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Thrombotic thrombocytopenic purpura

Abstract

Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic haemolytic anaemia and a variable degree of ischaemic organ damage, particularly affecting the brain, heart and kidneys. Acute TTP was almost universally fatal until the introduction of plasma therapy, which improved survival from <10% to 80–90%. However, patients who survive an acute episode are at high risk of relapse and of long-term morbidity. A timely diagnosis is vital but challenging, as TTP shares symptoms and clinical presentation with numerous conditions, including, for example, haemolytic uraemic syndrome and other thrombotic microangiopathies. The underlying pathophysiology is a severe deficiency of the activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), the protease that cleaves von Willebrand factor (vWF) multimeric strings. Ultra-large vWF strings remain uncleaved after endothelial cell secretion and anchorage, bind to platelets and form microthrombi, leading to the clinical manifestations of TTP. Congenital TTP (Upshaw–Schulman syndrome) is the result of homozygous or compound heterozygous mutations in ADAMTS13, whereas acquired TTP is an autoimmune disorder caused by circulating anti-ADAMTS13 autoantibodies, which inhibit the enzyme or increase its clearance. Consequently, immunosuppressive drugs, such as corticosteroids and often rituximab, supplement plasma exchange therapy in patients with acquired TTP.

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Figure 1: Structure of ADAMTS13.
Figure 2: Structure of von Willebrand factor.
Figure 3: Pathophysiology of TTP.
Figure 4: Diagnostic algorithm and likelihood of TTP.

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Acknowledgements

The authors thank M. Akiyama, National Cerebral and Cardiovascular Center, Suita, Japan, for preparing the crystal structures for Figures 1 and 2, and N. A. Turner, Department of Bioengineering, Rice University, Houston, Texas, USA, for preparing Figure 3.

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Introduction (J.L.M.); Epidemiology (J.A.K.H.); Mechanisms/pathophysiology (J.A.K.H., T.M. and K.V.); Diagnosis, screening and prevention (B.L. and T.M.); Management (J.A.K.H., P.C. and B.L.); Quality of life (B.L.); Outlook (J.A.K.H., J.L.M. and K.V.); Overview of Primer (J.A.K.H.).

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Correspondence to Johanna A. Kremer Hovinga.

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Competing interests

J.A.K.H. serves on the advisory boards of Ablynx for the development of caplacizumab, and Baxalta for the development of recombinant ADAMTS13. Outside the present work, she has received project funding from Baxalta, Bayer, CSL Behring and Novo Nordisk. The hereditary TTP registry (www.ttpregistry.net, Clinicaltrials.gov identifier: NCT01257269) is supported by an investigator-initiated research grant from Baxalta. In addition, she receives research funding from the Swiss National Science Foundation (grant 310030–160269), the International Society on Thrombosis and Haemostasis (ISTH) 2007 Presidential Fund and the Answering T.T.P. Foundation. P.C. is a member of the advisory boards of Ablynx for the development of caplacizumab, Alexion for the development of eculizumab and Octapharma for the development of Octaplas. He has received funds from Ablynx, Alexion, Octapharma and Roche. The French Reference Center for Thrombotic Microangiopathies (www.cnr-mat.fr) is in part supported by the French Ministry of Health (Plan National Maladies Rares, Direction Générale de l’Offre de Soin) and the Programme Hospitalier de Recherche Clinique (PHRC 2012 P120118, Clinicaltrials.gov identifier: NCT02134171). B.L. serves on the advisory board of Ablynx for the development of caplacizumab. He was chairman of the Data Safety Monitoring Board of Baxalta's BAX930 (recombinant ADAMTS13) study in patients with Upshaw–Schulman syndrome. He has received congress and travel support from Alexion, Baxalta and Siemens, and a lecture fee from Siemens. He holds a patent on ADAMTS13. He is supported by the Bundesministerium für Bildung und Forschung (BMBF), Germany. J.L.M. receives research funding from the Mary R. Gibson Foundation and the Mabel and Everett Hinkson Memorial Fund. T.M. reports personal fees from Bayer, Daiich-Sankyo and Alexion, outside the submitted work and is a member of Alexion's atypical haemolytic uraemic syndrome advisory board. He has a patent for Specific substrate and activity measurement method for von Willebrand factor-cleaving protease, Japan Patent Number 3,944,586 issued, and a patent for Substrate polypeptides for von Willebrand factor-cleaving protease ADAMTS13, US Patent Number 7,718,763 issued. K.V. is a member of the advisory board of Ablynx for the development of caplacizumab. She receives research funding from the European Union Framework Program for Research and Innovation (Horizon2020 Marie Sklodowska Curie Innovative Training Network PROFILE grant), the Answering T.T.P Foundation, the Research Foundation Flanders and the KU Leuven Research Foundation.

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Kremer Hovinga, J., Coppo, P., Lämmle, B. et al. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 3, 17020 (2017). https://doi.org/10.1038/nrdp.2017.20

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