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Semin Thromb Hemost 2005; 31(6): 700-708
DOI: 10.1055/s-2005-925476
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Relapse of Thrombotic Thrombocytopenic Purpura: Is It a Continuum of Disease?

Monte S. Willis1 , Nicholas Bandarenko1 , 2
  • 1University of North Carolina, Department of Pathology & Laboratory Medicine, Chapel Hill, North Carolina
  • 2Associate Professor, Department of Pathology & Laboratory Medicine, Chapel Hill, North Carolina
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Publication History

Publication Date:
30 December 2005 (online)

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ABSTRACT

The recurrence of thrombotic thrombocytopenic purpura (TTP) in 20 to 50% of patients who survive their initial episode, is not only a challenge to manage clinically, but brings to light our lack of understanding of the underlying pathophysiology. Recurrence may occur close to apparent hematologic remission or remotely, months later. Given that surveillance of TTP relies on surrogate measures such as hematologic recovery, normalization of serum lactate dehydrogenase (LDH) and resolution of clinical signs, it is plausible that some recurrences are actually a continuum of disease. Standardizing definitions for remission, exacerbation, and relapse are important for consistency of patient management and interpreting the medical literature. When TTP recurs, several adjuncts to therapeutic plasma exchange (TPE) have been used, including splenectomy, vincristine, and rituximab. Although it would seem intuitive that more severe disease would predict a greater likelihood of relapse, the degree of thrombocytopenia at presentation, the persistence of schistocytosis at discontinuation of TPE, the elevation of LDH, and the length of time to attain clinical remission are not reliable indicators of the clinical outcome of any individual TTP patient. Measurement of ADAMTS13 activity and its inhibitor offer new promise for prognostic and pathophysiologic significance; however, more extensive scientific investigation is needed.

KEYWORDS

Thrombotic thrombocytopenic purpura (TTP) - prognostic factors - relapse - adjunct therapy

REFERENCES

  • 1 Sadler J E, Moake J L, Miyata T, George J N. Recent advances in thrombotic thrombocytopenic purpura.  Hematology (Am Soc Hematol Educ Program). 2004;  1 407-423
    PubMedGoogle Scholar
  • 2 George J N. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.  Blood. 2000;  96 1223-1229
    PubMedGoogle Scholar
  • 3 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
  • 4 Bandarenko N, Brecher M E. 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 Apheresis. 1998;  13 133-141
    CrossrefPubMedGoogle Scholar
  • 5 Egan J A, Hay S N, Brecher M E. Frequency and significance of schistocytes in TTP/HUS patients at the discontinuation of plasma exchange therapy.  J Clin Apheresis. 2004;  19 165-167
    CrossrefPubMedGoogle Scholar
  • 6 Committee AET .Guidelines for Therapeutic Hemapheresis. Bethesda, MD; American Association of Blood Banks 1993
    Google Scholar
  • 7 Gilcher R O, Strauss R G, Ciavarella D et al.. Management of renal disorders.  J Clin Apheresis. 1993;  8 258-269
    PubMedGoogle Scholar
  • 8 Downes K A, Yomtovian R, Tsai H M, Silver B, Rutherford C, Sarode R. Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident.  J Clin Apheresis. 2004;  19 86-89
    CrossrefPubMedGoogle Scholar
  • 9 Furlan M, Robles R, Morselli B, Sandoz P, Lammle B. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura.  Thromb Haemost. 1999;  81 8-13
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Zheng X L, Kaufman R M, Goodnough L T, Sadler J E. 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 4043-4049
    CrossrefPubMedGoogle Scholar
  • 11 Rock G, Anderson D, Clark W et al.. Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet.  Br J Haematol. 2005;  129 79-86
    CrossrefPubMedGoogle Scholar
  • 12 Rock G. Thrombotic thrombocytopenic purpura: Current therapies and diagnostic tools.  J Clin Apheresis. 2005;  20 9 , (abst)
    PubMedGoogle Scholar
  • 13 George J N, Vesely S K, Terrell D R. The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS.  Semin Hematol. 2004;  41 60-67
    CrossrefPubMedGoogle Scholar
  • 14 Rock G, Shumak K H, Sutton D M, Buskard N A, Nair R C. Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Members of the Canadian Apheresis Group.  Br J Haematol. 1996;  94 383-386
    CrossrefPubMedGoogle Scholar
  • 15 Lakey M A, Boctor F N, Knight C W, Marques M B. VWF-cleaving protease activity and inhibitor levels do not predict duration of treatment in TTP and HUS.  J Clin Apheresis. 2005;  20 7 , (abst)
    PubMedGoogle Scholar
  • 16 Egan J A, Hay S N, Millward P A, Bandarenko N, Brecher M E. Effect of discontinuation of plasma exchange in pseudo-refractory thrombotic thrombocytopenic purpura patients.  J Clin Apheresis. 2005;  20 8 , (abst)
    PubMedGoogle Scholar
  • 17 Hay S H, Egan J A, Millward P A. Declining platelet counts in TTP patients receiving daily plasma exchange: frequency and Outcome.  J Clin Apheresis. 2005;  20 10 , (abst)
    PubMedGoogle Scholar
  • 18 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
  • 19 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
  • 20 Reutter J C, Sanders K F, Brecher M E, Jones H G, Bandarenko N. Incidence of allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of thrombotic thrombocytopenic purpura.  J Clin Apheresis. 2001;  16 134-138
    CrossrefPubMedGoogle Scholar
  • 21 Mokrzycki M H, Kaplan A A. Therapeutic plasma exchange: complications and management.  Am J Kidney Dis. 1994;  23 817-827
    PubMedGoogle Scholar
  • 22 Sutton D M, Nair R C, Rock G. Complications of plasma exchange.  Transfusion. 1989;  29 124-127
    CrossrefPubMedGoogle Scholar
  • 23 McLeod B C, Sniecinski I, Ciavarella D et al.. Frequency of immediate adverse effects associated with therapeutic apheresis.  Transfusion. 1999;  39 282-288
    CrossrefPubMedGoogle Scholar
  • 24 Schneider P A, Rayner A A, Linker C A, Schuman M A, Liu E T, Hohn D C. The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura.  Ann Surg. 1985;  202 318-322
    PubMedGoogle Scholar
  • 25 Veltman G A, Brand A, Leeksma O C, ten Bosch G J, van Krieken J H, Briet E. The role of splenectomy in the treatment of relapsing thrombotic thrombocytopenic purpura.  Ann Hematol. 1995;  70 231-236
    PubMedGoogle Scholar
  • 26 Winslow G A, Nelson E W. Thrombotic thrombocytopenic purpura: indications for and results of splenectomy.  Am J Surg. 1995;  170 558-561
    CrossrefPubMedGoogle Scholar
  • 27 Aqui N A, Stein S H, Konkle B A, Abrams C S, Strobl F J. Role of splenectomy in patients with refractory or relapsed thrombotic thrombocytopenic purpura.  J Clin Apheresis. 2003;  18 51-54
    CrossrefPubMedGoogle Scholar
  • 28 Islam M N, Iskander M N. Microtubulin binding sites as target for developing anticancer agents.  Mini Rev Med Chem. 2004;  4 1077-1104
    PubMedGoogle 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 Gutterman L A. Treatment of TTP and HUS: the role of vincristine. In: Kaplan BS, Trompeter RS, Moake JL Hemolyic Uremic Syndrome and Thrombotic Thrombocytopenic Purpua. New York; Dekker 1992: 513-530
    Google Scholar
  • 31 [No author] . Treatment for thrombotic thrombocytopenic purpura: plasma, vincristine, hemodialysis and exchange transfusions.  N Engl J Med. 1978;  298 971-972
    PubMedGoogle Scholar
  • 32 Ziman A, Mitri M, Klapper E, Pepkowitz S H, Goldfinger D. Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution's experience and review of the literature.  Transfusion. 2005;  45 41-49
    CrossrefPubMedGoogle Scholar
  • 33 Dervenoulas J, Tsirigotis P, Bollas G et al.. Efficacy of intravenous immunoglobulin in the treatment of thrombotic thrombocytopaenic purpura. A study of 44 cases.  Acta Haematol. 2001;  105 204-208
    CrossrefPubMedGoogle Scholar
  • 34 Castaman G, Rodeghiero F, Ruggeri M, di Bona E, Dini E. Long-lasting remission after high-dose intravenous immunoglobulins in a case of relapsing thrombotic thrombocytopenic purpura.  Haematologica. 1991;  76 511-512
    PubMedGoogle Scholar
  • 35 Kondo H, Imamura T. Effects of intravenous immunoglobulin in a patient with intermittent thrombotic thrombocytopenic purpura.  Br J Haematol. 2000;  108 880-882
    CrossrefPubMedGoogle Scholar
  • 36 Chambers S A, Isenberg D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases.  Lupus. 2005;  14 210-214
    CrossrefPubMedGoogle Scholar
  • 37 Fakhouri F, Teixeira L, Delarue R, Grunfeld J P, Veyradier A. Responsiveness of thrombotic thrombocytopenic purpura to rituximab and cyclophosphamide.  Ann Intern Med. 2004;  140 314-315
    PubMedGoogle Scholar
  • 38 Fakhouri F, Vernant J P, Veyradier A et al.. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13 deficient-thrombotic thrombocytopenic purpura: a study of 11 cases.  Blood. 2005;  106 1932-1937
    CrossrefPubMedGoogle Scholar
  • 39 Chemnitz J, Draube A, Scheid C et al.. Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab.  Am J Hematol. 2002;  71 105-108
    CrossrefPubMedGoogle Scholar
  • 40 Maloney D G. Concepts in radiotherapy and immunotherapy: anti-CD20 mechanisms of action and targets.  Semin Oncol. 2005;  32(1 suppl 1) S19-S26
    CrossrefPubMedGoogle Scholar
  • 41 Ahmad A, Aggarwal A, Sharma D et al.. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP).  Am J Hematol. 2004;  77 171-176
    CrossrefPubMedGoogle Scholar
  • 42 Gutterman L A, Kloster B, Tsai H M. Rituximab therapy for refractory thrombotic thrombocytopenic purpura.  Blood Cells Mol Dis. 2002;  28 385-391
    CrossrefPubMedGoogle Scholar
  • 43 Reddy P S, Deauna-Limayo D, Cook J D et al.. Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura.  Ann Hematol. 2005;  84 232-235
    CrossrefPubMedGoogle Scholar
  • 44 Sallah S, Husain A, Wan J Y, Nguyen N P. Rituximab in patients with refractory thrombotic thrombocytopenic purpura.  J Thromb Haemost. 2004;  2 834-836
    CrossrefPubMedGoogle Scholar
  • 45 Stein G Y, Zeidman A, Fradin Z, Varon M, Cohen A, Mittelman M. Treatment of resistant thrombotic thrombocytopenic purpura with rituximab and cyclophosphamide.  Int J Hematol. 2004;  80 94-96
    PubMedGoogle Scholar
  • 46 Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai H M. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature.  Br J Haematol. 2004;  124 787-795
    CrossrefPubMedGoogle Scholar
  • 47 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
  • 48 Galbusera M, Bresin E, Noris M et al.. Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report.  Blood. 2005;  106 925-928
    CrossrefPubMedGoogle Scholar
  • 49 Bandarenko N, Stagg K F, Hay S N, Brecher M E. Cardiogenic shock complicates successful treatment of refractory TTP with rituximab.  Transfusion. 2004;  4(9S) 44A , (abst)
    PubMedGoogle Scholar
  • 50 Silverman G J, Goodyear C S, Siegel D L. On the mechanism of staphylococcal protein A immunomodulation.  Transfusion. 2005;  45 274-280
    CrossrefPubMedGoogle Scholar
  • 51 Nand S, Molokie R. Therapeutic plasmapheresis and protein A immunoadsorption in malignancy: a brief review.  J Clin Apheresis. 1990;  5 206-212
    PubMedGoogle Scholar
  • 52 Gaddis T G, Guthrie Jr T H, Drew M J, Sahud M, Howe R B, Mittelman A. Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption.  Am J Hematol. 1997;  55 55-58
    CrossrefPubMedGoogle Scholar
  • 53 Drew M J. Resolution of refractory, classic thrombotic thrombocytopenic purpura after staphylococcal protein A immunoadsorption.  Transfusion. 1994;  34 536-538
    CrossrefPubMedGoogle Scholar
  • 54 Musio F, Bohen E M, Yuan C M, Welch P G. Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus.  Semin Arthritis Rheum. 1998;  28 1-19
    CrossrefPubMedGoogle Scholar
  • 55 Creager A J, Brecher M E, Bandarenko N. Thrombotic thrombocytopenic purpura that is refractory to therapeutic plasma exchange in two patients with occult infection.  Transfusion. 1998;  38 419-423
    CrossrefPubMedGoogle Scholar
  • 56 Tarantolo S R, Landmark J D, Iwen P C, Kessinger A, Chan W C, Hinrichs S H. Bartonella-like erythrocyte inclusions in thrombotic thrombocytopenic purpura.  Lancet. 1997;  350 1602
    CrossrefPubMedGoogle Scholar
  • 57 Vesely S K, Li X, McMinn J R, Terrell D R, George J N. Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.  Transfusion. 2004;  44 1149-1158
    PubMedGoogle Scholar
  • 58 Kojouri K, Vesely S K, George J N. Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes.  Ann Intern Med. 2001;  135 1047-1051
    CrossrefPubMedGoogle Scholar
  • 59 Bennett C L, Davidson C J, Raisch D W, Weinberg P D, Bennett R H, Feldman M D. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention.  Arch Intern Med. 1999;  159 2524-2528
    CrossrefPubMedGoogle Scholar
  • 60 Zakarija A, Bandarenko N, Pandey D K et al.. Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration.  Stroke. 2004;  35 533-537
    CrossrefPubMedGoogle Scholar
  • 61 Dlott J S, Danielson C F, Blue-Hnidy D E, McCarthy L J. Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a concise review.  Ther Apher Dial. 2004;  8 102-111
    CrossrefPubMedGoogle Scholar
  • 62 Egan J A, Bandarenko N, Hay S N et al.. Differentiating thrombotic microangiopathies induced by severe hypertension from anemia and thrombocytopenia seen in thrombotic thrombocytopenia purpura.  J Clin Apheresis. 2004;  19 125-129
    CrossrefPubMedGoogle Scholar
  • 63 Vesely S K, George J N, Lammle 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
  • 64 Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.  Best Pract Res Clin Haematol. 2001;  14 437-454
    CrossrefPubMedGoogle Scholar

Nicholas BandarenkoM.D. 

University of North Carolina Hospitals, Transfusion Medicine Service

1021 East Wing Campus Box #7600, 101 Manning Drive, Chapel Hill, NC 27514

Email: nbandare@unch.unc.edu