Immune TTP: interplay between haplotypes & environment
tive complement pathway to promote the generation of terminal complement complexes (C5b-9).94 These observations therefore deserve systematic explorations to unravel the role of the alternative complement pathway and its regulators (CFH, CFI, MCP and thrombomodulin) in iTTP pathophysiology. Interestingly, HLA-DRB1*11 was reported to be protective against tuberculosis, whereas HLA-DRB1*04 was associated with an increased risk of tuberculosis and severe malaria.95,96 These observations raise the intriguing possibility that autoimmunity against ADAMTS13 leading to iTTP could represent the cost of an efficient ancestral immune response selected to fight against historically harmful infectious agents.
Perspectives: future directions Despite the considerable progress made in unravelling the role of ADAMTS13 in primary hemostasis, our under-
References 1. Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Prim 2017;317020. 2. Scully M, McDonald V, Cavenagh J, Hunt BJ. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1754. 3. Hie M, Gay J, Galicier L, et al. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014;124(2):204-210. 4. Westwood J-P, 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 LP-1166. 5. Scully M, Knobl 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. 6. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2017;15(7):1448-1452. 7. Kremer Hovinga JA, Voorberg J. Improving on nature: redesigning ADAMTS13. Blood. 2012;119(16):3654-3655. 8. Furlan M, Robles R, Solenthaler M, Lä B. Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura. Blood. 1998;91(8):2839-2846. 9. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339(22):1585-1594. 10. Scheiflinger F, Kno P, Trattner B, Plaimauer B, Mohr G, Dockal M. Nonneutralizing IgM and IgG antibodies to von Willebrand factor – cleaving protease ( ADAMTS-13 ) in a patient with thrombotic thrombocytopenic purpura. Blood. 2003;102(9):3241-3243.
haematologica | 2018; 103(7)
standing of the immunopathogenesis of iTTP is still not complete. Future studies will have to reveal a reason for the paradoxically extremely low incidence of the disease considering the frequent occurrence of identified genetic risk factors within the HLA-class II locus in the healthy population. Another field of investigation involves the mechanisms determining the reoccurrence of autoreactive lymphocytes in patients following immunomodulation with B-cell depleting therapies in order to better anticipate relapses. Moreover, a new therapeutic area is being opened in the field with the development of the recombinant ADAMTS13; its interactions with the immune system of iTTP patients will require further investigation. Acknowledgements The authors would like to thank the Horizon 2020 Framework program for Research and Innovation of the European Union for funding this work under 675746 (PROFILE).
11. Crawley JTB, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:292-299. 12. Sadler JE. What’s new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program. 2015;2015:631-636. 13. Thomas MR, de Groot R, Scully MA, Crawley JTB. Pathogenicity of AntiADAMTS13 Autoantibodies in Acquired Thrombotic Thrombocytopenic Purpura. EBioMedicine. 2015;2(8):942-952. 14. Ostertag EM, Kacir S, Thiboutot M, et al. ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro. Transfusion. 2016;56(7):1763-1774. 15. 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(3): 329-336. 16. Ferrari S, Palavra K, Gruber B, et al. Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura. Haematologica. 2014;99(4):779-787. 17. Ferrari S, Knöbl P, Kolovratova V, et al. Inverse correlation of free and immune complex-sequestered anti-ADAMTS13 antibodies in a patient with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2012;10(1):156-158. 18. Bianchi V, Robles R, Alberio L, Furlan M, Lammle B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100(2):710713. 19. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Ann Intern Med. 2004;103(11):4043-4049.
20. Peyvandi F, Ferrari S, Lavoretano S, Canciani MT, Mannucci PM. Von Willebrand factor cleaving (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura. Br J Haematol. 2004;127(4):433-439. 21. Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005;106(4):1262-1267. 22. Tsai HM, Raoufi M, Zhou W, et al. ADAMTS13-binding IgG are present in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 2006;95(5):886892. 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(5):819826. 24. 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(1):7-15. 25. Mariotte E, Azoulay E, Galicier L, et al. 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):e237-245. 26. Joly BS, Stepanian A, Leblanc T, et al. Childonset 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(11):e537-e546. 27. Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115(8):150011; quiz 1662. 28. Ferrari S, Mudde GC, Rieger M, Veyradier A, Kremer Hovinga JA, Scheiflinger F. IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura. J Thromb