Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya7596810.26442/00403660.2021.06.200894ReviewsОбзорыResearch ArticleTreatment of thrombotic thrombocytopenic purpuraЛечение приобретенной тромботической тромбоцитопенической пурпурыhttps://orcid.org/0000-0001-8818-8949GalstyanGennadii M.ГалстянГеннадий Мартинович
Russian Federation

д-р мед. наук, зав. отд-нием реанимации и интенсивной терапии ФГБУ «НМИЦ гематологии»

gengalst@gmail.comhttps://orcid.org/0000-0002-0016-6698MaschanAlexei A.МасчанАлексей Александрович
Russian Federation

чл.-кор. РАН, д-р мед. наук, проф., зам. ген. дир. – дир. Института гематологии, иммунологии и клеточных технологий ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева»

gengalst@gmail.comhttps://orcid.org/0000-0002-8141-9422KlebanovaElizaveta E.КлебановаЕлизавета Евгеньевна
Russian Federation

врач анестезиолог-реаниматолог отд-ния реанимации и интенсивной терапии ФГБУ «НМИЦ гематологии»

gengalst@gmail.comhttps://orcid.org/0000-0002-0813-5626KalininaIrina I.КалининаИрина Игоревна
Russian Federation

канд. мед. наук, врач-гематолог отд-ния детской гематологии/онкологии ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева»

gengalst@gmail.comNational Research Center for HematologyФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава РоссииRogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России150620219367367451007202110072021Copyright ©; 2021, Consilium MedicumCopyright ©; 2021, ООО "Консилиум Медикум"2021Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/75968

The review discusses approaches to treatment of acquired thrombotic thrombocytopenic purpuгa (aTTP). In patients with aTTP plasma exchanges, glucocorticosteroids allow to stop an acute attack of TTP, and use of rituximab allows to achieve remission. In recent years, caplacizumab has been used. Treatment options such as cyclosporin A, bortezomib, splenectomy, N-acetylcysteine, recombinant ADAMTS13 are also described. Separately discussed issues of management of patients with TTP during pregnancy, and pediatric patients with TTP.

Обсуждаются подходы к лечению приобретенной тромботической тромбоцитопенической пурпуры (ТТП). Плазмообмены, глюкокортикостероидные гормоны позволяют купировать острый приступ ТТП, а применение ритуксимаба – достигнуть ремиссии. В последние годы используется каплацизумаб, обсуждается его место в лечении ТТП. Описано также применение циклоспорина А, бортезомиба, спленэктомии, N-ацетилцистеина, рекомбинантного ADAMTS13, сопутствующей терапии. Обсуждаются вопросы ведения пациенток с ТТП во время беременности, лечения ТТП у детей.

ADAMTS13thrombotic thrombocytopenic purpurapregnancytherapeutic plasma exchangerituximabcyclosporine AbortezomibN-acetylcysteinecaplacizumabrecombinant ADAMTS13ADAMTS13тромботическая тромбоцитопеническая пурпурабеременностьплазмообменритуксимабциклоспорин АбортезомибN-ацетилцистеинкаплацизумабрекомбинантный ADAMTS13Scully M, Cataland S, Coppo P, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017;15(2):312-22. DOI:10.1111/jth.13571Yamada Y, Ohbe H, Yasunaga H, et al. Clinical Practice Pattern of Acquired Thrombotic Thrombocytopenic Purpura in Japan: A nationwide Inpatient Database Analysis. Blood. 2019;134(Suppl. 1):2374. DOI:10.1182/blood-2019-125170Picod A, Coppo P. When targeted therapies alleviate the burden of TPE: The example of immune-mediated TTP. Transf Apher Sci. 2019;58(3):273-7. DOI:10.1016/j.transci.2019.04.012Nguyen TC, Han YY. Plasma exchange therapy for thrombotic microangiopathies. Organogenesis. 2011;7(1):28-31. DOI:10.4161/org.7.1.14027Rock GA, Shumak KH, Buskard NA, et al. Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic Purpura. N Engl J Med. 1991;325(6):393-7. DOI:10.1056/NEJM199108083250604Henon P. Thrombotic thrombocytopenic purpura: Clinical results of a French controlled trial. Transfus Sci. 1992;13(1):63-72. DOI:10.1016/0955-3886(92)90123-XVon Baeyer H. Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher. 2002;6(4):320-8. DOI:10.1046/j.1526-0968.2002.00390.xRock G, Shumak KH, Sutton DMC, et al. Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Brit J Haematol. 1996;94(2):383-6. DOI:10.1046/j.1365-2141.1996.d01-1800.xAltuntas F, Aydogdu I, Kabukcu S, et al. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: A retrospective multicenter study. Transf Apher Sci. 2007;36(1):57-67. DOI:10.1016/j.transci.2006.05.014Zeigler ZR, Shadduck RK, Gryn JF, 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. DOI:10.1002/jca.1003Stefanello B, De Paula EV, Orsi FA, et al. Safety and efficacy of cryoprecipitate-poor plasma as a replacement fluid for therapeutic plasma exchange in thrombotic thrombocytopenic purpura: A single center retrospective evaluation. J Clin Apher. 2014;29(6):311-5. DOI:10.1002/jca.21336Raife TJ, Friedman KD, Dwyre DM. The pathogenicity of von Willebrand factor in thrombotic thrombocytopenic purpura: reconsideration of treatment with cryopoor plasma Thomas. Transfusion. 2006;46:74-9. DOI:10.1111/j.1537-2995.2006.00674.xRock G, Ahluwalia N, Anderson D. Metalloprotease levels are variably altered in thrombotic thrombocytopenic patients at presentation and after plasma exchange with either cryosupernatant plasma or fresh frozen plasma. Blood. 2001;102:539а.Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher. 2014;29(3):148-67. DOI:10.1002/jca.21302Knöbl P. Thrombotic thrombocytopenic purpura. Memo. 2018;11(3):220-6. DOI:10.1007/s12254-018-0429-6Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-35. DOI:10.1111/j.1365-2141.2012.09167.xZheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-502. DOI:10.1111/jth.15010Thejeel B, Garg AX, Clark WF, et al. Long-term outcomes of thrombotic microangiopathy treated with plasma exchange: A systematic review. Am J Hematol. 2016;91(6):623-30. DOI:10.1002/ajh.24339Azoulay E, Bauer PR, Mariotte E, et al. Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive Care Med. 2019;45(11):1518-39. DOI:10.1007/s00134-019-05736-5Matsumoto M, Fujimura Y, Wada H, et al. Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan. Int J Hematol. 2017;106(1):3-15. DOI:10.1007/s12185-017-2264-7Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2015;125(25):3860-7. DOI:10.1182/blood-2014-11-551580Bell WR, Ness PM, Kickler TS, et al. Improved survival in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: Clinical experience in 108 patients. N Engl J Med. 1991;325(6):398-403. DOI:10.1056/NEJM199108083250605Toyoshige M, Zaitsu Y, Okafuji K, et al. Successful treatment of thrombotic thrombocytopenic purpura with high‐dose corticosteroid. Am J Hematol. 1992;41(1):69. DOI:10.1002/ajh.2830410119Balduini 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(6):591-6. DOI:10.1007/s00277-009-0877-5Rojnuckarin P, Watanaboonyongcharoen P, Akkawat B, et al. The role of pulse dexamethasone in acquired idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost. 2006;4(5):1148-50. DOI:10.1111/j.1538-7836.2006.01879.xGeorge 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. DOI:10.1002/jca.20091Regazzi MB, Iacona I, Avanzini MA, et al. Pharmacokinetic behavior of rituximab: A study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit. 2005;27(6):785-92. DOI:10.1097/01.ftd.0000184162.60197.c1Tobinai K, Igarashi T, Itoh K, et al. Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol. 2004;15(5):821-30. DOI:10.1093/annonc/mdh176Chen H, Fu A, Wang J, et al. Rituximab as first-line treatment for acquired thrombotic thrombocytopenic purpura. J Int Med Res. 2017;45(3):1253-60. DOI:10.1177/0300060517695646Sadler JE. Pathophysiology of Thrombotic Thrombocytopenic Purpura. Blood. 2017;130(10):1181-8. DOI:10.1182/blood-2017-04-636431Westwood JP, Thomas M, Alwan F, et al. Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: Outcome and evaluation of dosing regimens. Blood Adv. 2017;1(15):1159-66. DOI:10.1182/bloodadvances.2017008268Scully 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(7):1746-53. DOI:10.1182/blood-2011-03-341131McDonald V, Manns K, Mackie IJ, et al. Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost. 2010;8(6):1201-8. DOI:10.1111/j.1538-7836.2010.03818.xChemnitz J, Draube A, Scheid C, et al. Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab. Am J Hematol. 2002;71(2):105-8. DOI:10.1002/ajh.10204Froissart A, Buffet M, Veyradier A, et al. Efficacy and safety of first-line 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(1):104-11. DOI:10.1097/CCM.0b013e31822e9d66Scully 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(3):451-61. DOI:10.1111/j.1365-2141.2006.06448.xUpreti H, Kasmani J, Dane K, et al. Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors. Blood. 2019;134(13):1037-45. DOI:10.1182/blood.2019001056Jestin M, Benhamou Y, Schelpe AS, et al. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018;132(20):2143-53. DOI:10.1182/blood-2018-04-840090Cataland SR, Jin M, Lin S, et al. Ciclosporin and plasma exchange in thrombotic thrombocytopenic purpura: Long-term follow-up with serial analysis of ADAMTS13 activity. Br J Haematol. 2007;139(3):486-93. DOI:10.1111/j.1365-2141.2007.06819.xPasquale D, Vidhya R, DaSilva K, et al. Chronic relapsing thrombotic thrombocytopenic purpura: Role of therapy with cyclosporine. Am J Hematol. 1998;57(1):57-61. DOI:10.1002/(SICI)1096-8652(199801)57:1<57::AID-AJH10>3.0.CO;2-6Subklewe M, Sebelin-Wulf K, Beier C, et al. Dendritic Cell Maturation Stage Determines Susceptibility to the Proteasome Inhibitor Bortezomib. Hum Immunol. 2007;68(3):147-55. DOI:10.1016/j.humimm.2006.12.005Patriquin CJ, Thomas MR, Dutt T, et al. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haematol. 2016;173(5):779-85. DOI:10.1111/bjh.13993Rutkow IM. Thrombotic thrombocytopenic purpura (TTP) and splenectomy: a current appraisal. Ann Surg. 1978;188(5):701-5. DOI:10.1097/00000658-197811000-00021Veltman GAM, Brand A, Leeksma OC, et al. The role of splenectomy in the treatment of relapsing thrombotic thrombocytopenic purpura. Ann Hematol. 1995;70(5):231-6. DOI:10.1007/BF01784041Kappers-Klunne MC, Wijermans P, Fijnheer R, et al. Splenectomy for the treatment of thrombotic thrombocytopenic purpura. Br J Haematol. 2005;130(5):768-76. DOI:10.1111/j.1365-2141.2005.05681.xDubois L, Gray DK. Splenectomy: Does it still play a role in the management of thrombotic thrombocytopenic purpura? Can J Surg. 2010;53(5):349-55.Sheffner AL, Medler EM, Jacobs LW, et al. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis. 1964;90:721-9.Tersteeg C, Roodt J, van Rensburg WJ, et al. N-acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura. Blood. 2017;129(8):1030-8. DOI:10.1182/blood-2016-09-738856Chen J, Reheman A, Gushiken FC, et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clini Invest. 2011;121(2):593-603. DOI:10.1172/JCI41062Li GW, Rambally S, Kamboj J, et al. Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report. Transfusion. 2014;54(5):1221-4. DOI:10.1111/trf.12440Cabanillas G, Popescu-Martinez A. N-Acetylcysteine for Relapsing Thrombotic Thrombocytopenic Purpura: More Evidence of a Promising Drug. Am J Ther. 2016;23(5):e1277-9. DOI:10.1097/MJT.0000000000000386Rottenstreich A, Hochberg-Klein S, Rund D, et al. The role of N-acetylcysteine in the treatment of thrombotic thrombocytopenic purpura. J Thromb Thrombolysis. 2016;41(4):678-83. DOI:10.1007/s11239-015-1259-6Cataland SR, Peyvandi F, Mannucci PM, et al. Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura. Am J Hematol. 2012;87(4):430-2. DOI:10.1002/ajh.23106Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. New Engl J Med. 2019;380(4):335-46. DOI:10.1056/nejmoa1806311Masias C, Cataland SR. Novel therapies in thrombotic thrombocytopenic purpura. Res Pr Thromb Haemost. 2018;2(1):19-26. DOI:10.1002/rth2.12066Duggan S. Caplacizumab: First Global Approval. Drugs. 2018;78(15):1639-42. DOI:10.1007/s40265-018-0989-0Lenting PJ, Christophe OD, Denis CV. Von Willebrand factor biosynthesis, secretion, and clearance: Connecting the far ends. Blood. 2015;125(13):2019-28. DOI:10.1182/blood-2014-06-528406Van Schooten CJ, Shahbazi S, Groot E, et al. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood. 2008;112(5):1704-12. DOI:10.1182/blood-2008-01-133181Sargentini-Maier ML, De Decker P, Tersteeg C, et al. Clinical pharmacology of caplacizumab for the treatment of patients with acquired thrombotic thrombocytopenic purpura. Exp Rev Clin Pharmacol. 2019;12(6):537-45. DOI:10.1080/17512433.2019.1607293Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-22. DOI:10.1056/NEJMoa1505533Le Besnerais M, Veyradier A, Benhamou Y, et al. Caplacizumab: a change in the paradigm of thrombotic thrombocytopenic purpura treatment. Expert Opin Biol Ther. 2019;19(11):1127-34. DOI:10.1080/14712598.2019.1650908European Medicines Agency E. Cablivi. 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/cablivi Accessed: 11.06.2021.Volker LA, Kaufeld J, Miesbach W, et al. ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP. Blood Adv. 2020;4(13):3093-101. DOI:10.1182/bloodadvances.2020001987Zheng XL, Vesely SK, Cataland SR, et al. ISTH Guidelines for Treatment of Thrombotic Thrombocytopenic Purpura. J Thromb Haemost. 2020;18(10):2496-502. DOI:10.1111/jth.15010Plaimauer B, Kremer Hovinga JA, Juno C, et al. Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost. 2011;9(5):936-44. DOI:10.1111/j.1538-7836.2011.04224.xJian C, Xiao J, Gong L, et al. Gain-of-function ADAMTS13 variants that are resistant to autoantibodies against ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura. Blood. 2012;119(16):3836-43. DOI:10.1182/blood-2011-12-399501Abdelgawwad MS, Cao W, Zheng L, et al. Transfusion of platelets loaded with recombinant ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) is efficacious for inhibiting arterial thrombosis associated with thrombotic thrombocytopenic purpura. Arter Thromb Vasc Biol. 2018;38(11):2731-43. DOI:10.1161/ATVBAHA.118.311407Benhamou Y, Baudel JL, Wynckel A, et al. Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center. Am J Hematol. 2015;90(6):E127-9. DOI:10.1002/ajh.23997Bobbio-Pallavicini E, Gugliotta L, Centurioni R, 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. PMID: 9299856Vinet E, Pineau C, Gordon C, et al. Biologic therapy and pregnancy outcomes in women with rheumatic diseases. Arthritis Rheum. 2009;61(5):587-92. DOI:10.1002/art.24462Scully M, Thomas M, Underwood M, et al. Thrombotic thrombocytopenic purpura and pregnancy: Presentation, management, and subsequent pregnancy outcomes. Blood. 2014;124(2):211-9. DOI:10.1182/blood-2014-02-553131Smith JB, Hellwig K, Fink K, et al. Rituximab, MS, and pregnancy. Neurol Neuroimmunol Neuroinflam. 2020;7(4):e734. DOI:10.1212/NXI.0000000000000734Harris C, Marin J, Beaulieu MC. Rituximab induction therapy for de novo ANCA associated vasculitis in pregnancy: a case report. BMC Nephrol. 2018;19(1):4-7. DOI:10.1186/s12882-018-0949-7Simister NE. Placental transport of immunoglobulin G. Vaccine. 2003;21:3365-9. DOI:10.1016/s0264-410x(03)00334-7Saji F, Samejima Y, Kamiura S, et al. Dynamics of immunoglobulins at the feto-maternal interface. Rev Reprod. 1999;4(2):81-9. DOI:10.1530/ror.0.0040081Ton E, Tekstra J, Hellmann PM, et al. Safety of rituximab therapy during twins’ pregnancy. Rheumatology. 2011;50(4):806-8. DOI:10.1093/rheumatology/keq403Das G, Damotte V, Gelfand JM, et al. Rituximab before and during pregnancy. Neurol Neuroimmunol Neuroinflamm. 2018;5(3):e453. DOI:10.1212/nxi.0000000000000453Jiang Y, McIntosh JJ, Reese JA, et al. Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood. 2014;123(11):1674-80. DOI:10.1182/blood-2013-11-538900Joly BS, Coppo P, Veyradier A. Pediatric thrombotic thrombocytopenic purpura. Eur J Haematol. 2018. DOI:10.1111/ejh.13107Joly BS, Stepanian A, Leblanc T, et al. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy. Lancet Haematol. 2016;3:e537-e546. DOI:10.1016/S2352-3026(16)30125-9Maschan A, Petrova U, Kalinina I, et al. Bortezomib induces long-term remission in children with immune thrombotic thrombocytopenic purpura, refractory to plasma exchange, glucocorticoids, and rituximab: A report on two cases. Pediatr Blood Cancer. 2020. DOI:10.1002/pbc.28818Maschan M, Bobrynina V, Khachatryan L, et al. Control of thrombotic thrombocytopenic purpura by sirolimus in a child with juvenile myelomonocytic leukemia and somatic N-RAS mutation. Pediatr Blood Cancer. 2014. DOI:10.1002/pbc.25013Bhoopalan SV, Hankins J, George J, et al. Use of caplacizumab in a child with refractory thrombotic thrombocytopenic purpura. Pediatr Blood Cancer. 2019;66(7):2-3. DOI:10.1002/pbc.27737Kaczmarek V, Holle J, Astudillo R, et al. Caplacizumab for relapsing thrombotic thrombocytopenic purpura. Pediatr Nephrol. 2019;34(9):1625-8. DOI:10.1007/s00467-019-04281-zLara PN, Coe TL, Zhou H, et al. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (multiple letters). Am J Med. 1999;107:573-9. DOI:10.1016/s0002-9343(00)00696-3Staley EM, Cao W, Pham HP, et al. Clinical factors and biomarkers predict outcome in patients with immune-mediated thrombotic thrombocytopenic purpura. Haematologica. 2019;104(1):166-75. DOI:10.3324/haematol.2018.198275Jasti 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(5):151-6. DOI:10.1002/jca.20172De 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. Transf Apher Sci. 2010;43(3):299-303. DOI:10.1016/j.transci.2010.09.018Page EE, Kremer Hovinga JA, Terrell DR, et al. Thrombotic thrombocytopenic purpura: Diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv. 2017;1(10):590-600. DOI:10.1182/bloodadvances.2017005124Deford CC, Reese JA, Schwartz LH, et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood. 2013;122(12):2023-9. DOI:10.1182/blood-2013-04-496752Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Ann Intern Med. 1995;122(8):569-72. DOI:10.7326/0003-4819-122-8-199504150-00002Jin M, Casper TC, Cataland SR, et al. Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse. Br J Haematol. 2008;141(5):651-8. DOI:10.1111/j.1365-2141.2008.07107.xSonneveld MAH, de Maat MPM, Portegies MLP, et al. Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. Blood. 2015;126(25):2739-46. DOI:10.1182/blood-2015-05-643338George JN. TTP-long-term outcomes following recovery. Hematol Am Soc Hematol Educ Progr. 2018;(1):548-52. DOI:10.1182/asheducation-2018.1.548Roriz M, Landais M, Desprez J, et al. Risk factors for autoimmune diseases development after thrombotic thrombocytopenic purpura. Medicine (Baltimore). 2015;94(42):e1598. DOI:10.1097/MD.0000000000001598Sukumar S, Brodsky M, Hussain S, et al. Cardiovascular Disease Is a Leading Cause of Death in Thrombotic Thrombocytopenic Purpura (TTP) Survivors. Blood. 2020;136(Suppl. 1):22-3. DOI:10.1182/blood-2020-138551Balasubramaniyam N, Yandrapalli S, Kolte D, et al. Cardiovascular Complications and Their Association With Mortality in Patients With Thrombotic Thrombocytopenic Purpura. Am J Med. 2021;134(2):e89-97. DOI:10.1016/j.amjmed.2020.06.020Ellithi M, Khalil F, Gowda SN, et al. Acute Coronary Syndrome in Patients with Thrombotic Thrombocytopenic Purpura. Blood. 2020;136(Suppl. 1):4-5. DOI:10.1182/blood-2020-138482