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Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is a life-threatening occlusive disorder of the microcirculation that is charac- terized by systemic platelet clumping, organ ischaemia (especially of the brain, heart, gastrointestinal tract and kidneys), profound thrombocytopenia (a low blood plate- let count, <100 × 10 9 cells per litre, often <30 × 10 9 cells per litre) and fragmentation of red blood cells. The disease was first described by Eli Moschcowitz in 1924 (REF. 1); however, its cause remained enigmatic until Moake et al. 2 reported four patients with chronic relapsing TTP who lacked the capacity to process von Willebrand factor (vWF). Subsequently, other investigators demonstrated that this inability to cleave vWF was the result of a severe deficiency of a metalloproteinase 3–5 , which was later characterized as a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13; FIG. 1) and identified as the protein with vWF-processing activ- ity that was defective or lacking in TTP 6–10 . Thus, TTP is defined as thrombotic microangiopathy (TMA) with severe deficiency of ADAMTS13 activity. Severe ADAMTS13 deficiency (<10% of the nor- mal enzyme activity) is the result of either homozygous or compound heterozygous mutations in ADAMTS13 (REFS 9,11–15) (hereditary or congenital TTP (cTTP); also known as Upshaw–Schulman syndrome 16,17 (Online Mendelian Inheritance in Man (OMIM) #274150)), or of anti-ADAMTS13 autoantibodies in acquired, immune-mediated TTP (iTTP) 3–5,18 , which is the more prevalent form. TTP is a chronic condition that can manifest as acute episodes of TMA. Although a rare disease, TTP is the focus of much investigation by clinicians and researchers because of its complex pathophysiology, the still high mortality of acute episodes (up to 20%) and the continuing risk of relapse in survivors of a first acute disease episode 19 . In this Primer, we discuss the molecular and clinical aspects of TTP, as well as future research directions. We also dis- tinguish TTP from other TMAs that have similar clinical presentations but often a distinct pathophysiology. Epidemiology iTTP iTTP mainly affects adults, with peak incidences in the third to fifth decades of life in Europe and the United States 20–23 , and in the seventh decade of life in Japan 24 . Similarly to other autoimmune diseases, black (African Americans or African Caribbeans) individuals and women are more frequently affected than non-black individuals and men, with female to male ratios ranging from 2.5:1 to 3.5:1 in different cohorts 21,22 . Of note, in the Japanese cohort, men and women ≥60 years of Correspondence to J.A.K.H. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Freiburgstrasse, CH-3010 Bern, Switzerland. [email protected] Article number:17020 doi:10.1038/nrdp.2017.20 Published online 6 Apr 2017 Thrombotic thrombocytopenic purpura Johanna A. Kremer Hovinga 1,2 , Paul Coppo 3 , Bernhard Lämmle 1,4 , Joel L. Moake 5 , Toshiyuki Miyata 6–8 and Karen Vanhoorelbeke 9 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. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17020 | 1 PRIMER ©2017MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.

Thrombotic thrombocytopenic purpura · Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is a life-threatening occlusive disorder of the microcirculation

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  • Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is a life-threatening occlusive disorder of the microcirculation that is charac-terized by systemic platelet clumping, organ ischaemia (especially of the brain, heart, gastrointestinal tract and kidneys), profound thrombocytopenia (a low blood plate-let count,

  • age were equally affected24. iTTP is very rare in individ-uals T (p.R1060W) in exon 24 (REFS 12,38,42,46–48). Whereas c.4143_4144dupA has been described in families originating from central and northern Europe and accounted for many cases of cTTP among unrelated individuals in Scandinavia and around the Baltic Sea42,46, the distribution of p.R1060W is even more widespread. It is the predominant mutation in British and French patients, but has also been reported in families with a history of cTTP from Scandinavia, central Europe, Italy and Turkey, as well as in North Americans of European descent38,47.

    cTTP affects men and women equally. Although the prevalence of cTTP is unknown, it has been postulated that it accounts for T (p.R1060W) of 0.04–0.33% and 0.3–1%, respectively. A slightly lower allelic frequency (0.06%) for the p.R1060W mutation was documented in the Rotterdam study, a population-based

    Author addresses

    1Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Freiburgstrasse, Bern, Switzerland.2Department of Clinical Research, University of Bern, Bern, Switzerland.3Centre de Référence des Microangiopathies Thrombotiques, Service d’ Hématologie, Hôpitaux Universitaires de l’Est Parisien et Université Pierre et Marie Curie (Paris 6), Paris, France.4Center for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany.5Department of Bioengineering, Rice University, Houston, Texas, USA.6Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.7Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.8Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan.9Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

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  • cohort study in the Netherlands51. In all population screen ings carried out to date, only heterozygous mutation carriers have been identified.

    Age at diagnosis in cTTP shows a bimodal distrib-ution, with about half of patients presenting with their first episode of TTP by 2–5 years of age, and a second peak in early adulthood, with the inaugural episode specifically frequent during pregnancy41,43,52,53. Indeed, among women who had an episode of TTP during their first pregnancy, the frequency of cTTP was 25–66%44,45. In this subgroup of women with cTTP, the prevalence of p.R1060W is remarkable: in the UK and French cTTP cohorts, 17 out of 23 (74%) and 16 out of 21 (76%) patients, respectively, were either compound heterozygous or homozygous carriers of this mutation23,45. Of note, patients with cTTP heterozygous for p.R1060W have regularly measurable residual ADAMTS13 activity of 3–6% of the physio-logical levels; homozygous p.R1060W carriers even have 5–12%53,54. This observation suggests that, unlike most cTTP-associated mutations, which result in no residual ADAMTS13 activity, p.R1060W causes a less severe loss of enzymatic function. The level of residual ADAMTS13 activity was suggested to be an important determinant of clinical severity with early onset (1 associated with ADAMTS13 activity of

  • together with an equimolar amount of vWF propeptide, in Weibel–Palade bodies (storage granules) in endothe-lial cells or in α-granules of megakaryocytes and plate-lets68,69. Upon stimulation by various agonists, such as cytokines (for example, tumour necrosis factor or IL-8) and histamine, or by fluid shear stress, ultra-large vWF multimers are rapidly secreted from endothelial cells and can remain anchored to the endothelial surface as long, string-like, hyper-adhesive structures or can be released into the circulation. The shear conditions of the blood flow unfold both anchored and freshly released ultra-large vWF multimers70,71, thereby exposing other-wise cryptic platelet-binding sites and the ADAMTS13 cleavage site (FIG. 2b).

    ADAMTS13 activity is regulated by conformational changes in its substrate, in a so-called molecular zipper mechanism72. Conformational activation was shown to also occur in ADAMTS13 (REFS 73–75), which circu-lates in a closed conformation with its CUB domains interacting with the spacer domain73 (FIG. 1). Binding of vWF to this closed ADAMTS13 conformation leads to the exposure of functional exosites (secondary binding sites) in the ADAMTS13 spacer domain and, hence, con-formational activation of the protease73,74. This process possibly optimizes vWF cleavage under fluid shear stress in vivo but might also make ADAMTS13 suscep tible to immune recognition73,74. Proteolysis of ultra-large vWF multimers generates shorter multi mers of vari able molecular weight, depending on where ADAMTS13

    cleavage takes place. The resulting smaller multimers again adopt a folded conformation, which prevents spontaneous binding of platelets and further digestion by ADAMTS13 (REF. 72).

    TTP pathogenesisWhen ADAMTS13 activity is lacking, ultra-large vWF multimers persist in the circulation (FIG. 3), and the spon-taneous binding of platelets is no longer restrained. Thus, the ultra-large vWF multimers bind to, accumulate and activate platelets, forming the vWF-rich microthrombi that are a hallmark of TTP (FIG. 3b). These dissemin-ated microthrombi scavenge platelets, which causes thrombo cytopenia, mechanically destroy red blood cells, which leads to haemolytic anaemia with fragmented red blood cells (schistocytes) that are visible on the periph-eral blood smear, occlude the microcirculation and cause organ ischaemia.

    Anti‑ADAMTS13 autoantibodiesiTTP is characterized by the appearance of inhibitory or non-inhibitory autoantibodies against ADAMTS13. In the majority of patients, strong functional ADAMTS13 inhibitors can be demonstrated by Bethesda-like assays (see below)4,5,76. However, 10–25% of patients have non-inhibitory anti-ADAMTS13 autoantibodies, which have been postulated to acceler ate ADAMTS13 clear-ance77–79. As the plasma levels of ADAMTS13 antigen are also severely reduced in the majority of patients with

    Figure 2 | Structure of von Willebrand factor. a   |  Schematic representation of the domain structure of von Willebrand factor (vWF): a signal peptide (SP), five D domains (D1, D2, Dʹ, 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 DʹD3 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.

    A2 unfolded

    A2 folded

    Met1606

    Met1606

    Tyr1605

    Shear

    D1

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    C1

    C2

    C3

    C4

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    C6

    CK C

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    2C

    3C

    4C

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    C2

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    C6

    CK

    D3D2 D′ A1 A2 A3 D4 D3D′ A1 A2 A3 D4

    D3D′ A1 A2 A3 D4

    Tyr1605

    Propeptide Mature vWF

    ADAMTS13cleavage site

    GPIb- and collagen-

    bindingsite

    Collagen- bindingsite

    αIIbβ3- binding site

    ab

    Cleavage site

    ADAMTS13

    Nature Reviews | Disease Primers

    D1 D2

    C1 C2 C3 C4 C5 C6 CKA2 A3

    D4A1

    A1

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  • iTTP, clearance of the enzyme is probably an important contributing mechanism to the reduced protease activity, besides the direct inhibition by autoantibodies78–80.

    Autoantibodies that recognize the spacer domain of ADAMTS13 are present in 97–100% of patients with iTTP79,81–83, and virtually all inhibitory anti-ADAMTS13 autoantibodies that are identified by routine assays are directed to the ADAMTS13 spacer domain79. Epitope fine mapping showed that five amino acid residues (FIG. 1) constituted the principal antigenic surface for the majority of inhibitory anti-ADAMTS13 autoanti-bodies84–88. However, the autoimmune response against ADAMTS13 is polyclonal, and about two-thirds of patients also have antibodies against other ADAMTS13 domains79,81–83, although these epitopes have not been fine mapped.

    Non-inhibitory anti-ADAMTS13 autoantibodies have also been observed in 4–15% of healthy controls and blood donors, as well as in numerous patients with cTTP, in whom titres were often fluctuating. In some of these patients with cTTP, the treatment interval of regular plasma prophylaxis to supplement ADAMTS13 levels had to be shortened based on clinical judgement (mainly because of the development of neurocognitive symptoms), despite full recovery and a normal plasma half-life of infused exogenous plasma ADAMTS13 (REFS 40,43). So far, functional ADAMTS13 inhibitors have been described in only two patients with cTTP43,89. These inhibitors were not boosted by subsequent plasma therapy, and are thus reminiscent of low-titre inhibitors in haemophilia A.

    Anti-ADAMTS13 autoantibodies are predomin-antly of the IgG class, but also IgM and IgA have been reported in a limited number of patients with iTTP29,90,91. Among the anti-ADAMTS13 IgG autoantibodies, the IgG4 subclass prevails, followed by IgG1, IgG2 and IgG3 (REFS 86,91). High IgG4 titres were shown to be associ-ated with an increased risk of relapse, and IgG4 was often the only anti-ADAMTS13 isotype. In a small number of patients, the presence of IgA or IgG1, or both, at pres-entation with an acute TTP episode was associated with adverse outcome90,91.

    Anti-ADAMTS13 autoantibodies frequently use VH1‑69 and VH1‑3 in the variable segment of the heavy-chain locus88,92, and somatic mutation rates of characterized anti-ADAMTS13 autoantibodies suggest affinity maturation88,92,93. In longitudinal studies over multiple relapses, functional maturation (that is, from non-inhibitory to inhibitory anti-ADAMTS13 auto-antibodies) or epitope spreading (the development of an immune response to additional ADAMTS13 epitopes), or both, was demonstrated in some patients, suggesting a continuous shaping of the autoimmune response to ADAMTS13 in iTTP79,94.

    The unexpectedly high ADAMTS13 antigen plasma levels in some samples of patients with iTTP, despite the presence of anti-ADAMTS13 autoantibodies, prompted the detection of circulating ADAMTS13 immune com-plexes78, which are formed by the integral binding of ADAMTS13 to an anti-ADAMTS13 autoantibody. These enzymatically inactive immune complexes

    were subsequently found not only during acute epi-sodes and relapses94–97 but also in patients in clinical remission, even years after the last acute TTP episode96. Moreover, the presence of ADAMTS13 immune com-plexes seemed to be predictive of a higher probability of recurrence of acute TTP events in the first 2 years after disease onset97.

    The mechanisms involved in the loss of tolerance to ADAMTS13 remain unknown. The formation and maturation of antibodies requires immune recognition, endocytosis and processing of ADAMTS13 into peptides that are presented on MHC class II molecules of antigen- presenting cells. Sugar moieties on ADAMTS13 can interact with mannose receptors on antigen- presenting cells, thereby promoting endocytosis of the protease98. Studies have shown that peptides derived from the CUB2 domain of ADAMTS13 were presented by MHC class  II molecules encoded by HLA‑DRB1*11 and HLA‑DRB1*03 and that patients with iTTP had circu-lating CD4+ T cells in peripheral blood that were reactive to peptides derived from the CUB2 domain99,100.

    Diagnosis, screening and preventionClinical presentationTTP often presents with an acute onset and severe dis-ease course101. Amorosi and Ultmann102 reviewed 271 patients from the literature and delineated the diag-nostic pentad of clinical findings that were present in 88–98% of patients (however, owing to early diagnosis, the complete pentad is now rarely present in patients diagnosed with acute TTP101,103–106). These signs are fever, purpura or haemorrhage associated with thrombo-cytopenia, haemolytic anaemia with schistocytes on the blood smear, neurological manifestations (which are often transient, ranging from headache or mental changes to focal signs, seizures and coma) and vari-able degrees of renal dysfunction. Haemolytic uraemic syndrome (HUS), which is a TMA that predominantly affects the kidneys, was recognized as one of the possible differential diagnoses107.

    Although the onset of disease is typically sudden, prodromal manifestations (including fatigue, arthralgia, myalgia and abdominal or lumbar pain) that suggest a flu-like episode are frequently reported at the time of diagnosis or during the preceding days. Cardiac events may include non-ST-elevation myocardial infarction (non-STEMI) and STEMI, congestive heart failure, arrhythmias, cardiogenic shock and sudden cardiac arrest. An increased serum cardiac troponin level upon presentation was an accurate predictor of subse-quent acute myocardial infarction, as well as death and treatment refractoriness108,109. Digestive tract involve-ment, including abdominal pain, nausea, vomiting and diarrhoea, was reported in up to one-fourth of cases. Autopsy studies revealed that microvascular thrombi are present in almost all organs: particularly in the brain (primarily in the cerebral cortex), heart, kidneys and the digestive tract, but also in the spleen, pancreas and adrenal glands. In the absence of adequate management, patients develop multiple organ failure and eventually die within days or weeks.

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  • Differential diagnosis of TTPThe clinical signs, even when all symptoms of the clas-sic pentad are simultaneously present, are not specific for TTP, and a series of other TMAs and disorders that result in similar manifestations have to be considered. Because TTP is a medical emergency, a rapid diagnosis is essential. Assessment of ADAMTS13 activity is piv-otal in evaluating a patient who presents with an acute

    TMA. However, the results of ADAMTS13 activity assays are not always readily available, and because of high mortality rates, treatment cannot be postponed. Thus, a presumptive diagnosis has to be made and treatment initiated based on clinical presentation, the presence or absence of certain conditions or comorbid-ities and routine laboratory tests (FIG. 4). Although the leading signs might guide the clinician in formulating

    Figure 3 | Pathophysiology of TTP. 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

  • a diagnosis, it should be kept in mind that none of the routine biomarkers, such as creatinine and lactate dehydro genase levels and platelet counts, is specific for or can formally rule out one condition.

    Shiga toxin-associated HUS. A differential diagno-sis of TTP is Shiga toxin (STX)-associated HUS (also known as typical HUS), caused by STX-producing, enterohaemorrhagic bacteria, mainly Escherichia coli. STX-HUS mostly occurs in children

  • Connective tissue disorders. TMA can occur in individ-uals affected by connective tissue disorders, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis. A large study from Japan that included 127 patients with TMA associated with con-nective tissue disorders showed that the majority of these patients had normal or mildly to moderately decreased ADAMTS13 activity, although some patients with sys-temic lupus erythematosus or rheumatoid arthritis had a severe autoantibody-mediated ADAMTS13 deficiency and, therefore, iTTP secondary to connective tissue disorders30. Thus, iTTP secondary to systemic lupus erythematosus is possible.

    Pregnancy-induced TMA. Correctly diagnosing preg-nant women who present with an acute TMA is challeng-ing, as pregnancy has been associated with a wide range of TMAs44,105,130. Pre-eclampsia and HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome show features that are difficult to distinguish from classic TTP. Arterial hypertension and oedema in pre-eclampsia and severe liver damage in HELLP syndrome are differential diagnostic clues. Both pre- eclampsia and HELLP syn-drome usually manifest in the third trimester, typically after the 34th gestational week and promptly resolve

    within days after delivery103. In HELLP syndrome, ADAMTS13 activity is normal or mildly reduced, but the vWF A1 domain might be more often in a glyco-protein Ib-binding conformation131. cTTP is much less common than HELLP, but might first manifest during pregnancy44,52,130,132. Virtually every woman with cTTP will have an acute episode of TTP during her first preg-nancy, often before the third trimester, even if she had been asymptomatic until then. iTTP can also manifest during pregnancy44. However, whereas women with cTTP will almost invariably show a disease flare-up during an ensuing pregnancy, women with iTTP who experience an episode during their first pregnancy seem to have a moderate risk of relapse but an increased risk of pre-eclampsia in a consecutive pregnancy133.

    ADAMTS13 assays and interpretationThe status of ADAMTS13 in a patient can be assessed in various ways. Activity assays measure the ability of the enzyme to cleave vWF multimers or vWF peptides, anti-body assays determine the presence of anti-ADAMTS13 autoantibodies and/or their inhibitory potential, and antigen assays measure the plasma concentration of the protease (TABLE 1). ADAMTS13 activity assays using multimeric vWF substrate used to be difficult to per-form and laborious. In 2004, Kokame et al.134 found that the minimal functional substrate for ADAMTS13 comprised 73 amino acid residues (D1596 to R1668) in the vWF A2 domain and developed a fluorescence resonance energy transfer (FRET)-based assay135. This FRETS-VWF73 assay and other similar assays136 have become widely available in diagnostic laboratories, show very good reproducibility and are now pushing towards detection limits below 5%135–139. The presence and levels of functional ADAMTS13 inhibitory autoantibodies are assessed in a Bethesda-like assay by mixing a sample of heat-inactivated plasma from the patient with a plasma pool from healthy controls and measuring the residual ADAMTS13 activity in the mixture. The inhibitory autoantibodies in the plasma of the patient neutralize ADAMTS13 that is present in the control sample. One inhibitor unit (Bethesda unit per ml) is defined as the amount of autoantibodies that reduces ADAMTS13 activity in control plasma to 50%140. The total plasma level of anti-ADAMTS13 IgG antibodies (whether inhibitory or non-inhibitory) can be assessed by various custom- made or commercially available enzyme-linked immunosorbent assays (ELISAs), using ADAMTS13 as immobilized antigen. In addition, the plasma levels of ADAMTS13 antigen can be assessed by ELISA, but the levels of ADAMTS13 antigen are not considered relevant for diagnosis or for guiding treatment in TTP.

    There are limitations to each of these tests. In the FRETS-VWF73 assay, free haemoglobin or bilirubin in the plasma of patients who are hyperbilirubinaemic, which may occur in TTP as a result of haemolysis, act as fluorescence quenchers, resulting in inaccurately low ADAMTS13 activity141. In the absence of protease inhib-itors, such as Pefabloc SC (Sigma-Aldrich), other pro-teases that are present in plasma samples might interfere with accurate measurement of ADAMTS13 activity136.

    Figure 4 | Diagnostic algorithm and likelihood of TTP. Diagnostic flowchart in a patient presenting with thrombotic microangiopathy (TMA), consisting of microangiopathic haemolytic anaemia and thrombocytopenia with or without organ failure. Monitoring a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity during remission contributes to distinguishing congenital thrombotic thrombocytopenic purpura (TTP) from immune-mediated TTP, as in the latter, ADAMTS13 activity should recover during remission. STX-HUS, Shiga toxin-producing, enterohaemorrhagic bacteria-induced haemolytic uraemic syndrome.

    • Platelet count• Creatinine level

  • In particular, leukocyte-derived proteases cleave near or at the scissile bond in the vWF A2 domain, which may theoretically lead to overestimating ADAMTS13 activ-ity142. In patients with iTTP, extensive plasma dilution required for some assays might lead to the dissociation of ADAMTS13 immune complexes, resulting in over-estimation of ADAMTS13 activity94. An improved assay using undiluted plasma samples has been reported143. ADAMTS13 inhibitor levels assessed by static assays are not always consistent with those obtained by assays per-formed under flowing fluid conditions, possibly because certain ADAMTS13 epitopes are selectively exposed under shear144 or because ADAMTS13 inhibitory autoantibodies that target an epitope in the ADAMTS13 carboxy-terminal domains are not identified by vWF peptide-based activity assays. A negative result of a Bethesda-like assay or an antibody ELISA should be controlled in a second sample.

    Distinction between iTTP and cTTPDistinction between iTTP and cTTP is mandatory to help guide treatment and follow-up. In cTTP, the func-tional ADAMTS13 inhibitory autoantibody test is neg-ative, severely reduced ADAMTS13 activity persists over time and a full recovery of ADAMTS13 activity is expected upon plasma infusion with a plasma half-life of infused ADAMTS13 of 2–3 days (REFS 65,145). Molecular analysis to determine the presence of caus-ative ADAMTS13 mutations can help to distinguish between cTTP and iTTP.

    ManagementAcute TTP episodes are medical emergencies: max-imal resuscitative measures might be required and the immedi ate outcome might not be predictable. In several centres, patients are routinely treated in intensive care units during the first few days. Older age, an increased plasma level of cardiac troponin, which indicates dam-age to the myocardium, and very high levels of lactate dehydro genase at diagnosis were associated with increased mortality and treatment refractoriness108,109,146.

    Plasma therapyPlasma therapy is used to manage both iTTP and cTTP. There are two kinds of plasma therapy: plasma infu-sions and therapeutic plasma exchange (TPE). TPE with replacement of fresh frozen or solvent detergent plasma remains the cornerstone of current management of iTTP. By replacing large volumes of the plasma of the patient, TPE replenishes the activity of ADAMTS13 and removes anti-ADAMTS13 autoantibodies, ADAMTS13 immune complexes, high-molecular-weight vWF multimers and inflammatory cytokines, although this removal has not been formally demonstrated. The introduction of TPE in the early 1980s led to an impressive improvement in the prognosis of TTP, with survival rates rising from 80%147. In 1991, a randomized controlled trial of plasma infusion versus TPE for the treatment of adult patients with TTP established a plasma volume- dependent response rate (defined as a platelet count of >150 × 109 cells per litre and no new neurological events)

    Table 1 | ADAMTS13 assays

    Test Substrate Mechanism Output

    ADAMTS13 activity

    FRETS‑VWF73* vWF A2‑derived peptide

    FRET using ADAMTS13 cleavable, fluorophore-tagged substrate

    Fluorescence intensity is proportional to ADAMTS13 activity

    vWF multimer assay*

    Full-length vWF vWF proteolysis by ADAMTS13 in the presence of low-ionic strength and urea, and analysis of the vWF multimer size in SDS–agarose gels and western blotting

    Reduction of vWF multimeric size is proportional to ADAMTS13 activity

    vWF fragment assay*

    Full-length vWF vWF proteolysis by ADAMTS13 in the presence of low-ionic strength and guanidinium chloride and SDS–polyacrylamide gel electrophoresis of cleaved vWF

    Occurrence of disulfide‑linked dimers of carboxy‑terminal 176 kDa fragments is proportional to ADAMTS13 activity

    Residual collagen- binding assay*

    Full-length vWF Proteolysis of vWF by ADAMTS13 reduces the ability of vWF to bind to collagen

    Reduction of vWF function is proportional to ADAMTS13 activity

    Residual ristocetin cofactor assay*

    Full-length vWF Proteolysis of vWF by ADAMTS13 reduces vWF ristocetin cofactor function

    Reduction of vWF function is proportional to ADAMTS13 activity

    Platelet string assay‡

    Full-length vWF Endothelial cell cultures are stimulated to release long vWF strings, which are perfused with labelled platelets and plasma

    Abundance of platelet strings is reciprocal to ADAMTS13 activity

    Vortex assay‡ Full-length vWF vWF proteolysis by ADAMTS13 in the presence of shear stress, and analysis of vWF multimer size in SDS–agarose gels and western blotting

    Reduction of vWF multimeric size is proportional to ADAMTS13 activity

    Anti‑ADAMTS13 autoantibodies

    Bethesda‑like assays*

    Control plasma mixed with heat-inactivated patient plasma

    Inhibitory anti-ADAMTS13 autoantibodies reduce ADAMTS13 activity of control plasma

    Residual ADAMTS13 activity inversely correlates with the presence of functional inhibitory autoantibodies

    ELISA* Immobilized ADAMTS13

    Binding of anti‑ADAMTS13 autoantibodies in a plasma sample to immobilized ADAMTS13

    Quantification of anti-ADAMTS13 autoantibodies

    ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13; ELISA, enzyme-linked immunosorbent assay; FRET, fluorescence resonance energy transfer; SDS, sodium dodecyl sulfate; vWF, von Willebrand factor. *Static. ‡Flow.

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  • by day 9 of 47% for TPE versus 27% for plasma infusion, and survival at 6 months of 78% versus 49%, respec-tively)148. TPE is performed daily until the platelet count has stably recovered, haemolysis has ceased and no addi-tional organ dysfunction occurs. TPE initially usually requires the exchange of 1.5 times the patient’s plasma volume, then the volume can be reduced to 1 times the patient’s plasma volume after a few days. A twice-daily TPE treatment in severe, initially refractory iTTP has been reported149,150, but the benefit of this regimen was difficult to assess as other treatments were often initiated or intensified simultaneously.

    In cTTP, plasma infusions are usually sufficient, although, sometimes, a few TPE sessions might be required to treat acute episodes43–45,132. Regular plasma infusions are effective in preventing acute episodes in cTTP, but there are no official guidelines indicating when a prophylactic plasma regimen should be started.

    CorticosteroidsGiven the autoimmune nature of iTTP, there is a ration-ale for the use of corticosteroids, although there are few randomized controlled trials. Before the systematic use of TPE was introduced, it was reported that 30 out of 54 (55%) patients with TTP without consider able organ involvement responded within 48–72 hours to cortico-steroids alone151. A randomized controlled trial compared standard-dose with high-dose methylprednisolone as an adjunctive therapy to TPE in 60 patients with newly diag-nosed iTTP152. After 23 days of treatment, remission was achieved in 77% and 47% of patients in the high-dose and standard-dose arms, respectively. Following the introduc-tion of corticosteroids as routine adjunctive treatment to TPE in the Oklahoma TTP-HUS registry, the reported number of TPE sessions required to achieve remission was reduced, a finding that was paralleled by a reduc-tion of treatment-associated complications153. Altogether, these data indicate that corticosteroids in association with TPE are beneficial in the management of iTTP.

    Biologic therapyRituximab, a humanized anti-CD20 monoclonal anti-body that was originally developed to treat CD20+ B cell neoplasia, was first introduced as iTTP treatment in patients who had a suboptimal response (that is, dis-ease exacerbation, defined as a recurrence of thrombo-cytopenia during the period of daily TPE or within 30 days of stopping TPE, or refractoriness) to con-ventional therapy, with the aim of suppressing the production of anti-ADAMTS13 autoantibodies154–160. In these patients, daily TPE was usually continued and rituximab was administered periodically after a TPE session, most often weekly for 4 weeks (TABLE 2). Rituximab was associated with a rapid and substantial depletion of peripheral B cells, more-frequent recovery of ADAMTS13 activity and more-effective depletion of anti-ADAMTS13 autoantibodies. In addition, two prospective studies reported on patients treated with rituximab as front-line therapy158,161, which resulted in fewer and delayed relapses158–160, prompting the suggestion that all patients with iTTP should be treated up-front with rituximab in conjunction with TPE; how-ever, this suggestion is still being debated162. To pre-vent overtreatment, it is important to consider that at least 50% of patients can recover from an acute iTTP episode with standard TPE alone or with the addition of corticosteroids4,19,124,148,163.

    SplenectomySplenectomy was performed as a last resort in patients with TTP for many years with mixed results (reviewed in REF. 164) before the introduction of TPE and in the absence of any effective treatment. The understanding of the pathophysiology of iTTP now provides a ration-ale to treat patients who relapse or are refractory to TPE and/or rituximab treatment by splenectomy76,88,165. A study reporting the long-term (median: ~9 years) follow-up of 33 patients with recurring or refractory TTP who underwent splenectomy showed that it led

    Table 2 | Reports involving ≥10 patients with acquired, immune-mediated TTP treated with rituximab in the acute phase

    Refs n Complete remission achieved (%)

    Median days to complete remission (range)

    History of previous iTTP (%)

    Relapse (%)

    Median months to relapse (range)

    Serious adverse events

    Scully et al.154* 25 100 11 (7–21) 44 0 NA One fatal pneumonia, after achieving complete remission, and one morbilliform rash

    Jasti et al.155‡ 12 83 18 (14–41) 8 8 23 One varicella zoster virus transverse myelitis and encephalitis

    Ling et al.156‡ 13 92 NA 54 0 NA None

    de la Rubia et al.157‡ 24 87.5 14 (7–35) 42 12.5 29 (7–29) None

    Scully et al.158§ 40 82.5 12 (NA) 15 10 27 (17–31) None

    Froissart et al.159* 22 82 12 ± 6.7 14 14 24 (20–36) None

    Page et al. 160‡,|| 16 100 NA 0 12.5 30 and 118.8|| Formally none; however, two patients died of systemic lupus erythematosus during the study

    Vazquez‑Mellado et al.161*,§,¶

    11 100 NA 9 9 8 None

    iTTP, acquired immune‑mediated thrombotic thrombocytopenic purpura; NA, data not available. *Prospective. ‡Retrospective. §Rituximab as front-line therapy. ||Only survivors are reported (two additional patients died). ¶Rituximab dosage was lower than in all other studies.

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  • to remission in all but one patient, and the 10-year relapse-free survival in the whole cohort was 70%166. Comparing the efficacy of splenectomy with that of rituximab in the treatment of refractory or recurrent iTTP would require a difficult-to-perform randomized controlled trial. Evidence suggests that splenic B cells that produce anti-ADAMTS13 autoantibodies might escape anti-CD20 therapy in some patients88. If splenec-tomy is considered in a patient with relapsing or refrac-tory iTTP, a laparoscopic surgical procedure should be preferred, and the patient should at least be partially stabilized by TPE166.

    Other drugsImmunomodulatory drugs. These drugs aim to suppress the production of anti-ADAMTS13 auto-antibodies in patients with refractory iTTP who had suboptimal responses to other treatments and are often prescribed as a last resort. Vincristine was used mainly in the pre-rituximab era. Although a review of 56 studies showed that 73% of patients receiving vincristine achieved stable remission167, it is likely that many (or most) treatment failures of vincristine were not reported, as the confidence of haematologists in this drug to treat iTTP waned over the years and it is now rarely used.

    Cyclosporine A has been reported to be effective168, with clinical responses correlating with improved ADAMTS13 activity and the suppression of anti- ADAMTS13 autoantibody production169. However, a recent randomized clinical trial showed no statistically significant difference in the exacerbation rate between patients treated with cyclosporine A or corticosteroids as adjunctive therapy170.

    Platelet count and ADAMTS13 activity can recover with cyclophosphamide171, but because of its severe adverse effects (that is, bone marrow suppression, infectious complications, decreased fertility and a long-term risk of malignancy), this drug is justified only in rituximab-resistant, refractory patients.

    Bortezomib, a proteasome inhibitor used to treat multiple myeloma and antibody-mediated rejection of transplanted solid organs, was effectively used to elimin-ate anti-ADAMTS13 autoantibody-producing plasma cells that are resistant to the usual immunosuppressive therapies in some patients172–175.

    N-acetylcysteine. N-acetylcysteine (NAC) is approved for the treatment of acetaminophen toxicity or for bronchoalveolar obstruction, and has been shown to inhibit platelet adherence to endothelial cell-anchored vWF multimers (possibly soluble ones too)176,177 and to reduce the size of soluble high-molecular-weight vWF multimers in vitro176. The anti-thrombotic effect of NAC might predominantly result from the reduc-tion of the 1278–1458 disulfide bond in the vWF A1 domain that is important for vWF binding to platelet glycoprotein Ibα176–178.

    Recent studies in animal models of TTP demon-strated that NAC alone was effective in preventing the development of severe acute TTP signs (in mice),

    but could not reverse them once established (in mice and baboons)179. NAC has not been approved for use in TTP or other TMAs. As of 2017, three papers have described the successful ‘off-label’ use of NAC (in con-junction with continued TPE) in five patients with refractory TTP178,180,181, whereas NAC treatment failed in three other patients with refractory TMA174,182–184.

    Quality of lifeRelapseEach acute TTP episode exposes the patient to a risk of morbidity and mortality. The prevention of relapses is, therefore, a rationale to treat patients with TTP in clinical remission. In cTTP, relapses may become fre-quent after the first episode and some patients depend on regular plasma infusions every 2–3 weeks to main-tain normal platelet count and to avoid clinical TTP manifestations and long-term morbidity52.

    In iTTP, relapses occur in as many as 40% of patients who survive the first disease episode within 7–10 years of follow-up19. In a series of patients with other forms of TMA besides iTTP, relapses affected almost exclusively individuals with iTTP19,163, and recurrent episodes were usually associated with severe acquired ADAMTS13 deficiency90. Although a few patients with iTTP might achieve and remain in remission despite persisting severely reduced ADAMTS13 activity19,90,185, the majority of patients recover ADAMTS13 activity upon remission. It has been suggested that the decrease in ADAMTS13 activity during remission is a strong risk factor for ensuing disease recurrence186,187. Thus, routine measurements of ADAMTS13 activity and auto antibody titres may help in long-term disease management. In a small prospective study, lower ADAMTS13 activ-ity and younger age were predictive of relapse within 3 months, whereas inhibitory auto antibody titres were not correlated186. However, another study suggested that high titres of inhib itory anti- ADAMTS13 IgG antibod-ies at presentation were associ ated with undetectable ADAMTS13 activity during remission and predicted relapses within 18 months90. Recently, Page et al.188 reported on patients with iTTP from the Oklahoma TTP-HUS registry who had prolonged periods of severe ADAMTS13 deficiency without experiencing acute TTP episodes. In some patients, ADAMTS13 activity recovered spontaneously to normal levels and none of these patients relapsed, whereas up to 60% of patients with a severe ADAMTS13 deficiency in remis-sion experienced at least one TTP relapse. The French TMA Reference Center Network recently reported their results on 30 patients with iTTP who were pre- emptively treated with rituximab during remission189. Rituximab reduced the incidence of relapse with min-imal adverse effects; however, in about one-third of patients, further cycles of rituximab were required to maintain detectable levels of ADAMTS13 activity, and 16% of patients required other immunomodulatory drugs and/or splenectomy189. Nevertheless, pre-emptive rituximab treatment should be considered for patients in remission who experience frequent and/or severe episodes of iTTP189.

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  • Comorbidities and sequelaeMany patients with iTTP experience reduced health- related quality of life190. Detailed neurocognitive investi-gation of 24 patients who were followed up for a median of 4 years after an acute episode of iTTP revealed that their concentration, information processing, rapid language generation and memory performance were significantly worse than standardized adjusted data191. These deficits were interpreted as the result of diffuse subcortical microvascular disease, although they did not correlate with the presence or severity of neurological symptoms during the acute TTP episode or episodes.

    Survivors (n = 57) of a first acute episode of iTTP who were enrolled in the Oklahoma TTP-HUS registry were followed up for a median of 8 years28. The point prevalences of arterial hypertension (40%) and major depression (19%) in these patients were greater than expected from the matched general population (23% and 6%, respectively). Furthermore, the mortality of the cohort was substantially higher than that of the US and local Oklahoma populations, respectively, and this increase was suggested to be related to the higher number of comorbidities in patients with iTTP than in the general population28.

    However, whether cognitive alterations, depression, arterial hypertension, other comorbidities and increased mortality are specific features of individuals who sur-vive an acute episode of iTTP or are equally present in patients surviving other acute severe diseases remains to be investigated. In addition, a possibly ongoing auto-immune response, evidenced by the presence of circu-lating ADAMTS13 immune complexes even years after an acute iTTP episode96, as well as other autoimmune disorders (particularly connective tissue diseases) that might develop over time28,192 could have a role. The creation of comprehensive prospective registries, regu-lar follow-up and long-term observation will be instru-mental in finally improving the outlook for patients with iTTP and cTTP.

    OutlookAlthough the clinicians’ awareness of TTP as well as our understanding of its underlying pathophysiology have substantially increased, diagnosing and treating TTP remain a challenge.

    New drugsvWF A1 domain targeted therapy. Two small molecules that specifically block the vWF A1 domain, thereby preventing platelet binding, have been tested in patients with iTTP. ARC1779, an oligonucleotide aptamer, was not further explored after early termination of the phase II trial owing to difficulties in patient recruit-ment and financing, but the study still provided valu-able proof of principle for the vWF A1 domain-blocking approach193,194. The second compound, caplacizumab (formerly known as ALX-0081), is a nanobody (that is, a single-domain antibody) derived from single-chain antibodies that naturally occur in Camelidae. It was assessed in the TITAN trial, a multicentre, randomized, placebo-controlled phase II study in patients with iTTP.

    Time to platelet recovery was significantly shorter and biomarkers reflecting ischaemic organ damage normal-ized more rapidly in patients who received caplacizumab in addition to standard-of-care treatment195. The inci-dence of exacerbations was also reduced, but because caplacizumab does not target the ongoing autoimmune response, the relapse rate shortly after withdrawal of the study drug per protocol (30 days after the last TPE session) was increased. Many relapsing patients had persistent severe ADAMTS13 deficiency, indicating that blocking the vWF A1 domain prevented platelet clumping in the microvasculature. Bleeding-related adverse events were more common in the caplacizumab arm (53% versus 38% in the placebo group), but most were mild and did not require an intervention, and the frequency of serious bleeding events was similar in both treatment arms195. Caplacizumab is currently under further evaluation in the HERCULES trial, a multicentre phase III study196.

    Recombinant ADAMTS13. Recombinant ADAMTS13 is expected to benefit patients with cTTP who depend on plasma therapy. Inaugural in vitro experiments on plasma from patients with cTTP as well as iTTP197,198 have demonstrated that the addition of recombinant ADAMTS13 effectively restored vWF-cleaving activity. In the presence of functional ADAMTS13 inhibitory autoantibodies, the required amount of recombinant ADAMTS13 was dependent on the inhibitor titre198. Efficacy and feasibility were also proved in various animal models of cTTP and iTTP199–201. A phase I trial using recombinant ADAMTS13 (BAX930) in patients with cTTP has been completed202, and first results are expected in late 2017.

    ‘Second trigger’ hypothesisSome patients with cTTP do not develop acute TTP for many years, and, similarly, some patients with iTTP may remain in remission while having undetectable levels of ADAMTS13 activity for prolonged periods of time19,23,188. These findings led to the hypothesis that a second hit or a trigger is needed to induce overt TTP203. Patients often report infections in the week or weeks preceding an acute TTP episode. In vitro, increased levels of cytokines (for example, tumour necrosis factor and IL-8) that are released during infection and inflam-mation stimulate human endothelial cells to release vWF from Weibel–Palade bodies204, whereas human neutrophil peptides, which are released from activated and degranulated neutrophils, inhibit proteolytic cleav-age of vWF by ADAMTS13 in vitro205. Another pos-sible trigger are nucleosomes, which are detected at presentation in the majority of patients with an acute TTP episode206. These nucleosomes are derived, at least in part, from neutrophil extracellular traps, which are networks made of nuclear DNA, histones, granular and cytoplasmic proteins that are released by neutro-phils in response to infections. Neutrophil extracellular traps, circulating extracellular DNA and histones have been shown to be prothrombotic and may promote organ damage206.

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  • 1. Moschcowitz, E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc. N. Y. Pathol. Soc. 24, 21–24 (1924).

    2. Moake, J. L. et al. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N. Engl. J. Med. 307, 1432–1435 (1982).

    3. Furlan, M. et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89, 3097–3103 (1997).

    4. Furlan, M. et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N. Engl. J. Med. 339, 1578–1584 (1998).

    5. Tsai, H. M. & Lian, E. C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N. Engl. J. Med. 339, 1585–1594 (1998).

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    protease and its identification as a new member of the metalloproteinase family. Blood 98, 1662–1666 (2001).

    8. Soejima, K. et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? J. Biochem. 130, 475–480 (2001).

    9. Levy, G. G. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413, 488–494 (2001).

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    11. Kokame, K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Natl Acad. Sci. USA 99, 11902–11907 (2002).

    12. Schneppenheim, R. et al. Von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 101, 1845–1850 (2003).

    13. Assink, K. et al. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int. 63, 1995–1999 (2003).

    14. Matsumoto, M. et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103, 1305–1310 (2004).

    15. Veyradier, A. et al. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J. Thromb. Haemost. 2, 424–429 (2004).

    16. Schulman, I., Pierce, M., Lukens, A. & Currimbhoy, Z. Studies on thrombopoiesis. I: a factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency. Blood 16, 943–957 (1960).

    17. Upshaw, J. D. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N. Engl. J. Med. 298, 1350–1352 (1978).This is an exemplary report on a case of what we now know as congenital TTP.

    18. Moake, J. L. Thrombotic microangiopathies. N. Engl. J. Med. 347, 589–600 (2002).This is an excellent review on the new developments on TTP between 1982 and 2002.

    Disease modifiersGiven the overlapping clinical features between TTP and HUS, pre-eclampsia, HELLP syndrome and (cata-strophic) antiphospholipid syndrome, the genes and proteins involved in these conditions might have a role as disease modifiers and modulators of the severity of TTP.

    Other proteases as a possible rescue system. Other proteases might help to regulate the size of vWF multi-mers, as vWF proteolysis has been observed in the acute phase of TTP when ADAMTS13 activity is undetect-able207. In vitro studies have shown that various enzymes, including various leukocyte proteases142, plasmin208, granzyme B209 and thrombin210, can cleave vWF, and injection of streptokinase (to generate plasmin) attenu-ated TTP symptoms in an Adamts13−/− mouse model of TTP211. Although it is tempting to assign a back-up role to some of these enzymes in the absence of ADAMTS13, this hypothesis has not been proved. Furthermore, plasmin, thrombin and factor Xa (although all in supra-physiological concentrations) have been reported to cleave ADAMTS13, thereby reducing its activity212. Interestingly, a case of acquired TTP has been described in which ADAMTS13 activity was severely deficient as ADAMTS13 was proteolysed during the acute phase of the disease, which was linked to an acquired, transient deficiency of α2-antiplasmin activity213.

    β2-glycoprotein I. β2-glycoprotein I interacts with the vWF A1 domain in its glycoprotein Ib-binding conforma-tion, that is, platelet-binding conformation, and thereby abrogates platelet binding to vWF. Anti-β2-glycoprotein I antibodies are found in patients with antiphospholipid syndrome and are thought to contribute to the pro-thrombotic state in this condition. Du et al.214 found reduced levels of β2-glycoprotein I in patients with iTTP who present with acute TTP episodes and in remission, which directly correlated with ADAMTS13 activity. In addition, this study showed that adhesion of β2-glycoprotein I to erythrocytes and platelets was enhanced in the presence of ultra-large vWF multimers

    or a hyperactive vWF A1 domain, which, at least in part, explains the reduced levels of β2-glycoprotein I during acute iTTP episodes.

    Alternative complement pathway. Secreted and endothelial cell-anchored ultra-large vWF multimers are hyperadhesive sites that initiate platelet adhesion and aggregation, but can also activate the alternative complement pathway215. In vitro, C3b, the active form of C3, binds to the endothelial cell-anchored ultra-large vWF multimers and initiates the assembly of C3 conver-tase (C3b–Bb) and C5 convertase (C3b–Bb–C3b) on the multimer strings215 (FIG. 3b). In vivo, the activation of the alternative complement pathway by ultra-large vWF strings may progress further to generate terminal com-plement complexes (C5b–9)216–218, possibly causing direct endothelial cell injury and stimulating endothelial cells to secrete additional ultra-large vWF multimeric strings.

    The alternative complement pathway and its regu-lators (CFH, CFI, MCP and thrombomodulin) are of particular interest because of their role in aHUS116, and because CFH has been reported to have vWF reduc-tase capacity219,220. Noris et al.221 described three siblings affected by cTTP: two sisters with phenotypically distinct clinical courses (only one had renal involvement) and an asymptomatic brother. In addition to ADAMTS13 muta-tions, the sister with renal involvement also carried a CFH mutation, previously described in aHUS, whereas the other two siblings did not carry it. Fan et al.222 reported that, in 32 patients with cTTP, of whom 13 had renal involvement including end-stage renal disease, missense sequence variants in genes encoding complement factors and complement regulatory proteins, previously reported to be associated with an increased risk for aHUS, had the same prevalence in patients, regardless of whether they had renal insufficiency or not. However, 1 out of 13 patients with renal involvement carried a novel C3 muta-tion, p.K155Q, located in the C3 macroglobulin-like 2 domain, a region where aHUS-associated mutations cluster. Although complement aberrations might con-tribute to renal complications, there have to be other, still unrecognized factors shaping the phenotype in cTTP.

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  • 19. Kremer Hovinga, J. A., Vesely, S. K., Terrell, D. R., Lämmle, B. & George, J. N. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 115, 1500–1511 (2010).This clinical cohort study describes the variable clinical course of TMA in relation to ADAMTS13 activity and demonstrates that relapses occur almost exclusively in individuals with severe ADAMTS13 deficiency, that is, those with iTTP.

    20. Terrell, D. R. et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J. Thromb. Haemost. 3, 1432–1436 (2005).

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    23. Mariotte, E. 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. 3, e237–e245 (2016).Cross-sectional study on patients presenting with adult-onset TTP over 15 years in France.

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    27. Coppo, P. et al. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. Medicine (Baltimore) 83, 233–244 (2004).

    28. Deford, C. C. et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood 122, 2023–2029 (2013).This cohort study describes the long-term morbidity and mortality in survivors of a first TTP episode.

    29. Rieger, M. et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 106, 1262–1267 (2005).

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    32. Scully, M. et al. Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link. J. Thromb. Haemost. 8, 257–262 (2010).

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