Skip to main content

Advertisement

SpringerLink
Log in

Thrombotic thrombocytopenic purpura: recognition and management

  • Progress in Hematology
  • Recent advance in thrombotic thrombocytopenic purpura
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Thrombotic thrombocytopenic purpura is a life-threatening multisystem disorder that represents both a diagnostic and a management challenge to clinicians. Early recognition of the condition coupled with rapid institution of plasma exchange has led to a dramatic improvement in prognosis. Studies performed over the past decade have elucidated the predominant pathophysiology, stemming from a deficiency of ADAMTS13, that accounts for the widespread microvascular deposition of platelet–von Willebrand factor in many sites, including the brain, kidney, and mesenteric vessels. However, in light of the mortality rate of 10–20%, much work remains to be done to translate advances in our understanding of pathophysiology into clinical practice. Improvements in medical management using immunosuppressive and other drugs are being actively explored in clinical trials. Agents that target ADAMTS13 autoantibody production by B-cells, such as anti-CD20 monoclonal antibodies, have the potential to shorten the duration of plasma exchange treatment, reduce relapses, and transform the management of this once enigmatic disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Vesely SK, George JN, Lammle B, Studt JD, Alberio L, El-Harake MA, 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(1):60–8.

    Article  CAS  PubMed  Google Scholar 

  2. George JN, Terrell DR, Swisher KK, Vesely SK. Lessons learned from the Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome registry. J Clin Apher. 2008;23:129–37.

    Article  PubMed  Google Scholar 

  3. Coppo P, Veyradier A. Thrombotic microangiopathies: towards a pathophysiology-based classification. Cardiovasc Haematol Disord Drug Targ. 2009;9:36–50.

    Article  CAS  Google Scholar 

  4. Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haem. 2008;142:819–26.

    Article  Google Scholar 

  5. Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y, Wada H, et al. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol. 2004;41(1):68–74.

    Article  PubMed  Google Scholar 

  6. Antoine G, Zimmermann K, Plaimauer B, Grillowitzer M, Studt J, Lämmle 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 Haem. 2003;120:821–4.

    Article  CAS  Google Scholar 

  7. Scheiflinger F, Knöbl P, Trattner B, Plaimauer B, Mohr G, Dockal M, et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS13) in a patient with thrombotic thrombocytopenic purpura. Blood. 2003;102:3241–3.

    Article  CAS  PubMed  Google Scholar 

  8. Rieger M, Mannucci PM, Hovinga JAK, Herzog A, Gerstenbauer G, Konetschny C, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005;106:1262–7.

    Article  CAS  PubMed  Google Scholar 

  9. Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003;14(4):1072–81.

    Article  PubMed  Google Scholar 

  10. Karpac CA, Li X, Terrell DR, Kremer Hovinga JA, Lämmle B, Vesely SK, et al. Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison. Br J Haem. 2008;141:696–707.

    Article  Google Scholar 

  11. Allford S, Hunt BJ, Rose P, Machinet SJ, On Behalf of the Haemostasis and Thrombosis Task Force of the British Committee For Standards In Hematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anemias. Br J Haem. 2003;120:556–73.

    Article  Google Scholar 

  12. Melnyk AMS, Solez K, Kjellstrand CM. Adult hemolytic-uremic syndrome. Arch Intern Med. 1995;155:2077–84.

    Article  CAS  PubMed  Google Scholar 

  13. Zakarija A, Bennett C. Drug-induced thrombotic microangiopathy. Semin Thromb Hemost. 2005;31(6):681–90.

    Article  CAS  PubMed  Google Scholar 

  14. Bennett CL, Kim B, Zakarija A, Bandarenko N, Pandey DK, Buffie CG, et al. Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol. 2007;50:1138–43.

    Article  CAS  PubMed  Google Scholar 

  15. Kojouri K, Vesely SK, George JN. Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes. Ann Intern Med. 2001;135:1047–51.

    CAS  PubMed  Google Scholar 

  16. Park YA, Hay SN, King KE, Matevosyan K, Poisson J, Powers A, et al. Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy. J Clin Apher. 2009;24(3):115–9.

    Article  PubMed  Google Scholar 

  17. Uchida T, Wada H, Mizutani M, Iwashita M, Ishihara H, Shibano T, et al. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood. 2004;104:2081–3.

    Article  CAS  PubMed  Google Scholar 

  18. Becker S, Fusco G, Fusco J, Balu R, Gangjee S, Brennan C, et al. HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: an observational study. Clin Infect Dis. 2004;39(Suppl 5):S267–75.

    Article  PubMed  Google Scholar 

  19. Gruszecki AC, Wehrli G, Ragland BD, Reddy VVB, Nabell L, Garcia-Hernandez A, et al. Management of a patient with HIV infection-induced anemia and thrombocytopenia who presented with thrombotic thrombocytopenic purpura. Am J Hematol. 2002;69:228–31.

    Article  PubMed  Google Scholar 

  20. Novitsky N, Thomson J, Abraham L, du Toit C, McDonald A. TTP in patients with retroviral infection is highly responsive to plasma infusion therapy. Br J Haematol. 2005;128:373–9.

    Article  Google Scholar 

  21. Francis KK, Kalyanam N, Terrell DR, Vesely SK. Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases. Oncologist. 2007;12:11–9.

    Article  PubMed  Google Scholar 

  22. Oberic L, Buffet M, Schwarzinger M, Veyradier A, Clabault K, Malot S, et al. Cancer awareness in atypical thrombotic microangiopathies. Oncologist. 2009;14:769–79.

    Article  PubMed  Google Scholar 

  23. Qu L, Kiss JE. Thrombotic microangiopathy in transplantation and malignancy. Semin Thromb Hemost. 2005;31:691–9.

    Article  PubMed  Google Scholar 

  24. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:571–5.

    Article  PubMed  Google Scholar 

  25. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112:11–8.

    Article  CAS  PubMed  Google Scholar 

  26. Mannucci PM, Peyvandi F. TTP and ADAMTS13: when is testing appropriate? Hematology. 2007;121–6.

  27. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004;103(11):4043–9.

    Article  CAS  PubMed  Google Scholar 

  28. Mori Y, Wada H, Gabazza EC, Minami N, Nobori T, Shiku H, et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity. Transfusion. 2002;42:572–80.

    Article  CAS  PubMed  Google Scholar 

  29. Böhm M, Betz C, Miesbach W, Krause M, Auer C, Geiger H, et al. The course of ADAMTS13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haem. 2005;129:644–52.

    Article  CAS  Google Scholar 

  30. Raife T, Atkinson B, Montgomery R, Vesely S, Friedman K, et al. Severe deficiency of vWF-cleaving protease (ADAMTS13) activity defines a distinct population of thrombotic microangiopathy patients. Transfusion. 2004;44:146–50.

    Article  CAS  PubMed  Google Scholar 

  31. Peyvandi F, Lavoretano S, Palla R, Feys HB, Vanhoorelbeke K, Battaglioli T, et al. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematology. 2008;93:232–9.

    Article  CAS  Google Scholar 

  32. Ferrari S, Scheiflinger F, Rieger M, Mudde G, Wolf M, Coppo P, et al. Prognostic value of anti-ADAMTS13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS13 activity. Blood. 2007;109(7):2815–22.

    CAS  PubMed  Google Scholar 

  33. Coppo P, Wolf M, Veyradier A, Bussel S, Malot GA, Millot C, et al. Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura. Br J Haem. 2005;132:66–74.

    Article  CAS  Google Scholar 

  34. Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, et al. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies. Thromb Haemost. 2009;101:233–8.

    CAS  PubMed  Google Scholar 

  35. Rock GA, Shuman KH, Buskard N, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991;325:393–7.

    CAS  PubMed  Google Scholar 

  36. Henon P. Treatment of thrombotic thrombopenic purpura. Results of a multicenter randomized clinical study. Presse Med. 1991;20:1761–7.

    CAS  PubMed  Google Scholar 

  37. Scott EA, Puca KE, Pietz BC, Duchateau BK, Friedman KD. Comparison and stability of ADAMTS13 activity in therapeutic plasma products. Transfusion. 2007;47:120–5.

    Article  CAS  PubMed  Google Scholar 

  38. Fontana S, Kremer Hovinga JA, Lämmle B, Taleghani BM. Treatment of thrombotic thrombocytopenic purpura. Vox Sang. 2006;90:245–54.

    Article  CAS  PubMed  Google Scholar 

  39. Hay SN, Egan JA, Millward PA, Bandarenko N, Brecher ME. Patterns of platelet response in idiopathic TTP/HUS: frequency of declining platelet counts with plasma exchange and the recognition and significance of a pseudo refractory state. Ther Apher Dial. 2006;10(3):237–41.

    Article  PubMed  Google Scholar 

  40. Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apher. 1998;13:16–9.

    Article  CAS  PubMed  Google Scholar 

  41. Egan JA, Hay SN, Brecher ME. Frequency and significance of shistocytes in TTP/HUS patients at the discontinuation of plasma exchange therapy. J Clin Apher. 2004;19(4):165–7.

    Article  PubMed  Google Scholar 

  42. Bandarenko N, Members of the US TTP Apheresis Study Group. United States thrombotic thrombocytopenic purpura apheresis study group (US TTP ASG): multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange. J Clin Apher. 1998;13:133–41.

    Article  CAS  PubMed  Google Scholar 

  43. Rose M, Eldor A. High incidence of relapses in thrombotic thrombocytopenic purpura. Clinical Study of 38 subjects. Am J Med. 1987;83:437–44.

    Article  CAS  PubMed  Google Scholar 

  44. Onundarson PT, Rowe JM, Heal JM, Francis CW. Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. Ann Intern Med. 1992;152:791–6.

    Article  CAS  Google Scholar 

  45. Nguyen L, Terrell DR, Duvall D, Vesely SK, George JN. Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. Transfusion. 2009;49: 392–4 (Letters To The Editor).

    Google Scholar 

  46. Bell WR, Braine JJ, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med. 1991;325:398–403.

    Article  CAS  PubMed  Google Scholar 

  47. Ziman A, Mitri M, Klapper E, Pepkowitz SH, Goldfinger D. Combination vincristine and plasma exchange as initial therapy in subjects with thrombotic thrombocytopenic purpura: one institutions’ experience and review of the literature. Transfusion. 2005;45:41–9.

    Article  CAS  PubMed  Google Scholar 

  48. George JN. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927–35.

    Article  CAS  PubMed  Google Scholar 

  49. Ferrara F, Copia C, Annunziata M, Spasiano A, Di Grazia C, Palmieri S, et al. Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura. Ann Hematol. 1999;78:521–3.

    Article  CAS  PubMed  Google Scholar 

  50. Crowther MA, Heddle N, Hayward CP, Warkentin T, Kelton JG. Splenectomy done during hematologic remission to prevent relapse in subjects with thrombotic thrombocytopenic purpura. Ann Intern Med. 1996;125:294–6.

    CAS  PubMed  Google Scholar 

  51. Cataland SR, Jin M, Ferketich AK, et al. An evaluation of cyclosporine and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura. Br J Haematol. 2006;132:146–9.

    Google Scholar 

  52. Cataland SR, Jin M, Zheng XL, George JN, Wu HM. An evaluation of cyclosporine alone for the treatment of early recurrences of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2006;4:1162–4.

    Article  CAS  PubMed  Google Scholar 

  53. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98:952–7.

    Article  CAS  PubMed  Google Scholar 

  54. Edwards JCW, Szczepanski L, Szechinski JD, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in subjects with rheumatoid arthritis. N Engl J Med. 2004;350:2572–81.

    Article  CAS  PubMed  Google Scholar 

  55. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood. 2004;104(9):2635–42.

    Article  CAS  PubMed  Google Scholar 

  56. Gutterman LA, Kloster B, Tsai HM. Rituximab therapy for refractory thrombotic thrombocytopenic purpura. Blood Cells Mol Dis. 2002;28:385–91.

    Article  PubMed  Google Scholar 

  57. Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai HM. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. Br J Haematol. 2004;124:787–95.

    Article  PubMed  Google Scholar 

  58. Millward PM, Bandarenko N, Chang PP, Stagg KF, Afenyi-Annan A, Brecher ME. Cardiogenic shock complicates successful treatment of refractory TTP with rituximab. Transfusion. 2005;45(9):1481–6.

    Article  CAS  PubMed  Google Scholar 

  59. Fakhouri F, Vernant JP, Veyradier A, Wolf M, Kaplanski G, Binaut R, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood. 2005;106:1932–7.

    Article  CAS  PubMed  Google Scholar 

  60. Tsai HM, Shulman K. Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura. Eur J Haematol. 2003;70:183–5.

    Article  PubMed  Google Scholar 

  61. Foley SR, Webert K, Arnold DM, Rock GA, Clark WF, Barth D, et al. A Canadian phase II study evaluating the efficacy of rituximab in the management of patients with relapsed/refractory thrombotic thrombocytopenic purpura. Kidney Int. 2009;75(Suppl 112):555–8.

    Google Scholar 

  62. George JN, Woodson RD, Kiss JE, Kojouri K, Vesely SK. Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the transfusion medicine/hemostasis clinical trials network with a systematic review of rituximab therapy for immune-mediated disorders. J Clin Apher. 2006;21:49–56.

    Article  PubMed  Google Scholar 

  63. Furlan M, Robles R, Galbursera M, Remuzzi G, Kyrle PA, Brenner B, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Eng J Med. 1998;339(22):1578–84.

    Article  CAS  Google Scholar 

  64. Tsai HM, Lian ECY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Eng J Med. 1998;339(22):1585–94.

    Article  CAS  Google Scholar 

  65. Veyradier A, Brivet F, Wolf M, Boyer-Neumann C, Obert B, Girma JP, et at. Total deficiency of specific von Willebrand factor-cleaving protease and recovery following plasma therapy in one patient with hemolytic-uremic syndrome. Hematol J. 2001;2(3):180–7.

    Article  PubMed  CAS  Google Scholar 

  66. 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(6):1765–72.

    Article  CAS  PubMed  Google Scholar 

  67. Peyvandi F, Ferrari S, Lavoretano S, Canciani MT, Mannucci PM. von Willebrand factor cleaving protease (ADAMTS13) and ADAMTS13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2004;12(11):891–8.

    Google Scholar 

  68. Coppo P, Bengoufa D, Veyradier A, Wolf M, Bussel A, Millot GA, et al. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. Medicine. 2004;83(4):233–44.

    Article  CAS  PubMed  Google Scholar 

  69. Bobbio-Pallavincini 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(4):429–35.

    Google Scholar 

  70. Zeigler ZR, Shadduck RK, Gryn JF, Rintels PB, George JN, Bessa EC, et al. Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP). J Clin Apher. 2001;16(1):19–22.

    Article  Google Scholar 

  71. Rock G. The management of thrombotic thrombocytopenic purpura in 2005. Sem Thromb Hemostasis. 2005;31(6):709–16.

    Article  Google Scholar 

  72. Mintz PD, Neff A, MacKenzie M, Goodnough LT, Hillyer C, Kessler C, et al. A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura. Transfusion. 2006;46(10):1659–62.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, 3636 Blvd. of the Allies, Pittsburgh, PA, 15213, USA

    Joseph E. Kiss

  2. Therapeutic Hemapheresis and Blood Services, The Institute for Transfusion Medicine, Pittsburgh, PA, USA

    Joseph E. Kiss

Authors
  1. Joseph E. Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph E. Kiss.

About this article

Cite this article

Kiss, J.E. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol 91, 36–45 (2010). https://doi.org/10.1007/s12185-009-0478-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-009-0478-z

Keywords

Search

Navigation