Molecular Mechanisms in Thrombotic Thrombocytopenic Purpura

 

 Buy Article Permissions and Reprints

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.

REFERENCES

• 1 Bukowski R M. Thrombotic thrombocytopenic purpura. A review.  Prog Hemost Thromb. 1982;  6 287-337
  PubMedGoogle Scholar
• 2 Tsai H M, Shulman K. Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura.  Eur J Haematol. 2003;  70 183-185
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 5 Bell W R. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome relapse: frequency, pathogenesis, and meaning.  Semin Hematol. 1997;  34 134-139
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 13 Loirat C. Post-diarrhea hemolytic-uremic syndrome: clinical aspects.  Arch Pediatr. 2001;  8(suppl 4) 776s-784s
  CrossrefPubMedGoogle Scholar
• 14 Taylor C M. Complement factor H and the haemolytic uraemic syndrome.  Lancet. 2001;  358 1200-1202
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 16 Noris M, Brioschi S, Caprioli J et al.. Familial haemolytic uraemic syndrome and a MCP mutation.  Lancet. 2003;  362 1542-1547
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 26 Kwaan H C. Role of fibrinolysis in thrombotic thrombocytopenic purpura.  Semin Hematol. 1987;  24 101-109
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 33 Tsai H M. Shear stress and von Willebrand factor in health and disease.  Semin Thromb Hemost. 2003;  29 479-488
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 43 Tsai H M. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.  J Mol Med. 2002;  80 639-647
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 51 Tang B L. ADAMTS: a novel family of extracellular matrix proteases.  Int J Biochem Cell Biol. 2001;  33 33-44
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 59 Jubinsky P T, Moraille R, Tsai H M. Thrombotic thrombocytopenic purpura in a newborn.  J Perinatol. 2003;  23 85-87
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 63 Tsai H M. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.  J Am Soc Nephrol. 2003;  14 1072-1081
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 68 Gutterman L, Kloster B, Tsai H. Rituximab therapy for refractory thrombotic thrombocytopenic purpura.  Blood Cells Mol Dis. 2002;  28 385-391
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Han-Mou TsaiM.D. 

Montefiore Medical Center, Division of Hematology

111 East 210th Street

Bronx, NY 10467

Email: htsai@montefiore.org