T. 2004. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin. Hematol. 41:34-40
110. Bongers TN, De Maat MP, Dippel DW, Uitterlinden AG, Leebeek FW. 2005. Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians. J. Thromb. Haemost. 3:805
111. Ruan C, Dai L, Su J, Wang Z. 2004. The frequency of P475S polymorphism in von Willebrand factor-cleaving protease in the Chinese population and its relevance to arterial thrombotic disorders. Thromb. Haemost. 91:1257-58
112. Yoo G, Blomback M, Schenck-Gustafsson K, He S. 2003. Decreased levels of von Willebrand factor-cleaving protease in coronary heart disease and thrombotic thrombocytopenic purpura: study of a simplified method for assaying the enzyme activity based on ristocetin-induced platelet aggregation. Br. J. Haematol. 121:123-29
113. Plaimauer B, Fuhrmann J, Mohr G, Wernhart W, Bruno K, et al. 2006. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood 107:118-25
114. Kinoshita S, Yoshioka A, Park YD, Ishizashi H, Konno M, et al. 2001. Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int. J. Hematol. 74:101-8
115. Savasan S, Taub JW, Buck S, Botterill M, Furlan M, Ravindranath Y. 2001. Congenital microangiopathic hemolytic anemia and thrombocytopenia with unusually large von Willebrand factor multimers and von Willebrand factor-cleaving protease. J. Pediatr. Hematol. Oncol. 23:364-67
116. Studt JD, Kremer Hovinga JA, Alberio L, Bianchi V, Lammle B. 2003. Von Willebrand factor-cleaving protease (ADAMTS-13) activity in thrombotic microangiopathies: diagnostic experience 2001/2002 of a single research laboratory. Swiss Med. Wkly. 133:325-32
117. Zheng XL, Richard KM, Goodnough LT, Sadler JE. 2004. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 103:4043-49
118. Rieger M, Mannucci PM, Kremer Hovinga JA, Herzog A, Gerstenbauer G, et al. 2005. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 106:1262-67
119. Scheiflinger F, Knoebl P, Trattner B, Plaimauer B, Mohr G, et al. 2003. Non-neutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura (TTP). Blood 102:3241-43
120. Sugio Y, Okamura T, Shimoda K, Matsumoto M, Yagi H, et al. 2001. Ticlopidine-associated thrombotic thrombocytopenic purpura with an IgG-type inhibitor to von Willebrand factor-cleaving protease activity. Int. J. Hematol. 74:347-51
121. Luken BM, Turenhout EA, Hulstein JJ, Van Mourik JA, Fijnheer R, Voorberg J. 2005. The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Thromb. Haemost. 93:267-74
122. Luken BM, Kaijen PH, Turenhout EA, Kremer Hovinga JA, Van Mourik JA, et al. 2006. Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/thrombospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 4:2355-64
123. Siegel D, Ostertag E. 2006. Inhibitory ADAMTS13 monoclonal autoantibodies cloned from TTP patients show restricted gene usage, inhibit murine ADAMTS13, and are blocked by rabbit anti-idiotypic antibodies. Blood 108:31a
124. Raife TJ, Lentz SR, Atkinson BS, Vesely SK, Hessner MJ. 2002. Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor-cleaving protease activity. Blood 99:437-42
125. Krieg S, Studt JD, Sulzer I, Lammle B, Hovinga JA. 2005. Is factor V Leiden a risk factor for thrombotic microangiopathies without severe ADAMTS 13 deficiency? Thromb. Haemost. 94:1186-89
126. Joseph G, Smith KJ, Hadley TJ, Djulbegovic B, Troup GM, et al. 1994. HLA-DR53 protects against thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome. Am. J Hematol. 47:189-93
127. Praprotnik S, Blank M, Levy Y, Tavor S, Boffa MC, et al. 2001. Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells. Int. Immunol. 13:203-10
128. Jimenez JJ, Jy W, Mauro LM, Horstman LL, Ahn YS. 2001. Elevated endothelial microparticles in thrombotic thrombocytopenic purpura: findings from brain and renal microvascular cell culture and patients with active disease. Br. J. Haematol. 112:81-90
129. Jimenez JJ, Jy W, Mauro LM, Horstman LL, Soderland C, et al. 2003. Endothelial microparticles released in thrombotic thrombocytopenic purpura express von Willebrand factor and markers of endothelial activation. Br. J. Haematol. 123:896-902
130. Schultz DR, Arnold PI, Jy W, Valant PA, Gruber J, et al. 1998. 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. 103:849-57
131. Wright JF, Wang H, Hornstein A, Hogarth M, Mody M, et al. 1999. Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura. Br. J. Haematol. 107:546-55
132. Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, et al. 1999. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J. Clin. Invest. 104:93-102
133. Carter AO, Borczyk AA, Carlson JA, Harvey B, Hockin JC, et al. 1987. A severe outbreak of Escherichia coli O157:H7-associated hemorrhagic colitis in a nursing home. N. Engl. J. Med. 317:1496-500
134. Griffin PM, Tauxe RV. 1991. The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epidemiol. Rev. 13:60-98
135. Alon U, Adler SP, Chan JC. 1984. Hemolytic-uremic syndrome associated with Streptococcus pneumoniae. Report of a case and review of the literature. Am. J. Dis. Child. 138:496-99
136. Neuhaus TJ, Calonder S, Leumann EP. 1997. Heterogeneity of atypical hemolytic uraemic syndromes. Arch. Dis. Child. 76:518-21
137. Tarr PI. 1995. Escherichia coli O157:H7: clinical, diagnostic, and epidemiological aspects of human infection. Clin. Infect. Dis. 20:1-8
138. Le Saux N, Spika JS, Friesen B, Johnson I, Melnychuck D, et al. 1993. Ground beef consumption in noncommercial settings is a risk factor for sporadic Escherichia coli O157:H7 infection in Canada. J. Infect. Dis. 167:500-2
139. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. 2000. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N. Engl. J. Med. 342:1930-36
140. Morel-Maroger L, Kanfer A, Solez K, Sraer JD, Richet G. 1979. Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults. Kidney Int. 15:548-58
141. Tsai HM, Chandler WL, Sarode R, Hoffman R, Jelacic S, et al. 2001. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr. Res. 49:653-59
142. Heptinstall RH. 1992. Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and systemic sclerosis (systemic scleroderma). In Pathology of the Kidney, ed. RH Heptinstall, 2:1163-233. Boston/Toronto/London: Little, Brown
143. Taylor CM. 2001. Hemolytic-uremic syndrome and complement factor H deficiency: clinical aspects. Semin. Thromb. Hemost. 27:185-90
144. Moake JL. 2002. Thrombotic microangiopathies. N. Engl. J. Med. 347:589-600
145. Nolasco LH, Turner NA, Bernardo A, Tao Z, Cleary TG, et al. 2005. Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106:4199-209
146. Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, et al. 2003. Complement factor H mutations and gene polymorphisms in hemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum. Mol. Genet. 12:3385-95
147. Richards A, Goodship JA, Goodship TH. 2002. The genetics and pathogenesis of hemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr. Opin. Nephrol. Hypertens. 11:431-35
148. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, et al. 2006. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267-79
149. Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, et al. 2007. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol. Immunol. 44:1835-44
150. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, et al. 2004. Complement factor I: a susceptibility gene for atypical hemolytic uraemic syndrome. J. Med. Genet. 41:e84
151. Kavanagh D, Goodship TH. 2006. Membrane cofactor protein and factor I: mutations and transplantation. Semin. Thromb. Hemost. 32:155-59
152. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, et al. 2007. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc. Natl. Acad. Sci. USA 104:240-45
153. Kavanagh D, Kemp EJ, Richards A, Burgess RM, Mayland E, et al. 2006. Does complement factor B have a role in the pathogenesis of atypical HUS? Mol. Immunol. 43:856-59
154. Kim Y, Miller K, Michael AF. 1977. Breakdown products of C3 and factor B in hemolytic-uremic syndrome. J. Lab. Clin. Med. 89:845-50
155. Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, et al. 2003. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J. Med. Genet. 40:676-81
156. Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, et al. 2006. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am. J. Transplant. 6:1948-52
157. Thompson RA, Winterborn MH. 1981. Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin. Exp. Immunol. 46:110-19
158. Buddles MR, Donne RL, Richards A, Goodship J, Goodship TH. 2000. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am. J. Hum. Genet. 66:1721-22
159. Taylor CM. 2001. Complement factor H and the hemolytic uraemic syndrome. Lancet 358:1200-2
160. Ault BH. 2000. Factor H and the pathogenesis of renal diseases. Pediatr. Nephrol. 14:1045-53
161. Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, et al. 2005. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 16:555-63
162. Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, et al. 2006. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 17:2017-25
163. Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, et al. 2003. Familial hemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542-47
164. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, et al. 2003. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc. Natl. Acad. Sci. USA 100:12966-71
165. Alper CA, Abramson N, Johnston RB Jr, Jandl JH, Rosen FS. 1970. Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N. Engl. J. Med. 282:350-54
166. Proesmans W. 1996. Typical and atypical hemolytic uremic syndrome. Kidney Blood Press. Res. 19:205-8
167. Siegler RL, Pavia AT, Hansen FL, Christofferson RD, Cook JB. 1996. Atypical hemolytic-uremic syndrome: a comparison with postdiarrheal disease. J. Pediatr. 128:505-11
168. Tonshoff B, Sammet A, Sanden I, Mehls O, Waldherr R, et al. 1994. Outcome and prognostic determinants in the hemolytic uremic syndrome of children. Nephron 68:63-70
169. Zipfel PF, Neumann HP, Jozsi M. 2003. Genetic screening in hemolytic uraemic syndrome. Curr. Opin. Nephrol. Hypertens. 12:653-57
170. Smith CA, Vogel CW, Muller-Eberhard HJ. 1984. MHC Class III products: an electron microscopic study of the C3 convertases of human complement. J. Exp. Med. 159:324-29