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Thrombotic thrombocytopenic purpura

  • Nature Reviews Disease Primers 3, Article number: 17020 (2017)
  • doi:10.1038/nrdp.2017.20
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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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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.

Figure 1: Structure of ADAMTS13.
Figure 1

ADAMTS13 (which encodes a disintegrin and metalloproteinase with thrombospondin motifs 13, a metalloproteinase of 1,427 amino acids with a multidomain structure) is located on chromosome 9q34, covers about 37 kb (Ref. 9) and neighbours the ABO blood group locus. The calculated molecular weight of ADAMTS13 is 145 kDa, and plasma-purified ADAMTS13 has an apparent molecular weight of 180–190 kDa owing to glycosylation of about 20% of its mass. The schematic representation of the domain structure of ADAMTS13 shows: a signal peptide (SP), a propeptide (P), a metalloproteinase domain (M), a disintegrin-like domain (D), a first thrombospondin type 1 repeat (T1), a cysteine-rich domain (C), a spacer domain (S), seven thrombospondin type 1 repeats (T2–T8) and two CUB domains (CUB1 and CUB2) that are highly homologous to domains found in the complement receptor complex, complement C1r subcomponent–complement C1s subcomponent (C1r–C1s), the embryonic sea urchin epidermal growth factor and bone morphogenetic protein 1. Almost all patients with acquired, immune-mediated thrombotic thrombocytopenic purpura (iTTP) have anti-ADAMTS13 autoantibodies with an epitope in the spacer domain (antibody in green), although in many patients, anti-ADAMTS13 autoantibodies with epitopes in other ADAMTS13 domains are also present. In patients with hereditary TTP, mutations in ADAMTS13 (*) are spread over the different protease domains. Left inset: crystal structure of the DTCS domains with a modelled structure of the M domain. Five amino acid residues (shown in blue) — Arg568, Phe592, Arg660, Tyr661 and Tyr665 — constitute an antigenic surface that is recognized by the majority of the inhibitory anti-ADAMTS13 autoantibodies. The active site is indicated by a red arrow. Right inset: molecular model of ADAMTS13 as determined by small angle X-ray scattering. Left inset adapted with permission from Ref. 223, National Academy of Sciences. Right inset reproduced with permission from Ref. 74, National Academy of Sciences.

Figure 2: Structure of von Willebrand factor.
Figure 2

a | Schematic representation of the domain structure of von Willebrand factor (vWF): a signal peptide (SP), five D domains (D1, D2, D′, D3 and D4), three A domains (A1, A2 and A3), six C domains (C1–C6) and one cystine knot (CK) domain. The vWF A1 domain harbours the platelet glycoprotein Ib (GPIb) and a collagen-binding site, the vWF A2 domain contains the a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) cleavage site, the vWF A3 domain has another collagen-binding site and the vWF C4 domain contains the platelet integrin αIIbβ3-binding site69,224. The CK domain is involved in tail-to-tail dimerization and the D′D3 domain in head-to-head multimerization of vWF dimers. Drawings represent the conformation of two propeptides and a vWF dimer. b | Domain structure of vWF with highlighted crystal structure of the folded A2 domain with hidden ADAMTS13 cleavage site (upper panel) and a model of the unfolded A2 domain with an accessible ADAMTS13 cleavage site, which occurs after shear-induced unfolding of vWF (lower panel). First, ADAMTS13 binds through its thrombospondin type 1 repeats T5-CUB domains to the D4-CK domains of folded vWF66,225. Next, shear forces expose cryptic vWF A2 domain exosites, which interact with the ADAMTS13 spacer domain72, followed by the ADAMTS13 disintegrin-like domain and the metalloproteinase domain, which finally proteolyses the Tyr1605–Met1606 scissile bond in the vWF A2 domain226. Part b adapted with permission from Ref. 223, National Academy of Sciences.

Figure 3: Pathophysiology of TTP.
Figure 3

a | A microvessel (arteriole or capillary) in a healthy individual. Proteolysis by a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) of ultra-large von Willebrand factor (vWF) multimeric strings that are anchored to or secreted from stimulated microvascular endothelial cells. ADAMTS13 cleaves the A2 domain of a vWF monomeric subunit at Tyr1605–Met1606 to prevent and regulate platelet adherence (via glycoprotein Ib) to the A1 domain. b | A microvessel in thrombotic thrombocytopenic purpura (TTP). When ADAMTS13 activity is <10% of normal level, cleavage of secreted or anchored ultra-large vWF strings is severely reduced. The results are: excessive microthrombi formation, shear injury to red blood cells flowing through microvessels that are partially occluded by platelet clumps (producing schistocytes and haemolysis) and activation of the alternative complement pathway on the uncleaved ultra-large vWF strings (inset). Activated complement factors C3 (C3b) and B (Bb) attach to a string in complexes of C3b–Bb (C3 convertase) and C3b–Bb–C3b (C5 convertase). C3a and C5a are anaphylatoxins that are liberated by proteolytic cleavage of C3 and C5, respectively. Other components that bind to uncleaved ultra-large vWF strings are: complement factor D (not shown), which cleaves and activates factor B; complement factor P (properdin), which stabilizes C3 convertase and C5 convertase; and complement factor H and factor I (not shown), which are the negative regulators of C3 convertase. However, the binding of factor H and factor I is insufficient to block C3 convertase activity generated on the strings. c | Plasma vWF. Sodium dodecyl sulfate (SDS)–agarose gel electrophoresis of plasma from a healthy individual (control) and a patient with congenital TTP (cTTP) in remission highlights high-molecular-weight (HMW) vWF multimers and ultra-large (UL) vWF multimers. Of note, ultra-large vWF multimers are less likely to be seen during relapse, perhaps because these hyperadhesive forms adhere to and aggregate platelets in the microcirculation. MAC, membrane attack complex.

Author information

Affiliations

  1. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Freiburgstrasse, Bern, Switzerland.

    • Johanna A. Kremer Hovinga
    •  & Bernhard Lämmle
  2. Department of Clinical Research, University of Bern, Bern, Switzerland.

    • Johanna A. Kremer Hovinga
  3. Centre de Référence des Microangiopathies Thrombotiques, Service d’ Hématologie, Hôpitaux Universitaires de l’Est Parisien et Université Pierre et Marie Curie (Paris 6), Paris, France.

    • Paul Coppo
  4. Center for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany.

    • Bernhard Lämmle
  5. Department of Bioengineering, Rice University, Houston, Texas, USA.

    • Joel L. Moake
  6. Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Toshiyuki Miyata
  7. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Toshiyuki Miyata
  8. Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan.

    • Toshiyuki Miyata
  9. Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

    • Karen Vanhoorelbeke

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Contributions

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.).

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.

Corresponding author

Correspondence to Johanna A. Kremer Hovinga.