Molecular Mechanisms in Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolysis. Unlike the typical hemolytic uremic syndrome (HUS), which follows infection with shiga toxin-producing microorganisms, most cases of TTP do not have an obvious etiology. Recent studies revealed that a plasma zinc metalloprotease ADAMTS (a disintegrin and metalloprotease with thrombospondin type 1 motif) 13 cleaves von Willebrand factor in a shear-dependent manner. Deficiency of ADAMTS13, due to autoimmune inhibitors of the protease or genetic mutation in the ADAMTS13 gene, results in a propensity to the development of von Willebrand factor-platelet aggregation and intravascular thrombosis characteristic of TTP. The identification of the molecular defect in TTP raises the prospect that this hitherto mysterious disorder will be managed with a more rationally designed strategy in the near future.

KEYWORDS

Thrombotic thrombocytopenic purpura - TTP - metalloprotease - ADAMTS - von Willebrand factor

REFERENCES

• 1 Bukowski R M. Thrombotic thrombocytopenic purpura. A review.  Prog Hemost Thromb. 1982;  6 287-337
• 2 Tsai H M, Shulman K. Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura.  Eur J Haematol. 2003;  70 183-185
• 3 Torok T J, Holman R C, Chorba T L. Increasing mortality from thrombotic thrombocytopenic purpura in the United States-analysis of national mortality data, 1968-1991.  Am J Hematol . 1995;  50 84-90
• 4 Shumak K H, Rock G A, Nair R C. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group.  Ann Intern Med. 1995;  122 569-572
• 5 Bell W R. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome relapse: frequency, pathogenesis, and meaning.  Semin Hematol. 1997;  34 134-139
• 6 Rock G A, Shumak K H, Buskard N A et al.. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.  N Engl J Med. 1991;  325 393-397
• 7 Bell W R, Braine H G, Ness P M, Kickler T S. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.  N Engl J Med. 1991;  325 398-403
• 8 Allford S L, Hunt B J, Rose P, Machin S J. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.  Br J Haematol. 2003;  120 556-573
• 9 Chow T W, Hellums J D, Moake J L. Erythrocyte fragments can be produced in vitro by high shear stress and quantified by flow cytometry in thrombotic thrombocytopenic purpura (TTP) blood.  Blood. 1999;  94(suppl 1) 452a
• 10 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 1578-1584
• 11 Tsai H M, Lian E C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.  N Engl J Med. 1998;  339 1585-1594
• 12 Levy G G, Nichols W C, Lian E C et al.. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.  Nature. 2001;  413 488-494
• 13 Loirat C. Post-diarrhea hemolytic-uremic syndrome: clinical aspects.  Arch Pediatr. 2001;  8(suppl 4) 776s-784s
• 14 Taylor C M. Complement factor H and the haemolytic uraemic syndrome.  Lancet. 2001;  358 1200-1202
• 15 Richards A, Kemp E J, Liszewski M K et al.. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.  Proc Natl Acad Sci USA. 2003;  100 12966-12971
• 16 Noris M, Brioschi S, Caprioli J et al.. Familial haemolytic uraemic syndrome and a MCP mutation.  Lancet. 2003;  362 1542-1547
• 17 Schulman I, Pierce M, Lukens A, Currimbhoy Z. Studies on thrombopoiesis. I. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency.  Blood. 1960;  16 943-957
• 18 Upshaw Jr J D. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia.  N Engl J Med. 1978;  298 1350-1352
• 19 Veyradier A, Obert B, Haddad E et al.. Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome.  J Pediatr. 2003;  142 310-317
• 20 Fujimura Y. Is Upshaw-Schulman syndrome congenital thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome? Yes to both.  J Thromb Haemost. 2003;  1 2457-2458
• 21 Tsai H M, Rice L, Sarode R, Chow T W, Moake J L. 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;  132 794-799
• 22 Van der Plas R M, Schiphorst M E, Huizinga E G et al.. von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic thrombocytopenic purpura.  Blood. 1999;  93 3798-3802
• 23 Arai S, Allan C, Streiff M, Hutchins G M, Vogelsang G B, Tsai H M. Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.  Hematol J. 2001;  2 292-299
• 24 Fontana S, Gerritsen H E, Hovinga J K, Furlan M, Lämmle B. Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease.  Br J Haematol. 2001;  113 100-102
• 25 Forman R B, Benkel S A, Novik Y, Tsai H M. Presence of ADAMTS13 activity in a patient with metastatic cancer and thrombotic microangiopathy.  Acta Haematol. 2003;  109 150-152
• 26 Kwaan H C. Role of fibrinolysis in thrombotic thrombocytopenic purpura.  Semin Hematol. 1987;  24 101-109
• 27 Siddiqui F A, Lian E C. Platelet-agglutinating protein p37 from a thrombotic thrombocytopenic purpura plasma forms complexes with platelet membrane glycoprotein IV (CD36).  Biochem Int. 1992;  27 485-496
• 28 Kelton J G, Moore J C, Warkentin T E, Hayward C P. Isolation and characterization of cysteine proteinase in thrombotic thrombocytopenic purpura.  Br J Haematol. 1996;  93 421-426
• 29 Burns E R, Zucker-Franklin D. Pathologic effects of plasma from patients with thrombotic thrombocytopenic purpura on platelets and cultured vascular endothelial cells.  Blood. 1982;  60 1030-1037
• 30 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;  13 203-210
• 31 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
• 32 Romani D W, Fijnheer R, Brinkman H J, Kersting S, Hene R J, van Mourik J A. Endothelial cell activation in thrombotic thrombocytopenic purpura (TTP): a prospective analysis.  Br J Haematol. 2003;  123 522-527
• 33 Tsai H M. Shear stress and von Willebrand factor in health and disease.  Semin Thromb Hemost. 2003;  29 479-488
• 34 Dent J A, Berkowitz S D, Ware J, Kasper C K, Ruggeri Z M. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor.  Proc Natl Acad Sci USA. 1990;  87 6306-6310
• 35 Tsai H M, Sussman I I, Nagel R L. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma.  Blood. 1994;  83 2171-2179
• 36 Fowler W E, Fretto L J, Hamilton K K, Erickson H P, McKee P A. Substructure of human von Willebrand factor.  J Clin Invest. 1985;  76 1491-1500
• 37 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 4223-4234
• 38 Tsai H M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion.  Blood. 1996;  87 4235-4244
• 39 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;  130 475-480
• 40 Zheng X, Chung D, Takayama T K, Majerus E M, Sadler J E, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.  J Biol Chem. 2001;  276 41059-41063
• 41 Tsai H M, Sussman I I, Ginsburg D, Lankhof H, Sixma J J, Nagel R L. 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 1954-1962
• 42 Siedlecki C A, Lestini B J, Kottke-Marchant K K, Eppell S J, Wilson D L, Marchant R E. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor.  Blood. 1996;  88 2939-2950
• 43 Tsai H M. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.  J Mol Med. 2002;  80 639-647
• 44 Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic pupura, with special reference to factor VIII related antigen.  Thromb Res. 1985;  38 469-479
• 45 Tsai H M, Chandler W L, 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;  49 653-659
• 46 Hunt B J, Lämmle B, Nevard C H, Haycock G B, Furlan M. Von Willebrand factor-cleaving protease in childhood diarrhoea- associated haemolytic uraemic syndrome.  Thromb Haemost. 2001;  85 975-978
• 47 Moake J L, Rudy C K, Troll J H et al.. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.  N Engl J Med. 1982;  307 1432-1435
• 48 Tsai H M, Sarode R, Downes K A. Ultralarge von Willebrand factor multimers and normal ADAMTS13 activity in the umbilical cord blood.  Thromb Res. 2002;  108 121-125
• 49 Gerritsen H E, Robles R, Lämmle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease.  Blood. 2001;  98 1654-1661
• 50 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 1662-1666
• 51 Tang B L. ADAMTS: a novel family of extracellular matrix proteases.  Int J Biochem Cell Biol. 2001;  33 33-44
• 52 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 11902-11907
• 53 Schneppenheim R, Budde U, Oyen F et al.. Von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.  Blood. 2003;  101 1845-1850
• 54 Assink K, Schiphorst R, Allford S et al.. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency.  Kidney Int. 2003;  63 1995-1999
• 55 Savasan S, Lee S K, Ginsburg D, Tsai H M. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity.  Blood. 2003;  101 4449-4451
• 56 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;  120 821-824
• 57 Matsumoto M, Kokame K, Soejima K et al.. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.  Blood. 2003;  103 1305-1310
• 58 Pimanda J E, Maekawa A, Wind T, Paxton J, Chesterman C N, Hogg P J. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13.  Blood. 2003;  103 627-629
• 59 Jubinsky P T, Moraille R, Tsai H M. Thrombotic thrombocytopenic purpura in a newborn.  J Perinatol. 2003;  23 85-87
• 60 Lee T P, Bouhassira E E, Lyubsky S, Tsai H M. ADAMTS13, the von Willebrand factor cleaving metalloprotease, is expressed in the perisinusoidal cells of the liver.  Blood. 2002;  100(suppl 1) 497a
• 61 Majerus E M, Zheng X, Tuley E A, Sadler J E. Cleavage of the ADAMTS13 propeptide is not required for protease activity.  J Biol Chem. 2003;  278 46643-46648
• 62 Zheng X, Nishio K, Majerus E M, Sadler J E. Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13.  J Biol Chem. 2003;  278 30136-30141
• 63 Tsai H M. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.  J Am Soc Nephrol. 2003;  14 1072-1081
• 64 Moore J C, Hayward C P, Warkentin T E, Kelton J G. Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders.  Blood. 2001;  98 1842-1846
• 65 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;  100 778-785
• 66 Vesely S K, George J N, Lämmle 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 60-68
• 67 Zhou W, Tsai H M. Enzyme immunoassay of ADAMTS13 activity distinguishes patients of thrombotic thrombocytopenic purpura from normal individuals and carriers of ADAMTS13 mutations.  Thromb Haemost. 2004;  91 806-811
• 68 Gutterman L, Kloster B, Tsai H. Rituximab therapy for refractory thrombotic thrombocytopenic purpura.  Blood Cells Mol Dis. 2002;  28 385-391
• 69 Zheng X, Pallera A M, Goodnough L T, Sadler J E, Blinder M A. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab.  Ann Intern Med. 2003;  138 105-108
• 70 Yomtovian Y, Niklinski W, Silver B, Sarode R, Tsai H M. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: report of a case and review of the literature.  Br J Haematol. 2004;  124 787-795