Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in 2014—Current Knowledge and Outcomes with Plasma Exchange

Oncology & Hematology Review, 2014;10(2):82–9

Abstract:

Great progress has been made in our understanding of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome since Moschowitz first described this entity in 1925. This review provides a contemporary insight into the pathophysiology, diagnosis, and classification of these disorders in both adults and children. Lessons learned from major worldwide registry data and disease epidemics, including the 2011 German outbreak, are discussed with recommendations for management of specific clinical conditions based on available evidence, including the role of plasma exchange, rituximab, and eculizumab.

Keywords: Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical, diarrhea, idiopathic, secondary, ADAMTS-13, plasma exchange, plasma infusion, epidemic, rituximab, eculizumab
Disclosure: Myriam Farah, MD, FRCPC, Ainslie M Hildebrand, MD, FRCPC, Susan Huang, MD, FRCPC, Hassnah Dammas, MD, and William F Clark, MD, FRCPC, have no conflicts of interest to declare. No funding was received in the publication of this article.
Received: May 03, 2014 Accepted June 18, 2014 Citation Oncology & Hematology Review, 2014;10(2):82–9
Correspondence: William F Clark, MD, FRCPC, London Health Sciences Centre, A2-343, 800 Commissioners Road East, London, ON N6A 5W9, Canada. E: william.clark@lhsc.on.ca

Classification
The two basic forms of thrombotic microangiopathies, excluding disseminated intravascular coagulation (DIC), include thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS). Early historic reports noted the presence of hemolytic anemia and thrombocytopenia in both disorders and suggested differentiation of these two entities based on the presence of clinical symptoms. Predominant kidney failure, often seen in children with preceding diarrheal illness, led to the clinical diagnosis of HUS, while fever, neurologic changes, and kidney failure suggested TTP.1–3

This classification scheme has been challenged by several main observations. First, the classic triad of HUS (thrombocytopenia, hemolytic anemia, and renal failure) or pentad of TTP (thrombocytopenia, hemolytic anemia, neurologic signs, renal failure, and fever) is rarely complete at presentation and often in the case of TTP only at or near autopsy.4 Second, a significant number of TTP patients are afflicted with severe kidney failure and a preceding diarrheal illness, and neurologic symptoms are commonly reported in both TTP and HUS.5–8 Third, and most importantly, treatment with plasma exchange has dramatically reduced the mortality rate in TTP from nearly 90 % to approximately 20 %, thereby making urgent diagnosis and treatment of TTP a life-saving priority. Misclassification of a patient based on presenting clinical symptoms could have fatal consequences.

Current nomenclature has evolved to classify all adult patients who present with the dyad of unexplained thrombocytopenia and microangiopathic anemia with normal international normalized ratio (INR), partial thromboplastin time (PTT), and D-dimers as TTP-HUS. Within this category, both a primary form (either idiopathic/acquired or hereditary) and a secondary form (due to an identified underlying disorder) exist. Secondary TTP-HUS comprises 50 % of TTP-HUS cases in adults and has been described in eight major conditions as noted in Table 1. Registry data indicate that even when applying the above classification criteria, a small but significant number of patients with secondary TTP or DIC are misclassified as idiopathic TTP at initial resentation.9

The syndrome of HUS is more common in children but is also seen in adults. It comprises a primary/atypical form characterized by abnormal activation of the complement cascade, and a secondary/typical form seen in shiga toxin mediated diarrheal illness (Escherichia coli 0157:H7, E. coli 0104:H4, Shigella). The diagnosis of atypical HUS (aHUS) is usually, but not exclusively, made in childhood in patients with repeated episodes of clinical TTP-HUS and abnormalities in complement regulating genes.

References:
  1. Moschcowitz E, An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries; an undescribed disease, Arch Intern Med, 1925;36:89–93.
  2. Gasser C, Gautier E, Steck A, et al., [Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia], Schweiz Med Wochenschr, 1955;85:905–9.
  3. Amorosi EL, Ultman JE. Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature, Medicine (Baltimore), 1994;45: 139–59.
  4. 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.
  5. Rock G, Kelton JG, Shumak KH, et al., Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group, Br J Haematol, 1998;103:1031–6.
  6. George JN, Vesely SK, Terrell DR, The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS, Semin Hematol, 2004;41:60–7.
  7. Baron JM, Baron BW, Thrombotic thrombocytopenic purpura and its look-alikes, Clin Adv Hematol Oncol, 2005;3:868–74.
  8. Nathanson S, Kwon T, Elmaleh M, et al., Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2010;5:1218–28.
  9. Vesely SK, George JN, 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;102:60–8.
  10. Baehr G, Kelmerer P, Schifrin A, Acute febrile anemia and thrombocytopenic purport with diffuse platelet thrombosis of capillaries and arterioles, Tr A Am Physicians; 1936;51:43.
  11. Harker LA, Slichter SJ, Platelet and fibrinogen consumption in man, N Engl J Med, 1972;287:999–1005.
  12. Moake JL, Rudy CK, Troll JH, et al., Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura, N Engl J Med, 1982;307:1432–5.
  13. Moake JL, Byrnes JJ, Troll JH, et al., Abnormal VIII: von Willebrand factor patterns in the plasma of patients with the hemolyticuremic syndrome, Blood, 1984;64:592–8.
  14. Moake JL, Turner NA, Stathopoulos NA, et al., 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;78:1456–61.
  15. Sadler JE, Biochemistry and genetics of von Willebrand factor, Annu Rev Biochem, 1998;67:395–424.
  16. Arya M, Anvari B, Romo GM, et al., Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers, Blood, 2002;99:3971–7.
  17. Tsai HM, Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion, Blood, 1996;87:4235–44.
  18. Tsai HM, Lian EC, Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, N Engl J Med, 1998;339:1585–94.
  19. Furlan M, Robles R, Lämmle B, Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis, Blood, 1996;87:4223–34.
  20. Furlan M, Robles R, Galbusera M, et al., von Willebrand factorcleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, N Engl J Med, 1998;339:1578–84.
  21. Mori Y, Wada H, Gabazza EC, 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.
  22. Moore JC, Hayward CP, Warkentin TE, Kelton JG, Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders, Blood, 2001;98:1842–6.
  23. Veyradier A, Obert B, Houllier A, et al., Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases, Blood, 2001;98:1765–72.
  24. Rick ME, Moll S, Taylor MA, et al., Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura, Thromb Haemost, 2002;88:598–604.
  25. Bianchi V, Robles R, Alberio L, et al., Von Willebrand factorcleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura, Blood, 2002;100:710–3.
  26. Hovinga JA, Vesely SK, Terrell DR, et al., Survival and relapse in patients with thrombotic thrombocytopenic purpura, Blood, 2010;115:1500–11; quiz 662.
  27. Scully M, Yarranton H, Liesner R, et al., Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features, Br J Haematol, 2008;142:819–26.
  28. Coppo P, Schwarzinger M, Buffet M, et al., Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience, PLoS One, 2010;5:e10208.
  29. Jang MJ, Chong SY, Kim IH, et al., Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience, Int J Hematol, 2011;93:163–9.
  30. Fujimura Y, Matsumoto M, Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998–2008, Intern Med, 2010;49:7–15.
  31. Desch K, Motto D, Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome?, J Am Soc Nephrol, 2007;18:2457–60.
  32. Tarr PI, Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis. Kidney Int Suppl, 2009;S29–32.
  33. Rock GA, Clark WF, Mechanism of microthrombosis in HUS, Kidney Int Suppl, 2009;S15–6.
  34. Nolasco LH, Turner NA, Bernardo A, et al., Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers, Blood, 2005;106:4199–209.
  35. Davis AK, Makar RS, Stowell CP, et al., ADAMTS13 binds to CD36: a potential mechanism for platelet and endothelial localization of ADAMTS13, Transfusion, 2009;49:206–13.
  36. Waters AM, Licht C, aHUS caused by complement dysregulation: new therapies on the horizon, Pediatr Nephrol, 2011;26:41–57.
  37. Noris M, Remuzzi G, Atypical hemolytic-uremic syndrome, N Engl J Med, 2009;361:1676–87.
  38. Orth D, Khan AB, Naim A, et al., Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome, J Immunol, 2009;182:6394–400.
  39. Orth D, Würzner R, Complement in typical hemolytic uremic syndrome, Semin Thromb Hemost, 2010;36:620–4.
  40. Bukowski RM, Hewlett JS, Harris JW, et al., Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura, Semin Hematol, 1976;13:219–32.
  41. Bukowski RM, King JW, Hewlett JS, Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura, Blood, 1977;50:413–7.
  42. Rubinstein MA, Kagan BM, Macgillviray MH, et al., Unusual remission in a case of thrombotic thrombocytopenic purpura syndrome following fresh blood exchange transfusions, Ann Intern Med, 1959;51:1409–19.
  43. Pisciotta AV, Garthwaite T, Darin J, Aster RH, Treatment of thrombotic thrombocytopenic purpura by exchange transfusion, Am J Hematol, 1977;3:73–82.
  44. Byrnes JJ, Khurana M, Treatment of thrombotic thrombocytopenic purpura with plasma, N Engl J Med, 1977;297:1386–9.
  45. Rock GA, Shumak KH, Buskard NA, 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;325:393–7.
  46. Henon P, [Treatment of thrombotic thrombopenic purpura. Results of a multicenter randomized clinical study], Presse Med, 1991;20:1761–7.
  47. Bell WR, Braine HG, 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.
  48. Gurkan E, Baslamisli F, Guvenc B, et al., Thrombotic thrombocytopenic purpura in southern Turkey: a single-center experience of 29 cases, Clin Lab Haematol, 2005;27:121–5.
  49. Shamseddine A, Saliba T, Aoun E, et al., Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center, J Clin Apher, 2004;19:119–24.
  50. Bandarenko N, Brecher ME, 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.
  51. Dervenoulas J, Tsirigotis P, Bollas G, et al., Economopoulos T, et al., Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): treatment outcome, relapses, prognostic factors. A single-center experience of 48 cases, Ann Hematol, 2000;79:66–72.
  52. Forzley BR, Sontrop JM, Macnab JJ, et al., Treating TTP/HUS with plasma exchange: a single centre’s 25-year experience, Br J Haematol, 2008;143:100–6.
  53. Clark WF, Forzley BR, Sontrop JM, et al., TTP/HUS: observational studies generate hypotheses that lead to randomized controlled trials, Kidney Int Suppl, 2009;S50–1.
  54. Brunskill SJ, Tusold A, Benjamin S, et al., A systematic review of randomized controlled trials for plasma exchange in the treatment of thrombotic thrombocytopenic purpura, Transfus Med, 2007;17:17–35.
  55. Balduini CL, Gugliotta L, Luppi M, et al., High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study, Ann Hematol, 2010;89:591–6.
  56. Altuntas F, Aydogdu I, Kabukcu S, et al., Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study, Transfus Apher Sci, 2007;36:57–67.
  57. Toyoshige M, Zaitsu Y, Okafuji K, et al., Successful treatment of thrombotic thrombocytopenic purpura with high-dose corticosteroid, Am J Hematol, 1992;41:69.
  58. Sui T, Yang RC, [Treatment of thrombotic thrombocytopenic purpura with rituximab], Zhonghua Xue Ye Xue Za Zhi, 2011;32:487–8.
  59. Stein GY, Blickstein D, Orlin J, et al., Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura, Isr Med Assoc J, 2011;13:398–401.
  60. Scully M, Cohen H, Cavenagh J, et al., Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13, Br J Haematol, 2007;136:451–61.
  61. Scott SM, Szczepiorkowski ZM, Rituximab for TTP, Am J Hematol, 2005;80:87–8.
  62. Schleinitz N, Ebbo M, Mazodier K, et al., Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor, Am J Hematol, 2007;82:417–8.
  63. Scaramucci L, Niscola P, Palumbo R, et al., Rapid response and sustained remission by rituximab in four cases of plasmaexchange- failed acute thrombotic thrombocytopenic purpura, Int J Hematol, 2009;89:398–9.
  64. Sallah S, Husain A, Wan JY, Nguyen NP, Rituximab in patients with refractory thrombotic thrombocytopenic purpura, J Thromb Haemost, 2004;2:834–6.
  65. Rüfer A, Brodmann D, Gregor M, et al., Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature, Swiss Med Wkly, 2007;137:518–24.
  66. Reddy PS, Deauna-Limayo D, Cook JD, et al., Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura, Ann Hematol, 2005;84:232–5.
  67. Ozdogu H, Boga C, Kizilkilic E, et al., A dramatic response to rituximab in a patient with resistant thrombotic thrombocytopenic purpura (TTP) who developed acute stroke, J Thromb Thrombolysis, 2007;23:147–50.
  68. Niewold TB, Alpert D, Scanzello CR, Paget SA, Rituximab treatment of thrombotic thrombocytopenic purpura in the setting of connective tissue disease, J Rheumatol, 2006;33:1194–6.
  69. Niaz FA, Aleem A, Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus, Saudi J Kidney Dis Transpl, 2010;21:109–12.
  70. Narayanan P, Jayaraman A, Rustagi RS, et al., Rituximab in a child with autoimmune thrombotic thrombocytopenic purpura refractory to plasma exchange, Int J Hematol, 2012;96:122–4.
  71. Montoya RC, Poiesz BJ, Rituximab as prophylaxis in chronic relapsing thrombotic thrombocytopenic purpura: a case report and review of the literature, Blood Coagul Fibrinolysis, 2012;23:338–41.
  72. Lombardi AM, de Marinis GB, Scandellari R, et al., Clinical biological remission induced by rituximab in acute refractory chronic relapsing TTP, Thromb Res, 2010;126:e154–6.
  73. Ling HT, Field JJ, Blinder MA, Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature, Am J Hematol, 2009;84:418–21.
  74. Kuppachi S, Chander P, Yoo J, Membranous nephropathy and thrombotic thrombocytopenic purpura treated with rituximab, J Nephrol, 2009;22:561–4.
  75. Koshino M, Kudou D, Okoshi Y, et al., [Successful treatment with rituximab in a patient with refractory thrombotic thrombocytopenic purpura refractory to plasma exchange], Rinsho Ketsueki, 2010;51:127–31.
  76. Kivity S, Agmon-Levin N, Rituximab for thrombotic thrombocytopenic purpura, Isr Med Assoc J, 2011;13:436–7.
  77. Kameda T, Dobashi H, Kittaka K, et al., Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment, Clin Rheumatol, 2007;26:2159–62.
  78. Jasti S, Coyle T, Gentile T, et al., Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature, J Clin Apher, 2008;23:151–6.
  79. Illner N, Wolf G, [Rituximab as effective therapy in very severe thrombotic thrombocytopenic purpura (TTP)], Dtsch Med Wochenschr, 2010;135:71–4.
  80. Hull MJ, Eichbaum QG, Efficacy of rituximab and concurrent plasma exchange in the treatment of thrombotic thrombocytopenic purpura, Clin Adv Hematol Oncol, 2006;4:210–4; discussion 7–8.
  81. Hong H, Aoyama Y, Yamamura R, et al., [Rituximab provided long-term remission in a patient with severe thrombotic thrombocytopenic purpura refractory to plasma exchange], Rinsho Ketsueki, 2006;47:1528–32.
  82. Herbei L, Venugopal P, Recurrent thrombotic thrombocytopenic purpura treated repeatedly and successfully with the monoclonal antibody rituximab, Clin Adv Hematol Oncol, 2006;4:215–7; discussion 7–8.
  83. Heidel F, Lipka DB, von Auer C, et al., Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia, Thromb Haemost, 2007;97:228–33.
  84. Harambat J, Lamireau D, Delmas Y, et al., Successful treatment with rituximab for acute refractory thrombotic thrombocytopenic purpura related to acquired ADAMTS13 deficiency: a pediatric report and literature review, Pediatr Crit Care Med, 2011;12:e90–3.
  85. Hamasaki Y, Matsuoka A, Waki M, Kawakami K, [Effective treatment with rituximab for primary thrombotic thrombocytopenic purpura complicated with multiple cerebral infarctions], Rinsho Ketsueki, 2012;53:342–6.
  86. Hagel S, Jantsch J, Budde U, et al., Treatment of acquired thrombotic thrombocytopenic purpura (TTP) with plasma infusion plus rituximab, Thromb Haemost, 2008;100:151–3.
  87. Gutterman LA, Kloster B, Tsai HM, Rituximab therapy for refractory thrombotic thrombocytopenic purpura, Blood Cells Mol Dis, 2002;28:385–91.
  88. Gupta D, Roppelt H, Bowers B, et al., Successful remission of thrombotic thrombocytopenic purpura with rituximab in a patient with undifferentiated connective tissue disorder, J Clin Rheumatol, 2008;14:94–6.
  89. George JN, Woodson RD, Kiss JE, et al., 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.
  90. Galbusera M, Bresin E, Noris M, et al., Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report, Blood, 2005;106:925–8.
  91. Foley SR, Webert K, Arnold DM, 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 Suppl, 2009;S55–8.
  92. Ferrer E, Moral MA, Spotlight on rituximab as a new therapeutic option for dermatomyositis and thrombotic thrombocytopenic purpura, Drug News Perspect, 2006;19:482–4.
  93. Fakhouri F, Vernant JP, 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;106:1932–7.
  94. Elliott MA, Heit JA, Pruthi RK, et al., Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature, Eur J Haematol, 2009;83:365–72.
  95. Chow KV, Carroll R, Branley P, et al., Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange, Intern Med J, 2007;37:329–32.
  96. Chemnitz J, Draube A, Scheid C, et al., Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab, Am J Hematol, 2002;71:105–8.
  97. Carella AM, D’Arena G, Greco MM, et al., Rituximab for allo-SCTassociated thrombotic thrombocytopenic purpura, Bone Marrow Transplant, 2008;41:1063-5.
  98. Boctor FN, Smith JA, Timing of plasma exchange and rituximab for the treatment of thrombotic thrombocytopenic purpura, Am J Clin Pathol, 2006;126:965; author reply 6.
  99. Bhagirath VC, Kelton JG, Moore J, Arnold DM, Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura. Transfusion, 2012;52:2517–23.
  100. Benetatos L, Vassou A, Bourantas KL, Effectiveness of rituximab as prophylaxis in thrombotic thrombocytopenic purpura, Clin Lab Haematol, 2006;28:288–9.
  101. Basquiera AL, Damonte JC, Abichaín P, et al., Longterm remission in a patient with refractory thrombotic thrombocytopenic purpura treated with rituximab and plasma exchange, Ann Hematol, 2008;87:321–3.
  102. Ahmad A, Aggarwal A, Sharma D, et al., Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP), Am J Hematol, 2004;77:171–6.
  103. de la Rubia J, Moscardó F, Gómez MJ, et al., Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study, Transfus Apher Sci, 2010;43:299–303.
  104. Froissart A, Buffet M, Veyradier A, et al., Efficacy and safety of firstline rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center, Crit Care Med, 2012;40:104–11.
  105. Bresin E, Gastoldi S, Daina E, 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.
  106. Scully M, McDonald V, Cavenagh J, et al., A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura, Blood, 2011;118:1746–53.
  107. Schneider PA, Rayner AA, Linker CA, et al., The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura, Ann Surg, 1985;202:318–22.
  108. 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 Hematol, 1985;20:161–8.
  109. Höffkes HG, Weber F, Uppenkamp M, et al., Recovery by splenectomy in patients with relapsed thrombotic thrombocytopenic purpura and treatment failure to plasma exchange, Semin Thromb Hemost, 1995;21:161–5.
  110. Watt T, Warshaw B, Katzenstein HM, Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin, Pediatr Blood Cancer, 2009;53:90–1.
  111. Allan DS, Kovacs MJ, Clark WF, Frequently relapsing thrombotic thrombocytopenic purpura treated with cytotoxic immunosuppressive therapy, Haematologica, 2001;86:844–50.
  112. Gutterman LA, Stevenson TD, Treatment of thrombotic thrombocytopenic purpura with vincristine, JAMA, 1982;247:1433–6.
  113. Mazzei C, Pepkowitz S, Klapper E, Goldfinger D, Treatment of thrombotic thrombocytopenic purpura: a role for early vincristine administration, J Clin Apher, 1998;13:20–2.
  114. Akaogi J, Akasaka N, Yamada H, et al., Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE, Clin Rheumatol, 2004;23:541–3.
  115. Böhm M, Betz C, Miesbach W, et al., The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine, Br J Haematol, 2005;129:644–52.
  116. Stein GY, Zeidman A, Fradin Z, et al., Treatment of resistant thrombotic thrombocytopenic purpura with rituximab and cyclophosphamide, Int J Hematol, 2004;80:94–6.
  117. Pasquale D, Vidhya R, DaSilva K, et al., Chronic relapsing thrombotic thrombocytopenic purpura: role of therapy with cyclosporine, Am J Hematol, 1998;57:57–61.
  118. Amorosi EL, Karpatkin S, Antiplatelet treatment of thrombotic thrombocytopenic purpura, Ann Intern Med, 1977;86:102–6.
  119. Rosove MH, Ho WG, Goldfinger D, Ineffectiveness of aspirin and dipyridamole in the treatment of thrombotic thrombocytopenic purpura. Ann Intern Med, 1982;96:27–33.
  120. Coppo P, Lassoued K, Mariette X, et al., Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: a report of two cases, Am J Hematol, 2001;68:198–201.
  121. George JN, How I treat patients with thrombotic thrombocytopenic purpura: 2010, Blood, 2010;116:4060–9.
  122. Musio F, Bohen EM, Yuan CM, Welch PG, Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus, Semin Arthritis Rheum, 1998;28:1–19.
  123. Kfoury Baz EM, Mahfouz RA, Masri AF, Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis, Ther Apher, 1999;3:314–6.
  124. Egerman RS, Witlin AG, Friedman SA, Sibai BM, Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases, Am J Obstet Gynecol, 1996;175(4 Pt 1):950–6.
  125. Swisher KK, Doan JT, Vesely SK, et al., Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: report of five patients with a systematic review of published reports, Haematologica, 2007;92:936–43.
  126. McDonald V, Laffan M, Benjamin S, et al., Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry, Br J Haematol, 2009;144:430–3.
  127. Hart D, Sayer R, Miller R, et al., Human immunodeficiency virus associated thrombotic thrombocytopenic purpura – favourable outcome with plasma exchange and prompt initiation of highly active antiretroviral therapy, Br J Haematol, 2011;153:515–9.
  128. Benjamin M, Terrell DR, Vesely SK, et al., Frequency and significance of HIV infection among patients diagnosed with thrombotic thrombocytopenic purpura, Clin Infect Dis, 2009;48:1129–37.
  129. Gore EM, Jones BS, Marques MB, Is therapeutic plasma exchange indicated for patients with gemcitabine-induced hemolytic uremic syndrome?, J Clin Apher, 2009;24:209–14.
  130. Zakarija A, Kwaan HC, Moake JL, et al., Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008), Kidney Int Suppl, 2009;S20–4.
  131. Lesesne JB, Rothschild N, Erickson B, et al., Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry, J Clin Oncol, 1989;7:781–9.
  132. Cantrell JE, Phillips TM, Schein PS, Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy, J Clin Oncol, 1985;3:723–34.
  133. Ho VT, Cutler C, Carter S, 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.
  134. Ruutu T, Barosi G, Benjamin RJ, et al., Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group, Haematologica, 2007;92:95–100.
  135. Francis KK, Kalyanam N, Terrell DR, et al., Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases., Oncologist, 2007;12:11–9.
  136. Au WY, Ma ES, Lee TL, et al., Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab, Br J Haematol, 2007;137:475–8.
  137. George JN, Evaluation and management of patients with thrombotic thrombocytopenic purpura, J Intensive Care Med, 2007;22:82–91.
  138. Loirat C, Noris M, Fremeaux-Bacchi V, Complement and the atypical hemolytic uremic syndrome in children, Pediatr Nephrol, 2008;23:1957–72.
  139. Ariceta G, Besbas N, Johnson S, et al., Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol, 2009;24:687–96.
  140. Taylor CM, Machin S, Wigmore SJ, Goodship TH, Working party from the Renal Association tBCfSiHatBTS. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom, Br J Haematol, 2010;148:37–47.
  141. Licht C, Weyersberg A, Heinen S, et al., Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis, 2005;45:415–21.
  142. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al., Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome, J Am Soc Nephrol, 2007;18:2392–400.
  143. Caprioli J, Noris M, Brioschi S, et al., Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome, Blood, 2006;108:1267–79.
  144. Köse O, Zimmerhackl LB, Jungraithmayr T, et al., New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab, Semin Thromb Hemost, 2010;36:669–72.
  145. Al-Akash SI, Almond PS, Savell VH, et al., Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation, Pediatr Nephrol, 2011;26:613–9.
  146. Ariceta G, Arrizabalaga B, Aguirre M, et al., Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants, Am J Kidney Dis, 2012;59:707–10.
  147. Chandran S, Baxter-Lowe L, Olson JL, et al., Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation – a case report, Transplant Proc, 2011;43:2097–101.
  148. Châtelet V, Lobbedez T, Frémeaux-Bacchi V, et al., Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report, Transplant Proc, 2010;42:4353–5.
  149. Davin JC, Gracchi V, Bouts A, et al., Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation, Am J Kidney Dis, 2010;55:708–11.
  150. Dorresteijn EM, van de Kar NC, Cransberg K, Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count, Pediatr Nephrol, 2012;27:1193–5.
  151. Gruppo RA, Rother RP, Eculizumab for congenital atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:544–6.
  152. Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al., Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation, Am J Transplant, 2011;11:2523–7.
  153. Krid S, Roumenina L, Beury D, et al., Renal Transplantation Under Prophylactic Eculizumab in Atypical Hemolytic Uremic Syndrome with CFH/CFHR1 Hybrid Protein, Am J Transplant, 2012;12:1938–44.
  154. Lapeyraque AL, Frémeaux-Bacchi V, Robitaille P, Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome, Pediatr Nephrol, 2011;26:621–4.
  155. Larrea CF, Cofan F, Oppenheimer F, et al., Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation, 2010;89:903–4.
  156. Mache CJ, Acham-Roschitz B, Frémeaux-Bacchi V, et al., Complement inhibitor eculizumab in atypical hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2009;4:1312–6.
  157. Nester C, Stewart Z, Myers D, et al., Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome, Clin J Am Soc Nephrol, 2011;6:1488–94.
  158. Nürnberger J, Philipp T, Witzke O, et al., Eculizumab for atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:542–4.
  159. Ohanian M, Cable C, Halka K, Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome, Clin Pharmacol, 2011;3:5–12.
  160. Prescott HC, Wu HM, Cataland SR, Baiocchi RA, Eculizumab therapy in an adult with plasma exchange-refractory atypical hemolytic uremic syndrome, Am J Hematol, 2010;85:976–7.
  161. Shin JI, Lee JS, More on eculizumab for congenital atypical hemolytic-uremic syndrome, N Engl J Med, 2009;360:2142–3; author reply 3.
  162. Tschumi S, Gugger M, Bucher BS, et al., Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings, Pediatr Nephrol, 2011;26:2085–8.
  163. Legendre C, Babu S, Furman R, (editors), Safety and efficacy of eculizumab in aHUS resistant to plasma therapy: interim analysis from a phase II trial. American Society of Nephrology; 2010; Denver, CO, USA.
  164. Muus P, Legendre C, Douglas H, (editors), Safety and efficacy of eculizumab in aHUS patients on chronic plasma therapy: interim analysis of a phase II trial. American Society of Nephrology; 2010; Denver, CO, USA.
  165. Boyer O, Balzamo E, Charbit M, et al., Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies, Am J Kidney Dis, 2010;55:923–7.
  166. Tarr PI, Gordon CA, Chandler WL, Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome, Lancet, 2005;365:1073–86.
  167. Wong CS, Mooney JC, Brandt JR, et al., Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis, Clin Infect Dis, 2012;55:33–41.
  168. Michael M, Elliott EJ, Craig JC, et al., Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials, Am J Kidney Dis, 2009;53:259–72.
  169. Garg AX, Suri RS, Barrowman N, et al., Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression, JAMA, 2003;290:1360–70.
  170. Radhakrishnan S, Lunn A, Kirschfink M, et al., Eculizumab and refractory membranoproliferative glomerulonephritis, N Engl J Med, 2012;366:1165–6.
  171. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al., Eculizumab in severe Shiga-toxin-associated HUS, N Engl J Med, 2011;364:2561–3.
  172. Dundas S, Murphy J, Soutar RL, et al., Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak, Lancet, 1999;354:1327–30.
  173. Carter AO, Borczyk AA, Carlson JA, et al., A severe outbreak of Escherichia coli O157:H7 – associated hemorrhagic colitis in a nursing home, N Engl J Med, 1987;317:1496–500.
  174. Frank C, Werber D, Cramer JP, et al., Epidemic profile of Shigatoxin- producing Escherichia coli O104:H4 outbreak in Germany, N Engl J Med, 2011;365:1771–80.
  175. Colic E, Dieperink H, Titlestad K, Tepel M, Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study, Lancet, 2011;378:1089–93.
  176. Greinacher A, Friesecke S, Abel P, et al., Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4- associated haemolytic uraemic syndrome: a prospective trial, Lancet, 2011;378:1166–73.
  177. Magnus T, Röther J, Simova O, et al., The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak, Brain, 2012;135(Pt 6):1850–9.
  178. Birn H, Ivarsen P, Svensson M, et al., Should all adult patients with diarrhoea-associated HUS receive plasma exchange?, Lancet, 2012;379:515–6; author reply 6–7.
  179. recovery from thrombotic thrombocytopenic purpura, Transfusion, 2009;49:1092–101.
  180. Cataland SR, Scully MA, Paskavitz J, et al., Evidence of persistent neurologic injury following thrombotic thrombocytopenic purpura, Am J Hematol, 2011;86:87–9.
  181. Lewis QF, Lanneau MS, Mathias SD, et al., Long-term deficits in health-related quality of life after recovery from thrombotic thrombocytopenic purpura, Transfusion, 2009;49:118–24.
  182. Hawkins BM, Abu-Fadel M, Vesely SK, George JN, Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review, Transfusion, 2008;48:382–92.
  183. Gami AS, Hayman SR, Grande JP, Garovic VD, Incidence and prognosis of acute heart failure in the thrombotic microangiopathies, Am J Med, 2005;118:544–7.
  184. Patschan D, Witzke O, Dührsen U, et al., Acute myocardial infarction in thrombotic microangiopathies – clinical characteristics, risk factors and outcome, Nephrol Dial Transplant, 2006;21:1549–54.
  185. Clark WF, Sontrop JM, Macnab JJ, et al., Long term risk for hypertension, renal impairment, and cardiovascular disease after gastroenteritis from drinking water contaminated with Escherichia coli O157:H7: a prospective cohort study, BMJ, 2010;341:c6020.
  186. Clark WF, Kortas C, Suri RS, et al., Excessive fluid intake as a novel cause of proteinuria, CMAJ, 2008;178:173–5.
  187. Schiviz A, Wuersch K, Piskernik C, et al., A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13, Blood, 2012;119:6128–35.
  188. Schmidt CQ, Slingsby FC, Richards A, Barlow PN, Production of biologically active complement factor H in therapeutically useful quantities, Protein Expr Purif, 2011;76:254–63.
  189. Bitzan M, Schaefer F, Reymond D, Treatment of typical (enteropathic) hemolytic uremic syndrome, Semin Thromb Hemost, 2010;36:594–610.
Keywords: Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical, diarrhea, idiopathic, secondary, ADAMTS-13, plasma exchange, plasma infusion, epidemic, rituximab, eculizumab