Blood Reviews
Volume 20, Issue 1 , Pages 51-60 , January 2006

Thrombotic Thrombocytopenic Purpura: aetiology, pathophysiology and treatment

  • R.J.A. Murrin

      Affiliations

    • Department of Haematology, Sandwell General Hospital, Sandwell and West Birmingham Hospitals NHS Trust, West Midlands, UK
    • Corresponding Author InformationCorresponding author.
  • ,
  • J.A. Murray

      Affiliations

    • Department of Haematology, Selly Oak Hospital, University Hospital of Birmingham, NHS Foundation Trust, UK

References 

  1. Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capilliaries: a hitherto undescribed disease. Proc NY Pathol Soc. 1924;24:21–24
  2. Amorisi EL, Ultmann JE. Thrombotic thrombocytopenic purpura :report of 16 cases and review of the literature. Medicine. 1966;45:139–159
  3. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura: report of 25 cases and review of the literature. Medicine. 1981;60:413–428
  4. Rock G, Kelton JG, Shumak KH, Buskard NA, Sutton DM, Benny WB. Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Br J Haem. 1998;103:1031–1036
  5. Fava S, Galizia AC. Thrombotic thrombocytopenic purpura – like syndrome in the absence of schistocytes. Br J Haem. 1995;89:643–644
  6. Jandl JH. Textbook of Haematology. 2nd ed.. Boston, New York, Toronto, London: Little, Brown and Company; 1997;Chapters 8 and 31
  7. Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. Clin Apheresis. 1998;13:16–19
  8. Cuttner J. Thrombotic thrombocytopenic purpura: a ten year experience. Blood. 1980;56:302–306
  9. Silverstein A. Thrombotic thrombocytopenic purpura: the initial neurological manifestation. Arch Neurol. 1968;18:358–362
  10. Sarode R, Gottschall JL, Aster RH, McFarland JG. Thrombotic thrombocytopenic purpura: early and late responders. Am J Haem. 1997;54:102–107
  11. Rabkin Y, Fradin Z, Zeidman A, Schwartz A, Cohen A, Mittelman M. Chronic relapsing thrombocytopenic purpura with severe neurological manifestations and full recovery. Int J Haematol. 2000;71:184–187
  12. George JN. How I treat patients with thrombotic thrombocytopenic purpura – hemolytic uremic syndrome. Blood. 2000;96:1223–1229
  13. Olsen H. Thrombotic thrombocytopenic purpura as a cause of pancreatitis: report of a case and review of the literature. Dig Dis. 1973;18:238–246
  14. Elias M, Flatau E, Bar-El Y. Thrombotic thrombocytopenic purpura presenting as an acute abdomen. Br J Surg. 1985;72:286
  15. Winwood PJ, Iredale JP, Williamson PJ, Lesna M, Loehry CA. Thrombotic thrombocytopenic purpura mimicking acute small bowel Crohn’s disease. Gut. 1992;33:857–859
  16. Ross WK, Newton NE, Stivers RR. Sudden death due to thrombotic thrombocytopenic purpura. Am J Forensic Med Pathol. 1987;8:158–163
  17. Bell MD, Barnhart JS, Martin JM. Thrombotic thrombocytopenic purpura causing sudden unexpected death – a series of 8 patients. Am J Forensic Sci. 1990;35:601–613
  18. Ridolfi RL, Hutchins GM, Bell WR. The heart and cardiac conduction system in thrombotic thrombocytopenic purpura: a clinicopathologic study of 17 autopsied patients. Ann Intern Med. 1979;91:357–363
  19. Mead PS, Griffin PM. E. coli O157;H7. Lancet. 1998;352:1207–1212
  20. Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States – nalysis of national mortality data, 1968–1991. Am J Haem. 1995;50:84–90
  21. Levine SP. Thrombotic thrombocytopenic purpura and other forms of non-immunologic platelet destruction in: Wintrobe’s Clinical Haematology (Tenth Edition): Williams and Wilkins 1999.
  22. May HV, Harbert GM, Thornton WN. Thrombotic thrombocytopenic purpura associated with pregnancy. Am J Obstet Gynaecol. 1976;126:452–458
  23. Schriber JR, Herzig GP. Transplantation-associated thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Sem in Haematology. 1997;34:126–133
  24. Bennett CL, Weinberg PD, Rozenberg-Ben- Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med. 1998;128:541–544
  25. Leaf AN, Laubenstein LJ, Raphael B, Hochster H, Baez L, Karpatkin S. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus type 1 (HIV-1) infection. Ann Intern Med. 1988;109:194–197
  26. Raife TJ, Aster RH. Von Willebrand Factor proteolysis and doxycycline in thrombotic thrombocytopenic purpura. Lancet. 1998;352:324
  27. Gordon LI, Kwaan HC. Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura / haemolytic uraemic syndrome in the cancer patient. Seminars in Thrombosis and Haemostasis. 1999;25:217–221
  28. Allford SL, Hunt BJ, Rose P, Machin SJ on behalf of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haem. 2003;120:556–573
  29. Byrness JJ, Moake JL. Thrombotic thrombocytopenic purpura and the haemolytic uraemic syndrome; evolving concepts of pathogenesis and therapy. Clin Haematol. 1986;15:413–442
  30. Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura with special reference to factor VIII related antigen. Thromb Res. 1985;38:469–479
  31. Kwaan HC. Clinicopathologic features of thrombotic thrombocytopenic purpura. Sem in Haem. 1987;24:71–81
  32. Laurence J, Mitra D, Steiner M, Staiano-Coico L, Jaffe E. Plasma from patients with idiopathic and human immunodeficiency virus associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells. Blood. 1996;87:3254
  33. Dang CT, Magid MS, Weksler B, Chadburn A, Laurence J. Enhanced endothelial cell apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood. 1999;93:1264–1270
  34. Tandon N, Rock G, Jamieson GA. Anti CD 36 antibodies in thrombotic thrombocytopenic purpura. Br J Haem. 1994;88:816–825
  35. Sverlick RA, Lee KH, Wick TM, Lawley TJ. Human dermal microvascular endothelial but human umbilical vein endothelial cells express CD 36 in vivo and in vitro. Journal of Immunology. 1992;148:78–83
  36. Lian EC, Harkness DR, Byrnes JJ, Wallach H, Nunez R. Presence of a platelet aggregating factor in the plasma of patients with thrombotic thrombocytopenic purpura (TTP) and its inhibition by normal plasma. Blood. 1979;53:333–338
  37. Lian EC, Siddiqui FA, Jamieson GA, Tandon NN. Platelet agglutinating protein p37 causes platelet agglutination through its binding to membrane glycoprotein IV. Thromb Haemostas. 1991;65:102–106
  38. Murphy WG, Moore JC, Kelton JG. Calcium dependent cysteine protease activity in the sera of patients with thrombotic thrombocytopenic purpura. Blood. 1987;70:1683–1687
  39. Moore JC, Murphy WG, Kelton JG. Calpain proteolysis of von Willebrand Factor enhances its binding to platelet membrane glycoprotein IIb/IIIa: an explanation for platelet aggregation in thrombotic thrombocytopenic purpura. Br J Haem. 1990;74:457–464
  40. Kelton JG, Warkentin TE, Hayward CP, Murphy WG, Moore JC. Calpain activity in patients with thrombotic thrombocytopenic purpura is associated with platelet microparticles. Blood. 1992;80:2246–2251
  41. Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, et al. Unusually large plasma factor VIII: von Willebrand Factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Eng J Med. 1982;307:1432–1435
  42. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand Factor (VWF) multimers and unusually large VWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest. 1986;78:1456–1461
  43. Moake JL, Byrness JJ, Troll JH, Rudy CK, Hong SL, Weinstein MJ, et al. Effects of fresh frozen plasma and its cryosupernatant fraction on von Willebrand Factor mulimeric forms in chronic relapsing thrombotic thrombocytopenic purpura. Blood. 1985;65:1232–1236
  44. Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand Factor to fragments predicted by in vitro proteolysis. Blood. 1996;87:4223–4234
  45. Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle B. Deficient activity of von Willebrand Factor – cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood. 1997;89:3097–3103
  46. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. Von Willebrand Factor-cleaving protease in thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome. N Engl J Med. 1998;339:1578–1584
  47. Sarkodee-Adoo C, Gojo I, Heyman MR. Von Willebrand Factor-cleaving protease in thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome. N Engl J Med. 1999;340:1368
  48. Tsai HM, Lian EC. Antibodies to von Willebrand Factor – cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–1594
  49. Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type II Von Willebrand Factor. Proc Natl Acad Sci USA. 1990;87:6306–6310[Erratum: Proc Natl Acad Sci USA 1990;87:9508.]
  50. Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand Factor in normal plasma. Blood. 1994;83:2171–2179
  51. Tsai HM, Sussman II, Ginsberg D, Lankhof H, Sixma JJ, Nagel RL. Proteolytic cleavage of recombinant type 2A von Willebrand Factor mutants R843W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1. Blood. 1997;89:1954–1962
  52. 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
  53. Gerritsen HE, Robles R, Lämmle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood. 2001;98:1654–1661
  54. Levy GG, Nichols WC, Lian EC, Foroud T, McClintock JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–494
  55. Hurskainen TL, Hirohata S, Seldin MF, Apte SS. ADAM-TS5, ADAM-TS6 and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family. Journal of Biological Chemistry. 1999;274:25555–25563
  56. Mannucci PM. Thrombotic thrombocytopenic purpura: a simpler diagnosis at last. Thromb Haemostas. 1999;82:1380–1381
  57. Raife TJ, Montgomery RR. Von Willebrand Factor and thrombotic thrombocytopenic purpura. Current Opinion in Haematology. 2000;7:278–283
  58. Byrness JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med. 1977;297:1386–1389
  59. Lankford KV, Hillyer CD. Thrombotic thrombocytopenic purpura: new insights in disease pathogenesis and therapy. Transfusion Medicine Reviews. 2000;14:244–257
  60. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, 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
  61. Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haem. 2000;109:496–507
  62. Moake JL. Moschcowitz, multimers and metalloprotease. N Engl J Med. 1998;339:1629–1631
  63. Byrnes JJ, Moake JL, Klug P, Periman P. Effectiveness of the cryosupernatant fraction of plasma in the treatment of refractory thrombotic thrombocytopenic purpura. Am J Haem. 1990;34:169–174
  64. Rock G, Shumak KH, Dutton KMC, Buskard NA, Nair RC and the Members of the Canadian Apheresis Group. Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Br J Haem. 1996;94:383–386
  65. Owens MR, Sweeney JD, Tahhan RH, Fortkolt P. Influence of type of exchange fliud on survival in therapeutic apheresis for thrombotic thrombocytopenic purpura. Journal of Clinical Apheresis. 1995;10:178–182
  66. Ziegler Z, Shadduck RK, Gryn JF, Rintels PB, George JN, Besa EC, et al. North American TTP group. Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP). J Clin Apheresis. 2001;16:19–22
  67. Moake J, Chintagumpala M, Turner N, McPherson P, Nolasco L, Steuber C, et al. Solvent / detergent – treated plasma suppresses shear-induced platelet aggregation and prevents episodes of thrombotic thrombocytopenic purpura. Blood. 1994;84:490–497
  68. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. British Committee for Standards in Haematology, Blood Transfusion Task Force (J Duguid, Chairman). Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haem. 2004;126:11–28
  69. Bandarenko N, Brecher ME. United States Thrombotic Thrombocytopenic Purpura Study Group (US TTP ASG) : multicentre survey and retrospective analysis of current efficacy of therapeutic plasma exchange. Journal of Clinical Apheresis. 1998;13:133–141
  70. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura – haemolytic uraemic syndrome. Clinical experience in 108 patients. N Engl J Med. 1991;325:398–403
  71. Hoffman M, Monroe DM, Roberts HR. Platelet activation in patients with thrombotic thrombocytopenic purpura. Am J Haem. 1993;42:182–185
  72. Chow TW, Turner NA, Chintagumpala M, McPherson PD, Nolasco LH, Rice L, et al. Increased von Willebrand Factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Haem. 1998;57:293–302
  73. Moake JL, Turner NA, Stathopoulos NA, Nolasco L, Hellums JD. Shear induced platelet aggregation can be mediated by von Willebrand Factor released from platelets as well as by exogenous large or unusually large von Willebrand Factor multimers, requires adenosine triphosphate, and is resistant to aspirin. Blood. 1998;71:1366–1374
  74. Harkness DR, Byrness JJ, Lian EC, Williams WD, Hensley GT. Hazard of platelet transfusion in thrombotic thrombocytopenic purpura. JAMA. 1981;246:1931–1933
  75. Gordon LI, Kwaan HC, Rossi EC. Deleterious effects of platelet transfusion and recovery thrombocytosis in patients with thrombotic microangiopathy. Seminars in Haematology. 1987;24:194–201
  76. Brittingham TE, Chaplin H. Attempted passive transfer of thrombotic thrombocytopenic purpura. Blood. 1957;12:480–482
  77. Porta C, Bobbio-Pallavicini E, Centurioni R, Tacconi F. Thrombotic thrombocytopenic purpura resistant to plasma exchange: salvage treatment with high dose IgG or vincristine. Italian Cooperative Group for TTP. Int J Artif Organs. 1993;(Suppl 5):201–204
  78. Gaddis TG, Guthrie THJ, Drew MJ, Salund M, Howe RB, Mittelman A. Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption. Am J Haem. 1997;55:55–58
  79. Rowe JM, Francis CW, Cyran EM, Marder VJ. Thrombotic thrombocytopenic purpura: recovery after splenectomy associated with persistence of abnormally large von Willebrand Factor multimers. Am J Haem. 1985;20:161–168
  80. Schneider PA, Rayner AA, Linker CA, Schuman MA, Lin ET, Hohn DC. The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura. Ann Surg. 1985;202:318–321
  81. Hoffkes HG, Weber F, Uppenkamp M, Meusers P, Teschendorf C, Philipp T, et al. Recovery by splenectomy in patients with relapsed thrombotic thrombocytopenic purpura and treatment failure to plasma exchange. Semin Thromb Haemostas. 1995;21:161–165
  82. Burns ER, Zucker-Franklin D. Pathological effects of plasma from patients with thrombotic thrombocytopenic purpura on platelets and cultured vascular endothelial cells. Blood. 1982;60:1030–1037
  83. Welborn JL, Emrick P, Acevedo M. Rapid improvement of thrombotic thrombocytopenic purpura with vincristine and plasmapheresis. Am J Haem. 1990;35:18–21
  84. Bobbio-Pallavicini E, Porta C, Centurioni R, Gugliotta L, Vianelli N, Tacconi F, et al. Vincristine sulfate for the treatment of thrombotic thrombocytopenic purpura refractory to plasma exchange. The Italian Cooperative group for TTP. Eur J Haem. 1994;52:222–226
  85. Mazzel C, Pepkowitz S, Klapper E, Goldfinger D. Treatment of thrombotic thrombocytopenic purpura: a role for early vincristine administration. J Clin Apheresis. 1998;13:20–22
  86. Pasquale D, Vidhya R, DaSilva K, Tsan MF, Lansing L, Chikkappa G. Chronic relapsing thrombotic thrombocytopenic purpura: role of therapy with cyclosporine. Am J Haem. 1998;57:57–61
  87. Hand JP, Lawlor ER, Yong CKK, Davis JH. Successful use of cyclosporin A in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haem. 1998;100:597–599
  88. Pescador R, Porta R, Ferro L. An integrated view of the activities of defibrotide. Semin Thromb Haemost. 1996;22(Suppl 1):71–75
  89. Bianchi G, Barone D, Lanzarotti E, Tettamonti R, Porta R, Moltrasio D, et al. Defibrotide, a single stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993;238:327–334
  90. Pasini FL, Frigerio C, Copecchi PL, Ceccatelli L, Messa GL, Franchi M, et al. Modulation of venous endothelial activity and transcellular calcium transport by defibrotide: the adenosine hypothesis. Semin Thromb Haemost. 1996;22(Suppl 1):15–20
  91. Ulutin ON, Balkur-Ulutin S, Bezer-Goker B, Cizmeci G, Ferhanoglu B, Czsoy Y, et al. Effect of defibrotide on plateket function. Semin Thromb Haemost. 1996;22(Suppl 1):21–24
  92. Remuzzi G, Marchesi D, Mecca G, Misiani R, Livio M, Gaetano G, et al. Haemolytic uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity. Lancet. 1978;2:871–872
  93. Pogliani EM, Perseghin P, Parma M, Pioltelli P, Carneo G. Defibrotide in recurrent thrombotic thrombocytopenic purpura. Clin Appl Thromb Haemost. 2000;6:69–70
  94. Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, et al. Defibrotide as a growing treatment for thrombotic thrombocytopenic purpura in patients undergoing BMT. Bone Marrow Transplantation. 2002;29(6):542–543
  95. Perotti C, Torretta L, Castamagna L, Salvaneschi L. Thrombotic thrombocytopenic purpura after defibrotide therapy. Haematologica. 1994;79:569
  96. Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med. 1995;122:569–572
  97. Winslow GA, Nelson EW. Thrombotic thrombocytopenic purpura: indications for and results of splenectomy. Am J Surgery. 1995;170:558–561
  98. Crowther MA, Heddle N, Hayward CP, Warkentin T, Kelton JG. Splenectomy done during haematological remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Intern Med. 1996;125:294–296
  99. Bobbio-Pallavicini E, Gugliotta L, Centurioni R, Porta C, Vianelli N, Billio A, et al. Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP. Haematologica. 1997;82:429–435
  100. Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood. 2001;98:1765–1772
  101. Patton JF, Manning KR, Case D, Owen J. Serum lactate dehydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura. Am J Haem. 1994;47:94–99
  102. Blitzer JB, Granfortuna JM, Gottlieb AJ, Smith JR, Theodorakis ME, Zamkoff KW, et al. Thrombotic thrombocytopenic purpura: treatment with plasmapheresis. Am J Haem. 1987;24:329–339

PII: S0268-960X(05)00019-6

doi: 10.1016/j.blre.2005.02.001

Blood Reviews
Volume 20, Issue 1 , Pages 51-60 , January 2006