Clinical and Laboratory Features of Patients with Acquired Thrombotic Thrombocytopenic Purpura: Fourteen Years of the Milan TTP Registry

Abstract

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by the immune-mediated severe deficiency of ADAMTS13. We hereby report the demographic and disease-related data of acquired TTP patients recorded in the Milan TTP Registry (www.ttpdatabase.org). We performed a cross-sectional study of 302 individuals enrolled in our registry for an acute episode of acquired TTP occurred between 2002 and 2015 (female 77%; median age at onset 40 years, interquartile range: 30–50). Twenty per cent of patients had concomitant autoimmune disorders. Among potential triggers of acute episodes, infections were the most prevalent (27%), followed by estroprogestinics use and pregnancy (5 and 4% of women, respectively). At presentation, systemic (72%), bleeding (68%) and neurological (43%) symptoms were the most frequent, whereas a lower prevalence of renal (18%) and cardiovascular (10%) signs and symptoms was observed. Almost all acute events were treated by plasma exchange and steroids, and 15% by rituximab. Exacerbation of acute TTP occurred in 15% of events. The TTP-related mortality was 5%. In survivors, the median number of plasma exchange procedures to remission was 9 (interquartile range: 6–14), longer for first events than relapses (median difference 3, 95% confidence interval: 2–4). Of 251 survivors of the first TTP episode with at least a 6-month follow-up, 55% had a relapse. In conclusion, acquired TTP is a severe disease with highly variable clinical presentation, usually requiring a long hospitalization. The Milan TTP Registry represents a powerful tool to improve our knowledge and management of acquired TTP.

Keywords

ADAMTS13 - diagnosis management - register - thrombotic microangiopathy - thrombotic thrombocytopenic purpura

Authors' Contributions

I. Mancini designed the study, performed experiments, performed quality control and statistical analysis, interpreted the results and wrote the manuscript; S. Pontiggia performed experiments, collected clinical and/or experimental data, performed quality control and statistical analysis and contributed to write the manuscript; R. Palla interpreted the results, contributed to write and critically reviewed the manuscript; A. Artoni collected clinical data, interpreted the results and critically reviewed the manuscript; C. Valsecchi performed experiments, interpreted the results and critically reviewed the manuscript; B. Ferrari collected clinical data, interpreted the results and critically reviewed the manuscript; D. Mikovic, S.M. Trisolini, S. Capria, L. Facchini, K. Codeluppi, E. Rinaldi, D. Pastore, S. Campus, R.A. Podda, C. Caria, A. Caddori, D. Nicolosi, G. Giuffrida, V. Agostini, U. Roncarati, C. Mannarella, A. Fragasso, G.M. Podda, S. Birocchi, A.M. Cerbone, A. Tufano, G. Loffredo, G. Menna, M. Pizzuti, G. Re, M. Ronchi, A. De Fanti, S. Amarri, M. Defina, M. Bocchia and S. Cerù collected clinical data; F. Peyvandi designed the study, interpreted the results and critically reviewed the manuscript.

Study Group Members

The Italian Group of TTP Investigators includes: Silvia Maria Trisolini and Saveria Capria (Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, Sapienza University, Rome, Italy), Luca Facchini and Katia Codeluppi (Hematology Unit, Oncology Department, Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Italy), Erminia Rinaldi and Domenico Pastore (Hematology Unit, A. Perrino Hospital, Brindisi, Italy), Simona Campus and Rosa Anna Podda (Pediatric Unit, Ospedale Microcitemico, Cagliari, Italy), Cinzia Caria and Aldo Caddori (Internal Medicine Unit, S.S. Trinità Hospital, Cagliari, Italy), Daniela Nicolosi and Gaetano Giuffrida (Hematology Division, Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy), Vanessa Agostini and Umberto Roncarati (U.O. Immunoematologia e Medicina Trasfusionale/Officina Trasfusionale, Cesena e Forlì, Cesena, Italy), Clara Mannarella and Alberto Fragasso (Hematology Unit, Madonna delle Grazie Hospital, Matera, Italy), Gian Marco Podda and Simone Birocchi (Unità di Medicina III, ASST Santi Paolo e Carlo, Milano, Italy), Anna Maria Cerbone and Antonella Tufano (Department of Clinical Medicine and Surgery, AOU Federico II, Napoli, Italy), Giuseppe Loffredo and Giuseppe Menna (Department of Oncology, AORN Santobono-Pausilipon, Naples, Italy), Michele Pizzuti (Hematology Unit, AO San Carlo, Potenza, Italy), Giuseppe Re and Michela Ronchi (Internal Medicine Unit, Department of Medicine, Lugo Hospital, Ravenna, Italy), Alessandro De Fanti (Departmental Simple Unit of Pediatric Rheumatology, AUSL-IRCSS Reggio Emilia, Reggio Emilia, Italy), Sergio Amarri (Pediatrics Unit, AUSL-IRCSS Reggio Emilia, Reggio Emilia, Italy), Marzia Defina and Monica Bocchia (Università degli studi di Siena, Department of Medical, Surgery and Neuroscience, Hematology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy) and Silvia Cerù (Hematology Unit, Santa Chiara Hospital, Trento, Italy).

^* A complete list of the members of the Italian Group of TTP Investigators appears in section ”Study Group Members.”

• References

• 1 Reese JA, Muthurajah DS, Kremer Hovinga JA, Vesely SK, Terrell DR, George JN. Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired ADAMTS13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer 2013; 60 (10) 1676-1682
• 2 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 (05) 819-826
• 3 Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115 (08) 1500-1511 , quiz 1662
• 4 Wada H, Matsumoto T, Yamashita Y. Natural history of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Thromb Hemost 2014; 40 (08) 866-873
• 5 Scully M, Hunt BJ, Benjamin S. , et al; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158 (03) 323-335
• 6 Mariotte E, Azoulay E, Galicier L. , et al; French Reference Center for Thrombotic Microangiopathies. Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy. Lancet Haematol 2016; 3 (05) e237-e245
• 7 Matsumoto M, Bennett CL, Isonishi A. , et al. Acquired idiopathic ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in a population from Japan. PLoS One 2012; 7 (03) e33029
• 8 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 (02) 163-169
• 9 Blombery P, Kivivali L, Pepperell D. , et al; TTP registry steering committee. Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry. Intern Med J 2016; 46 (01) 71-79
• 10 Lotta LA, Mariani M, Consonni D. , et al. Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura. Br J Haematol 2010; 151 (05) 488-494
• 11 Zhou X, Ye X, Ren Y. , et al. Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single center experience of 60 cases. Front Med 2016; 10 (04) 430-436
• 12 Benhamou Y, Boelle PY, Baudin B. , et al; Reference Center for Thrombotic Microangiopathies; Experience of the French Thrombotic Microangiopathies Reference Center. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2015; 13 (02) 293-302
• 13 Brazelton J, Oster RA, McCleskey B, Fuller J, Adamski J, Marques MB. Increased troponin I is associated with fatal outcome in acquired thrombotic thrombocytopenic purpura. J Clin Apher 2017; 32 (05) 311-318
• 14 Zafrani L, Mariotte E, Darmon M. , et al. Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity. J Thromb Haemost 2015; 13 (03) 380-389
• 15 Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv 2017; 1 (10) 590-600
• 16 Scully M, Cataland S, Coppo P. , et al; International Working Group for Thrombotic Thrombocytopenic Purpura. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost 2017; 15 (02) 312-322
• 17 Peyvandi F, Palla R, Lotta LA, Mackie I, Scully MA, Machin SJ. ADAMTS-13 assays in thrombotic thrombocytopenic purpura. J Thromb Haemost 2010; 8 (04) 631-640
• 18 Mancini I, Valsecchi C, Lotta LA. , et al. FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients. Thromb Haemost 2014; 112 (02) 297-303
• 19 Peyvandi F, Lavoretano S, Palla R. , et al. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica 2008; 93 (02) 232-239
• 20 Bettoni G, Palla R, Valsecchi C. , et al. ADAMTS-13 activity and autoantibodies classes and subclasses as prognostic predictors in acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10 (08) 1556-1565
• 21 Lotta LA, Valsecchi C, Pontiggia S. , et al. Measurement and prevalence of circulating ADAMTS13-specific immune complexes in autoimmune thrombotic thrombocytopenic purpura. J Thromb Haemost 2014; 12 (03) 329-336
• 22 Bendapudi PK, Li A, Hamdan A. , et al. Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative. Br J Haematol 2015; 171 (05) 836-844
• 23 Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014; 35 (03) 347-369
• 24 Sardu C, Cocco E, Mereu A. , et al. Population based study of 12 autoimmune diseases in Sardinia, Italy: prevalence and comorbidity. PLoS One 2012; 7 (03) e32487
• 25 Eaton WW, Pedersen MG, Atladóttir HO, Gregory PE, Rose NR, Mortensen PB. The prevalence of 30 ICD-10 autoimmune diseases in Denmark. Immunol Res 2010; 47 (1-3): 228-231
• 26 John ML, Scharrer I. Autoimmune disorders in patients with idiopathic thrombotic thrombocytopenic purpura. Hamostaseologie 2012; 32 (Suppl. 01) S86-S89
• 27 Deford 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) 2023-2029 , quiz 2142
• 28 Douglas KW, Pollock KG, Young D, Catlow J, Green R. Infection frequently triggers thrombotic microangiopathy in patients with preexisting risk factors: a single-institution experience. J Clin Apher 2010; 25 (02) 47-53
• 29 Cserti CM, Landaw S, Uhl L. Do infections provoke exacerbations and relapses of thrombotic thrombocytopenic purpura?. J Clin Apher 2007; 22 (01) 21-25
• 30 Ma A, Goetz MB. Capnocytophaga canimorsus sepsis with associated thrombotic thrombocytopenic purpura. Am J Med Sci 2013; 345 (01) 78-80
• 31 Pos W, Luken BM, Sorvillo N, Kremer Hovinga JA, Voorberg J. Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2011; 9 (07) 1285-1291
• 32 Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104 (01) 100-106
• 33 Ferrari B, Maino A, Lotta LA. , et al. Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case-control study. Orphanet J Rare Dis 2014; 9: 193
• 34 Page Y, Tardy B, Zeni F, Comtet C, Terrana R, Bertrand JC. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet 1991; 337 (8744): 774-776
• 35 Bennett CL, Connors JM, Carwile JM. , et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342 (24) 1773-1777
• 36 Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015; 125 (04) 616-618
• 37 Vesconi S, Langer M, Rossi E, Mondonico P, Cambiaghi G, Donati MB. Thrombotic thrombocytopoenic purpura during oral contraceptive treatment. Thromb Haemost 1979; 40 (03) 563-564
• 38 Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood 1980; 56 (02) 302-306
• 39 McShane PM, Bern MM, Schiff I. Thrombotic thrombocytopenic purpura associated with oral contraceptives: a case report. Am J Obstet Gynecol 1983; 145 (06) 762-763
• 40 Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus 2011; 9 (02) 120-138
• 41 Gleicher N, Barad DH. Gender as risk factor for autoimmune diseases. J Autoimmun 2007; 28 (01) 1-6
• 42 Sadler JE. What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 631-636
• 43 Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol 2004; 41 (01) 68-74
• 44 Hawkins BM, Abu-Fadel M, Vesely SK, George JN. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion 2008; 48 (02) 382-392
• 45 Siersema PD, Kros JM, van den Berg B. Cardiac manifestations of thrombotic thrombocytopenic purpura. Neth J Med 1989; 35 (1-2): 100-107
• 46 Podolsky SH, Zembowicz A, Schoen FJ, Benjamin RJ, Sonna LA. Massive myocardial necrosis in thrombotic thrombocytopenic purpura: a case report and review of the literature. Arch Pathol Lab Med 1999; 123 (10) 937-940
• 47 James TN, Monto RW. Pathology of the cardiac conduction system in thrombotic thrombocytopenic purpura. Ann Intern Med 1966; 65 (01) 37-43
• 48 Peyvandi F, Scully M, Kremer Hovinga JA. , et al; TITAN Investigators. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med 2016; 374 (06) 511-522
• 49 Scully M, Knöbl P, Kentouche K. , et al. Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. Blood 2017; 130 (19) 2055-2063