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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).

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Haematologica, Volume 103, Issue 7  
Haematologica, Volume 103, Issue 7