-
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
SP
C1
C2
C3
C4
C5
C6
CK C
1C
2C
3C
4C
5C
6C
K
C1
C2
C3
C4
C5
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
D'D3
D'D3D1 D2
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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.
P R I M E R
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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.
P R I M E R
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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
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Other proteases as a possible rescue system. Other proteases
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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.
P R I M E R
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