Features and Relapse/Refractory Disease Risk Factors of Patients with Acquired Thrombotic Thrombocytopenic Purpura in the Western Mediterranean Region of Turkey

Öz

The importance of parameters that predict and prevent relapse has increased in thrombotic thrombocytopenic purpura (TTP), where response and overall survival rates exceed 90% with current approaches. In this respect, we examined the clinical presentations, laboratory findings, treatments, treatment responses, states of relapsed/refractory disease and overall survival rates of immune-mediated TTP (iTTP) patients in the western Mediterranean region. 35 adult patients who were diagnosed with iTTP in the last 10 years were included in the study. The median follow-up period of the patients was 46 (2-118) months, and 32 patients (91.4%) survived. While clinical remission was achieved in 20 (57.1%) patients in the first-line treatment group, clinical remission was achieved in 20 of 21 patients who received second-line treatment due to relapsed/refractory disease. Rituximab, which was used as the first-line treatment in only 4 patients, was given to 14 patients as the second-line treatment. Due to relapse, 5 patients received third-line treatment, and 2 patients received fourth-line treatment. There was no relationship between age, sex, clinical presentation, laboratory findings, the number of plasmapheresis treatments, and either ADAMTS13 inhibitor levels or relapsed/refractory disease. Although several parameters, such as age, low ADAMTS13 activation, and high lactate dehydrogenase, have been reported to be prognostic in the past, we believe that these findings should be reconsidered with current treatment approaches that provide a greater than 90% response and overall survival. In our study, we did not detect either a predictive factor for relapsed/refractory disease or a clinical indicator influenced by ADAMTS13 inhibitor levels.

Anahtar Kelimeler

• Immune Thrombotic Thrombocytopenic Purpura
• von Willebrand Factor
• ADAMSTS13

Türkiye’de Batı Akdeniz Bölgesindeki Edinsel Trombotik Trombositopenik Purpura Hastalarının Klinik Özellikleri ve Relaps/Refrakter Hastalık Risk Faktörleri

Öz

Güncel yaklaşımlarla yanıt ve genel sağkalım oranları %90’ın üzerine çıkan trombotik trombositopenik purpurada (TTP), relapsı öngördürücü ve engelleyici parametrelerin önemi artmıştır. Bu açıdan Batı Akdeniz bölgesindeki immun TTP (iTTP) hastalarının klinik prezentasyonlarını, laboratuvar bulgularını, tedavilerini, tedavi yanıtlarını, relaps/refrakter hastalık durumlarını ve genel sağkalım oranlarını inceledik. Son 10 yılda tanı almış, iTTP tanılı 35 erişkin hasta çalışmaya dahil edildi. Hastaların ortanca takip süresi 46 (2-118) ay olup, 32 hasta (%91.4) hayattaydı. Birinci basamak tedavide 20 (%57.1) hastada klinik remisyon sağlanırken, relaps/refrakter hastalık nedeniyle ikinci sıra tedavi verilen 21 hastanın 20 sinde klinik remisyon sağlanmıştı. Birinci basamakta sadece 4 hastada kullanılan rituksimab ikinci sıra tedavi alan 14 hastaya verilmişti. Relapslar nedeni ile 5 hasta üç basamak, 2 hasta ise dört basamak tedavi almıştı. Yaş, cinsiyet, klinik prezentasyon, laboratuvar bulguları ve plazmaferez sayısı ile hem ADAMTS13 inhibitör düzeyleri hem de relaps/refrakter hastalık arasında bir ilişki yoktu. Geçmişte yaş, ADAMTS13 aktivasyonunun düşüklüğü, yüksek laktat dehidrogenaz gibi bazı parametreler prognostik olarak bildirilse de, %90’ın üzerinde yanıt ve genel sağkalım sağlayan güncel tedavi yaklaşımları ile bu değerlendirmelerin yeniden ele alınması gerektiğini düşünüyoruz. Çalışmamızda hem relaps/refrakter hastalık öngördürücü bir faktör hem de ADAMTS13 inhibitör düzeyinin etkilediği bir klinik yansıma saptamadık.

Anahtar Kelimeler

• İmmun Trombotik Trombositopenik Purpura
• von Willebrand Faktör
• ADAMSTS13

Kaynakça

1. 1. 1Coppo P, Cuker A, George JN. Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine. Res Pract Thromb Haemost. 2019 Jan;3(1):26-37.
2. 2. Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Pathol Soc. 1924;24:21-24.
3. 3. 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(23):1432-1435.
4. 4. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578–84.
5. 5. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017 May 25;129(21):2836-2846.
6. 6. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488–94.
7. 7. 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(5):e237-e245.
8. 8. Siddiqui A, Journeycake JM, Borogovac A, et al. Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children. Pediatr Blood Cancer. 2021;68(5):e28949. Epub 2021 Mar 4.

9. 9. Reese JA, Muthurajah DS, Kremer Hovinga JA, et al. 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):1676-82.
10. 10. Sadler JE. What’s new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program. 2015;2015:631-636.
11. 11. Page 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.
12. 12. Cox EC. Thrombotic thrombocytopenic purpura: report of three additional cases and a short review of the literature. J S C Med Assoc. 1966 ;62(12):465-70
13. 13. Bell WR, Braine HG, Ness PM, et al. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med. 1991 08;325(6):398-403.
14. 14. Rock GA, Shumak KH, Buskard NA, et al; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N. Engl. J. Med. 1991;325:393–397.
15. 15. Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: A cohort study. Lancet Haematol. 2017;4:e157–e164.
16. 16. Lim W, Vesely SK, George JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015 Mar 5;125(10):1526-31.
17. 17. Özpolat HT, Stolla M. Rituximab in the treatment of immune-mediated thrombotic thrombocytopenic purpura. Blood Transfus. 2023 ;21(5):369-374.
18. 18. Coppo P, Bubenheim M, Azoulay E, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood. 2021;137:733–742.
19. 19. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N. Engl. J. Med. 2019;380:335–346.
20. 20. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021;137(14):1855
21. 21. Vesely SK, George JN, 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;102:60–8.
22. 22. Matsumoto M, Yagi H, Ishizashi H, et al. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol. 2004;41:68–74.
23. 23. 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.
24. 24. Jang MJ, Chong SY, Kim I-H, et al. Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience. Int J Hematol. 2011;93(2):163-169.
25. 25. 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(3):380-389.
26. 26. 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(1):71-79.
27. 27. 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(1):60-67.
28. 28. Paydary K, Banwell E, Tong J, et al. Diagnostic accuracy of the PLASMIC score in patients with suspected thrombotic thrombocytopenic purpura: A systematic review and meta-analysis. Transfusion. 2020;60(9):2047.
29. 29. Ayanambakkam A, Kremer Hovinga JA, Vesely SK, et al. Diagnosis of thrombotic thrombocytopenic purpura among patients with ADAMTS13 Activity 10%-20. Am J Hematol. 2017;92(11):E644.
30. 30. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura Blood. 2015;125(25):3860-67
31. 31. Jestin M, Benhamou Y, Schelpe AS, et al; French Thrombotic Microangiopathies Reference Center. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018 Nov 15;132(20):2143-2153.
32. 32. Scully M, Cataland SR, Peyvandi F, et al; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346.
33. 33. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496.
34. 34. Hovinga JAK, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010;115:1500–11.
35. 35. Benhamou Y, Assié C, Boelle PY, et al; Thrombotic Microangiopathies Reference Center. Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Haematologica. 2012 ;97(8):1181-6.
36. 36. Coppo P, Bengoufa D, Veyradier A, et al; Réseau d'Etude des Microangiopathies Thrombotiques de l'Adulte. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. Medicine (Baltimore). 2004 ;83(4):233-244.