Page 19 - Haematologica April 2020

Editorials
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14. Toscani D, Bolzoni M, Ferretti M, Palumbo C, Giuliani N. Role of Osteocytes in Myeloma Bone Disease: Anti-sclerostin Antibody as New Therapeutic Strategy. Front Immunol. 2018;9:2467.
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Animal models of thrombotic thrombocytopenic purpura: the tales from zebrafish
Paul Coppo1 and Bernhard Lämmle2,3,4
1Service d’Hématologie, Centre de Référence des Microangiopathies Thrombotiques, AP-HP.6, Paris, France; 2Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern Switzerland; 3Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany and 4Haemostasis Research Unit, University College London, London, United Kingdom
E-mail: PAUL COPPO - paul.coppo@aphp.fr or BERNHARD LÄMMLE - Bernhard.laemmle@uni-mainz.de doi:10.3324/haematol.2019.245043
Thrombotic thrombocytopenic purpura (TTP) results from systemic microvascular von Willebrand factor (VWF)-induced clumping of platelets causing throm- bocytopenia, microangiopathic hemolysis, and ischemia in the brain, kidneys, heart, and other organs.1 The identifica- tion of a severe deficiency of the specific VWF-cleaving protease, now denoted as ADAMTS13,1 by Furlan et al.2 and Tsai and Lian,3 provided an explanation for the accu- mulation of extremely adhesive, unusually large VWF mul- timers in the plasma of patients with chronic relapsing TTP first reported by Moake et al. in the 1980s.4,5 Severe deficiency of ADAMTS13 activity, caused by biallelic mutations of the encoding ADAMTS13 gene6-8 or, more commonly, by autoantibodies directed against various epi- topes of the metalloprotease resulting in functional inhibi- tion of the enzyme and/or the formation of immune com- plexes and enhanced clearance of ADAMTS132,3,9 underlies congenital (cTTP) and acquired, autoimmune TTP (iTTP), respectively.10
The novel insights into disease mechanisms identified in the laboratory during the past two decades were rapidly and successfully integrated into the clinical management,
to the benefit of patients.11 Targeted therapies were there- by progressively associated with the historical treatment empirically introduced in the 1970s-1980s, based on repeated plasma exchange, replacement of the deficient protease through fresh-frozen plasma, and corticosteroids, which had already dramatically improved the prognosis of patients with this previously mostly fatal disease.12 The successful story of these newly introduced therapeutic approaches include B-cell-depleting monoclonal antibodies that inhibit autoantibody production,13 and nanobodies that bind to the VWF A1 domain and inhibit the VWF- platelet glycoprotein Ib interaction.14,15 Recently, a recombi- nant form of human ADAMTS13 was successfully tested in a pharmacokinetics and safety study in 15 patients with cTTP16 and is expected to facilitate the management of cTTP and possibly iTTP in the near future. This ongoing development illustrates the strength of translational medi- cine when basic science and clinical research combine effi- ciently. This approach allowed TTP to fully enter the excit- ing era of targeted therapies and personalized medicine.
A crucial advance in TTP pathophysiology was the demonstration of the direct role of ADAMTS13 deficiency
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