Thrombosis Update 5 (2021) 100062

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Thrombosis Update
journal homepage: www.sciencedirect.com/journal/thrombosis-update

Updates on thrombotic thrombocytopenic purpura: Recent developments in

pathogenesis, treatment and survivorship
Senthil Sukumar a, Eleni Gavriilaki b, *, Shruti Chaturvedi c
a
Division of Hematology, Department of Internal Medicine, Ohio State University School of Medicine, Columbus, OH, 43210, USA
b
Hematology Department - BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
c
Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Thrombotic microangiopathies (TMAs) represent a heterogeneous group of entities characterized by the same
Thrombotic microangiopathy phenotype: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. Over the last decades,
Thrombotic thrombocytopenic purpura two major syndromes with distinct pathophysiology have been recognized: thrombotic thrombocytopenic pur­
Plasma exchange
pura (TTP) and hemolytic uremic syndrome (HUS). A severe deficiency of the ADAMTS13 (A Disintegrin And
Rituximab
Caplacizumab
Metalloproteinase with ThromboSpondin type 1 motifs, member 13) enzyme has been established as the key
ADAMTS13 feature for TTP. When ultra-large Von Willebrand factor (UL-VWF) multimers are allowed to accumulate due to
the lack of ADAMTS13, uncontrolled platelet aggregation and adhesion can occur forming disseminated
microthrombi resulting in clinical the clinical syndrome. TTP can be fatal without prompt recognition and
treatment. Over time, increasing awareness, improvements in diagnostic techniques, and advances in thera­
peutics have increased survival rates substantially. Once previously thought to be only an acute illness, long-term
complications in survivorship are being described with increasing frequency. As our understanding of this
devastating condition has evolved, a need for updates has emerged in this increasingly complex setting. In this
review, we summarize novel data regarding the pathophysiology, clinical diagnosis, acute management, long-
term follow up and emerging therapies for TTP.

1. Introduction Thrombotic thrombocytopenic purpura (TTP), caused by a congen­

Thrombotic microangiopathies (TMAs) represent a heterogeneous
group of syndromes characterized by disseminated microthrombi that
present with a clinical triad of microangiopathic hemolytic anemia
(MAHA), thrombocytopenia, and variable ischemic end-organ injury.
Considering that syndromes with different pathophysiology present
with the clinical phenotype of TMA, differential diagnosis is often
difficult. Table 1 summarizes diagnostic entities with their characteristic
features, including a most recent entity associated with coronavirus
disease-19 (COVID-19) that remains under investigation. TMA in
COVID-19 seems to resemble the pathophysiology of complement-
mediated TMAs, with genetic and functional evidence of complement
dysregulation [1–3].In the field of COVID-19, another cause of throm­
bocytopenia without the clinical phenotype of TMA has also recently
emerged: vaccine-induced immune thrombotic thrombocytopenia
(VITT). This entity belongs to a spectrum of platelet-activating anti-­
platelet factor 4/PF4-heparin disorders [4].
ital or immune mediated deficiency of the enzyme ADAMTS13 (a dis­
integrin and metalloproteinase with thrombospondin type 1 motifs,
member 13), is one of the best characterized TMAs [5–8]. In the decades
since the initial discovery and characterization of ADAMTS13, further
understanding of the underlying pathophysiology of TTP has led to
significant advancements in the diagnosis [9–11] and clinical manage­
ment [12,13] of these patients, as well as increasing interest in issues
related to TTP survivorship. In this review, we summarize recent up­
dates in TTP focusing on a) pathophysiology, b) clinical diagnosis, c)
current management including novel therapies, and d) long-term follow
up and survivorship.
1.1. Pathophysiology
TTP results from a severe deficiency of ADAMTS13, a von Willebrand
Factor cleaving protease, which leads to impaired processing and
accumulation of ultra large von Willebrand factor (ULVWF) multimers

* Corresponding author. Hematology Department - BMT Unit, G. Papanicolaou Hospital, Exochi, 57010, Thessaloniki, Greece.
E-mail address: elenicelli@yahoo.gr (E. Gavriilaki).

https://doi.org/10.1016/j.tru.2021.100062
Received 15 June 2021; Received in revised form 11 July 2021; Accepted 22 July 2021
Available online 23 July 2021
2666-5727/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Sukumar et al. Thrombosis Update 5 (2021) 100062

Table 1 remain to be identified. Environmental factors such as female sex,

Differential diagnosis of thrombotic microangiopathies (TMAs). obesity, or ethnicity/race may predispose to iTTP [28–31]. Certain
Diagnostic entity Diagnostic features human leukocyte antigen (HLA) haplotypes have been associated with
iTTP. For example, the class II locus DRB1*11 and DQB1*03 alleles are
Thrombotic Thrombocytopenic ADAMTS13 deficiency
Purpura (TTP) overrepresented in white iTTP patients while HLA-DRB1*04 appears to
Complement-mediated hemolytic Complement dysregulation have a protective effect in this population [32–35]. The frequency of
uremic syndrome (HUS) HLA-DRB1*04 is markedly reduced in populations with African
Infection-associated TMA Shiga-toxin, Campylobacter jejuni, ancestry, which possibly accounts for the 8-fold increased incidence rate
Streptococcus pneumonia, Human
immunodeficiency virus, Cytomegalovirus,
of iTTP among Blacks in the United States [29,30]. In contrast to white
Epstein–Barr virus, Parvovirus B19, BK virus, patients, the HLA-DRB1*11 or HLADRB1*04 alleles did not have a
Influenza predisposing or protective effect on iTTP in a Japanese patient popula­
Disseminated intravascular Abnormal coagulation, Underlying cause tion [36] in which HLA-DRB1*08:03, HLA-DRB3/4/5*blank,
coagulation
HLA-DQA1*01:03, and HLA-DQB*06:01 are identified as potentially
Secondary TMA Cancer, Transplantation, Systemic lupus
erythematosus, Antiphospholipid antibody predisposing factors [36].
syndrome, Scleroderma, Vasculitis/ Observations that ADAMTS13 deficiency is necessary but not always
glomerulonephritis sufficient to trigger iTTP relapse [37–39] suggest that additional
Malignant hypertension-induced Extreme elevations in blood pressure, mechanisms beyond the interaction of ADAMTS13 and VWF may pro­
TMA papilledema, headache
Drug-induced TMA Calcineurin or mTOR inhibitors, Quinine
vide a ‘second-hit’ that precipitates iTTP [40]. Specifically, activation of
Estrogen/progesterone, Gemcitabine/ the alternative pathway of the complement system may play a role in the
mitomycin C. Interferon acute phase of iTTP [41–43] where ULVWF multimers can serve as a
Vascular endothelial growth factor or scaffold for the activation of the alternative pathway of complement
proteasome inhibitors, Cocaine
[44]. More recently, the interrelationship between complement,
Metabolism-associated TMA Cobalamin responsive methylmalonic
academia, Diacylglycerolkinase epsilon ULVWF, and ADAMTS13 activity of patients in remission of iTTP has
mutation been further characterized [43]. Wu et al. demonstrated significant
Pregnancy-associated TMA HELLP (hemolysis, elevated liver enzymes, and overlap in ADAMTS13 activity between patients who did and did not
low platelets) syndrome, HUS, TTP have ULVWF multimers and found that higher levels of sC5b-9, C3a, and
COVID-19 associated TMA SARS-COV2 molecular diagnosis, evidence of
C5a, biomarkers of complement activation, correlated with an increased
microangiopathy (especially in lungs)
probabilty of detecting ULVWF multimers [43]. ULVWF multimers also
less efficiently perform essential regulatory functions which inhibit
and formation of microthrombi. Severe ADAMTS13 deficiency can be alternative pathway complement activation. Indeed, at physiologic
inherited as in congenital TTP (cTTP, or Upshaw–Schulman Syndrome sizes, VWF functions as a cofactor for complement factor I, which has an
OMIM 274150) [14,15] or, more commonly, acquired due to inhibitory effect on complement activation though the cleavage and
anti-ADAMTS13 autoantibodies resulting in immune-mediated TTP inactivation of complement C3b [45]. ADAMTS13 deficiency and com­
(iTTP) [6,16,17]. cTTP is caused by biallelic mutations in the plement dysregulation also have synergistic effects which were
ADAMTS13 gene located on chromosome 9q34 and is inherited in an elegantly demonstrated in a mouse model by Zheng et al. [46] Mutant
autosomal recessive pattern [18]. The location of the mutation appears mice with either absence of ADAMTS (ADAMTS13− /− ) or the hyper­
to influence phenotype; prespacer mutations are associated with earlier functional heterozygous complement Factor H (CFH) mutation (cfhW/R)
onset of symptoms [19]. did not develop spontaneous TMA. Mice with both ADAMTS13− /− and
The majority of patients with iTTP have detectable ADAMTS13 au­ cfhW/R however did go on to develop TMA. Though mice with a homo­
toantibodies, which continue to be an active source of investigation. zygous CFH mutation (cfhR/R) developed clinical TMA with or without
Inhibitory antibodies block proteolysis of ULVWF and non-inhibitory ADAMTS13− /− , the mortality rate was significantly higher in mice with
antibodies accelerate ADAMTS13 clearance from the circulation, with both defects than cfhR/R alone [46]. This corroborates clinical observa­
both types of antibodies described in patients with acute iTTP [20–22]. tions that evidence of complement activation is associated with
Anti-ADAMTS13 antibodies have been found against several domains of increased iTTP mortality in humans [42].
ADAMTS13. The spacer domain may represent a particularly immuno­ Further studies examining the specific functions of ADAMTS13 au­
genic region as antibodies to the spacer domain are present in a majority toantibodies, novel markers such as ADAMTS13 antigen or ULVWF, the
of individuals with iTTP and have an inhibitory function [23–26]. The importance of conformational status of ADAMTS13, and the role that
importance of non-inhibitory or “clearing” antibodies is still being complement may play leading up to or during the acute phase of disease
elucidated. In one study non-inhibitory antibodies were present in will provide opportunities for better prediction of severe/refractory
15/43 patients during an acute episode [22]. Additionally, ADAMTS13 disease, mortality, and relapse prediction. Novel insights into TTP
antigen levels were markedly reduced in samples from 91 patients at pathophysiology are presented in Fig. 1.
presentation of acute iTTP and mortality was also significantly increased
(OR 5.7, 95 % CI 1.5–21.8) for individuals with ADAMTS13 antigen 1.2. Diagnosis of TTP: clinical prediction tools and laboratory assays
levels in the lowest quartile at first presentation [22]. Although
ADAMTS13 circulates in a closed or folded conformation, it appears to iTTP most commonly presents in adulthood and comprises >90 % of
circulate in an open conformation during acute iTTP episodes and in all TTP cases. In contrast, cTTP usually presents prior to age 10 or in the
patients with reduced ADAMTS13 during clinical remission [9]. Roose context of pregnancy [19,47,48]. The defining characteristic of both
et al. have described “conformation-changing” ADAMTS13 autoanti­ iTTP and cTTP is the presence of severe ADAMTS13 deficiency (<10–20
bodies in iTTP have recently been shown to alter the conformation of % activity) [8]. iTTP may be distinguished from cTTP via the detection
ADAMTS13 into an “open” from a native “closed” state [9,10] thereby of ADAMTS13 autoantibodies during an acute episode or recovery of
leading to exposure of cryptic epitopes in the spacer region. Other an­ ADAMTS13 activity to >10–20 % in clinical remission [49]. However,
tibodies directed against the distal carboxy terminal of ADAMTS13 that not all patients with iTTP have detectable autoantibodies and some may
modulate its susceptibility to inhibitory antibodies have been described not recover ADAMTS13 activity in remission; sequencing of the
[27]. The role of these antibodies in the pathophysiology of iTTP has yet ADAMTS13 gene may be required to establish the diagnosis of cTTP.
to be fully characterized. TTP presents a diagnostic challenge since its clinical presentation of
The specific mechanisms leading to the loss of tolerance in iTTP TTP is similar to other TMAs with moderate to severe

2
S. Sukumar et al. Thrombosis Update 5 (2021) 100062

Fig. 1. Novel insights into iTTP pathogenesis. (A) ADAMTS13 activity is severely deficient due to functional (more common) or clearing ADAMTS13 antibodies. This
results in circulating ultra large von Willebrand factor (UL vWF) multimers that interact with platelets to form aggregates, which cause microthrombi leading to the
thrombotic microangiopathy and ischemic injury in TTP. (B) ADAMTS13 may circulate as a closed or circular form, which is more common during iTTP remission, or
an open form that appears to be more active/antigenic and is more common during acute episodes (or subclinical TTP associated with reduced ADAMTS13 activity
during clinical remission). Shear stress or conformation changing antibodies may lead to the conformational change to the open form. (C) Certain HLA class II alleles
are associated with risk of iTTP, and iTTP is more common in patients with a predisposition to autoimmune disorders. Finally, (D) observations that severely deficient
ADAMTS13 alone may not precipitate iTTP relapse in all cases suggests the role of additional environmental factors that may serve as ‘triggers’ for iTTP.

thrombocytopenia, microangiopathic hemolytic anemia, and evidence
of ischemic end organ injury. Measurement of the ADAMTS13 activity,
which is < 10–20 % in acute TTP, is required to establish the diagnosis
[8]. However, ADAMTS13 testing is not rapidly available at all hospitals
and results may take 2–5 days. iTTP is a medical emergency and we do
not recommend waiting for ADAMTS13 testing results before starting
plasma exchange in any patient where the suspicion of iTTP is high
(thrombocytopenia and microangiopathic hemolytic anemia without
another obvious etiology). Clinical scoring systems such as the French
score [50] and the PLASMIC [51] score have been devised and can guide
decision making when ADAMTS13 results are not immediately avail­
able. The scores rely heavily on the more severe thrombocytopenia
(platelet count < 30 × 109/L) and less renal involvement in iTTP and the
absence of other causes of TMA. They have been extensively validated
and perform well in most patients with iTTP but may have lower
sensitivity in detecting iTTP in older patients, particularly those >60
years, who may present with less severe thrombocytopenia and more
renal impairment [52]. It should be also noted that these scores were
derived in patients who already had a clinical phenotype of TMA.
Therefore, they are not to be applied to any patient with anemia and
thrombocytopenia. More importantly, clinical decision making for
initiation of plasma exchange is based on the clinical phenotype of TMA
and not on the results of these scores.
The most common ADAMTS13 assay in clinical settings is the fluo­
rescence resonance energy transfer (FRETS-VWF73) which detects VWF
cleavage products [53,54]. This test is considered the reference method
for ADAMTS13 activity measurement and is calibrated against the in­
ternational standard ADAMTS13 plasma set by the World Health Or­
ganization [55]. Other methods include surface-enhanced laser
desorption/ionization time-of-flight (SELDI-TOF) [56] and
enzyme-linked immunosorbent assays (ELISAs) [57]. As delays in
diagnosis and treatment lead to worse outcomes there has been a
concerted effort to develop faster, more efficient, and less
labor-intensive methods to measure ADAMTS13 activity. Recently a
fully automated chemiluminescent immunoassay was developed and
validated with release of results in approximately 30 min [11,58]. This
new assay eliminates inherent difficulties with highly manual tech­
niques like the FRETS-VWF73 and chromogenic ELISA, while providing
rapid results [11]. Furthermore, a semi-quantitative assay that delivers a
four-level display of ADAMTS13 activity has been developed, allowing
rapid identification of ADAMTS13 activity <10 % [59]. These new
techniques are not yet widely available but offer several potential ad­
vantages to clinicians who do not have immediate access to reference
laboratories. Real-time determination of severe ADAMTS13 deficiency
would allow prompt initiation of therapy, including earlier use of novel
agents like caplacizumab, and could also be used to tailor therapies such

3
S. Sukumar et al.
as immunosuppression and anti-VWF therapy.
All functional assays for ADAMTS13 activity are capable of detecting
the inhibitory autoantibodies with a wide range of sensitivities [60].
Immunological assays detect both inhibitory and non-inhibitory anti-­
ADAMTS13 antibodies. ELISA assays are also commercially available
and seem more sensitive than functional assays for anti-ADAMTS13 IgG
[61], with rather low specificity [20]. Western blotting assays have been
also described, but are more laborious, time-consuming and difficult to
use [38].
Certain biomarkers have been associated with an increased risk of
refractory disease or death. Elevated levels of Factor Bb and sC5b-9,
markers of complement activation, are associated with increased mor­
tality during acute iTTP [42]. Results from the French TMA registry
identified cardiac troponin I levels >0.25 mcg/L as an independent risk
factor associated with a 3-fold increase in refractory disease or death
[62]. More recently, a study in search of clinically meaningful bio­
markers of TTP has shown that prolonged activated partial thrombo­
plastin time, elevated fibrinogen, and elevated serum lactate
dehydrogenase (LDH), are significant markers of mortality in TTP pa­
tients. The study also confirmed prior observations from others that
presence of alternative pathway Bb fragments, and soluble C5b-9 or
membrane attack complex on admission are associated with mortality
[63]. These markers may help identify patients at risk for refractory or
more severe iTTP early; further work is needed to determine how best to
incorporate these clinically.
1.3. Management of acute iTTP
Treatment of iTTP is generally divided into two phases; management
of the acute phase and monitoring during remission. Prompt therapy is
required during the acute phase and brings the mortality rate of TTP
from 90 % to less than 15 % [64–66]. Daily therapeutic plasma exchange
(TPE), usually with fresh frozen plasma replacement, is employed at first
suspicion of the diagnosis [65,67]. TPE should not be delayed while
awaiting confirmatory testing with ADAMTS13 activity results as delays
in therapy lead to increased morbidity and mortality [68]. TPE is
theorized to remove anti-ADAMTS13 autoantibodies from the serum
and replace the deficient ADAMTS13 enzyme. However, this alone does
not address the underlying autoimmune issue.
Autoantibody production is targeted initially through use of corti­
costeroids in conjunction with TPE [67]. While there are no clinical
trials comparing TPE alone with TPE and steroids, the underlying
pathophysiology of iTTP calls for concurrent immunosuppression. The
only prospective study which examines the role of corticosteroids in this
setting was a small randomized trial comparing cyclosporine A with
prednisone as an adjunct to TPE for initial treatment of iTTP and found
that prednisone was superior [69]. Typically, high dose steroids are
utilized initially, then tapered over 3–4 weeks once a clinical response is
achieved. Another approach to immunosuppression is the use of the
B-cell depleting monoclonal antibody against CD-20, rituximab.
Initially, rituximab was administered in patients with suboptimal
response as a salvage treatment and then increasingly as frontline
treatment [70–72]. In a historical group of TTP patients, 74 % patients
with persistently undetectable ADAMTS13 activity relapsed within 7
years of follow-up. When rituximab was used pre-emptively in a similar
group of patients with persistently undetectable ADAMTS13, relapses
were reduced to 15 % [73]. A recent meta-analysis also suggests that
early rituximab use may reduce mortality in addition to improving the
relapse rate [74]. Additionally, rituximab is effective at eliciting a
clinical response in patients who have a poor or no response to initial
therapy with TPE plus corticosteroids [12,75]. As a result, front-line use
of rituximab for both initial and relapse events is endorsed by the In­
ternational Society of Thrombosis and Hemostasis (ISTH) treatment
guidelines for TTP [76]. Optimal dosing and schedule of rituximab
therapy remains to be established. Based on lymphoma doses, the most
common approach uses 375 mg/m2 weekly or twice a week for 4 to 8
4
Thrombosis Update 5 (2021) 100062
doses [77]. Low dose rituximab has also recently shown high
cost-effectiveness [78]. Of note, Rituximab is administered immediately
after plasma exchange, allowing maximal exposure before the following
exchange.
Beyond TPE and immunosuppression, caplacizumab represents a
recent breakthrough in TTP management. Caplacizumab is a first-in-
class nanobody directed against the A1 domain of VWF, which pre­
vents VWF dependent platelet aggregation and microthrombi formation.
In the double-blind, placebo-controlled phase 3 HERCULES trial,
caplacizumab, in conjunction with TPE and immunosuppression, led to
faster resolution of thrombocytopenia, a 74 % reduction in the com­
posite end point of iTTP-related death, recurrence and major thrombo­
embolic events, and somewhat reduced time to normalization of
markers of end-organ damage [79]. Caplacizumab also appears to pre­
vent refractory disease and may reduce mortality. An integrated analysis
of the phase 2 TITAN and phase 3 HERCULUES studies found that
caplacizumab significantly reduced mortality (0 vs 4 deaths p < 0.05)
and refractory disease (0 vs 8 patients p < 0.01) compared with placebo
[80]. Caplacizumab is relatively well tolerated with the main side effects
consisting of headache and minor bleeding [81]. Notably, caplacizumab
does not address the underlying immunopathology of iTTP and must be
used in conjunction with effective immunosuppression. Moreover,
despite positive results in clinical trials and the fact that it is approved by
the FDA and EMA and is also recommended by the ISTH iTTP treatment
guidelines [76], the high cost of caplacizumab (~$7700 for a single dose
and ~$270 000 for an average course of therapy) remains a major
barrier to use. An analysis favorably controlling for several variables
including general cost of admission, TPE, and other factors found that
the use of caplacizumab in all cases of iTTP is not cost-effective [82].
However, real world data may modify these estimates in three ways.
First, the optimal duration of caplacizumab therapy is unclear. In
HERCULES, caplacizumab was continued for at least 30 days after
stopping plasma exchange but many experts agree that it is likely safe to
discontinue caplacizumab once ADAMTS13 activity recovers to >10–20
% [83]. In a recent report of 60 patients from Germany that used
ADAMTS13 activity to guide duration of caplacizumab therapy, 58.3 %
of patients required treatment for less than 30 days resulting in cost
savings of 2.49 million euros (or 3.4 million USD) [84]. Second, the
impact, if any, of caplacizumab on long-term outcomes of iTTP (dis­
cussed below) is unknown and a reduction in adverse health outcomes
such as neurocognitive impairment, stroke, and reduced health-related
quality that are common in iTTP survivors may shift the balance [85].
Finally, drugs such as caplacizumab may pave the way for plasma free
treatment of iTTP, which would completely shift the treatment para­
digm [86]. Thus far, 9 patients have been described who were success­
fully treated with caplacizumab and immunosuppression alone in cases
where TPE was omitted for various indications (Fig. 2) [87–90].
1.4. Long-term management of iTTP
Over the last few decades as acute phase management has improved,
the mortality rate of TTP episodes has decreased dramatically from
approximately 90 % to <15 % [65,67]. Still, one or more relapses of
unpredictable severity occur in up to 50 % of patients, exposing them to
potentially lethal or long-term complications [91,92]. The risk of relapse
is highest when ADAMTS13 activity in clinical remission is persistently
<10–20 % [37,38]. Preemptive therapy with immunosuppression, most
often with rituximab, can prevent relapses in asymptomatic patients
with severely deficient ADAMTS13 activity reducing the relapse rate by
up to 85 % [73,74,93]. Our practice is to monitor ADAMTS13 activity
every 3 months during remission and offer preemptive therapy with
rituximab when ADAMTS13 activity is <20 %. Other immunosuppres­
sive agents, like cyclosporine represent alternatives for patients who are
intolerant of therapy with rituximab [94]. In patients with multiply
relapsing iTTP that has proven refractory to other pre-emptive therapy,
splenectomy can achieve durable remission with a 70 % relapse free 10
S. Sukumar et al.
Fig. 2. Timeline of the evolution of TTP treatment. When first described in, thrombotic thrombocytopenic purpura (TTP) was universally fatal. In 1970s, the
combination of steroids and plasma therapy improved outcomes. Plasma exchange (PEX) revolutionized the field with significant improvements in survival reported
in 1991. In 2000s, addition of anti-CD20 treatment with rituximab showed benefits initially in patients with suboptimal response to treatment and gradually as
frontline treatment. The first agent to be approved for the treatment of TTP was caplacizumab in 2017, combined with PEX and immunosuppressive treatment. Novel
therapies, such as recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) and others, are also expected in
the near future. The advent of effective immunosuppression and novel therapies targeting VWF and ADAMTS13 may also usher in an era of therapy that is not reliant
on plasma exchange.
year survival rate in some populations [95,96]. Though utilization of
splenectomy has declined in recent years it remains a viable option with
a >90 % response rate [97].
Initially TTP was thought to be an exclusively acute illness; that is
once the acute phase has been managed the patient has no further
sequelae of disease. However, TTP survivors are noted to have higher
rates of many health sequelae including depression, obesity, diabetes,
neurocognitive deficits, associated autoimmune disorders, chronic kid­
ney disease (CKD), cardiovascular disease, poor quality of life, and death
when compared to reference populations (Table 2) [85,98–100]. Many
Table 2
Long-term outcomes in iTTP survivors.
Survivorship aspect Outcome
Overall survival Shorter survival than age and sex matched general
population controls; iTTP relapse and
cardiovascular disease are leading causes of death
[102]
Lupus Prevalence of SLE 37-fold greater than expected
among age, race, and sex-matched reference
population; SLE is the most common additional
autoimmune disorder occurring in iTTP patients
[100]
Hypertension Lifetime prevalence in some cohorts is 45 %,
which is significantly greater than expected (23 %)
for the general population. The prevalence of HTN
in this cohort prior to a diagnosis of TTP did not
differ from the general population [100].
Stroke In addition to acute phase cerebral events, patients
are at 5-fold increased risk for stroke during
remission if ADAMTS13 activity <70 % [103]
Depression and post- Rates for depression and PTSD are >80 % and 35
traumatic stress disorder % respectively in some cohorts; Previous diagnosis
of depression and unemployment attributed to
TTP were associated with depression whereas
younger age, pre-existing anxiety, and
unemployment due to TTP were associated with
PTSD [99]
Quality of life Patients in remission consistently score lower
across all domains of HRQoL surveys; these results
do not improve over time and have no correlation
with severity of the index TTP episode [118]
Cognitive impairment Often develop impairment, particularly in certain
cognitive domains: complex attention and
sequencing, manual dexterity, rapid language
generation, and list learning; can lead to disability
and unemployment [119].
Pregnancy outcomes When index iTTP triggered by pregnancy,
subsequent pregnancy is associated with
recurrence. ADAMTS13 activity monitoring before
and during pregnancy, with pre-emptive
treatment, may prevent recurrence in this setting
[85]
HTN: hypertension; SLE: systemic lupus erythematosus, iTTP: immune-mediated
thrombotic thrombocytopenic purpura.
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Thrombosis Update 5 (2021) 100062
of these sequelae have a significant impact on quality of life and some
patients do not return to their previous baseline levels of functionality,
particularly after the development of mood disorders and/or cognitive
impairment [92,99–101]. Data from several registries worldwide have
also noted that TTP survivors have a higher mortality rate than expected
from the reference population [85,100,102]. Recently all-cause mor­
tality was compared and identified cardiovascular disease as well as TTP
relapse as the leading causes of death in two large cohorts in the United
States [102]. The etiology of an apparent increase in cardiovascular
complications in this population has yet to be understood but may be
related to increased development of various vascular risk factors such as
hypertension, obesity, diabetes, and CKD. Interestingly, reduced
ADAMTS13 activity in remission may give insight into the development
of these sequelae. Patients with an ADAMTS13 activity <70 % during
remission have a nearly 5-fold increased incidence of strokes [103].
Indeed an association was seen with all-cause mortality and lower
remission ADAMTS13 activity levels, but this did not reach statistical
significance likely due to limited sample size [102]. As these relation­
ships are further characterized, it may highlight the importance of not
only achieving clinical remissions, but also achieving complete
ADAMTS13 activity remission. Recognizing these long-term complica­
tions, the ISTH has released good practice statements for the clinical care
of TTP survivors which generally recommend following these patients
every 3–6 months, at least initially, with serial ADAMTS13 activity
measurements [104]. This may allow early detection of dropping
ADAMTS13 activity levels and initiation of pre-emptive therapy, like
rituximab, which can help prevent relapse events [70,93]. Further study
is needed, but prevention of relapse and aggressive management of early
modifiable risk factors in follow up may reduce mortality and improve
quality of life in TTP survivors.
1.5. Revised outcome definitions in iTTP
The duration of therapy (TPE) as well as clinical outcomes of iTTP
have traditionally been anchored by achieving normal platelet counts.
With the addition of caplacizumab to acute phase management, there
emerged a new clinical dilemma: platelet count, LDH, and parameters of
end-organ damage rapidly improve while the drug is being given, but
the underlying autoimmune disease pathology has yet to correct and
premature discontinuation of caplacizumab poses a risk of risk of
exacerbation [105]. In this new landscape of iTTP therapy, the Inter­
national Working group on TTP has proposed new consensus definitions
of clinical response and remission that incorporate ADAMTS13 activity
[106]. The definition for clinical response remains unchanged and
should still be used to guide discontinuation of TPE. To account for the
effect of caplacizumab on parameters utilized in the definition of clinical
response, two new definitions have been devised: partial ADAMTS13
remission and complete ADAMTS13 remission. [106] Partial ADAMTS13
remission is defined by an ADAMTS13 activity ≥20 % to < lower limit of
S. Sukumar et al.
normal (LLN) based on the observation that relapse risk is minimal at
ADAMTS13 > 20 %. Complete ADAMTS13 remission is an ADAMTS13
activity ≥ LLN and has been highlighted since emerging data suggests
that subnormal ADAMTS13 activity in remission is associated with
adverse outcomes such as stroke. The International Working Group on
TTP posits that caplacizumab therapy may be discontinued once at least
partial ADAMTS13 remission is achieved, but this yet needs to be vali­
dated prospectively [106].
1.6. Novel therapies
Other innovative treatments in the field of TTP principally involve
patients with congenital TTP. The first in-human phase 1 study of re­
combinant ADAMTS13 (rADAMTS13) has demonstrated pharmacody­
namic activity in patients with severe congenital ADAMTS13 deficiency
[107]. Interestingly, a recent experimental study has also shown
favorable effects in myocardial remodeling and functionality [108].
Regarding iTTP, the potential interactions of recombinant ADAMTS13
with the immune system of these patients needs to be intensively
investigated in future studies, but initial data from preserved patient
samples has shown promise [109]. Currently a phase 3 study for cTTP
(NCT03393975) and a phase 2 study for iTTP (NCT03922308) are
ongoing.
Beyond caplacizumab, previous attempts to incorporate an anti-VWF
therapies into acute iTTP treatment included N-acytlcysteine (NAC), a
common mucolytic. While there are case reports detailing its efficacy in
refractory cases [110], results in animal models are conflicting. NAC
administration has demonstrated an ability to prevent iTTP in mice, but
cannot resolve the acute disease in mice or baboon models [111]. In
2012, ARC1779 was evaluated – an aptamer which blocks platelet
binding to the A1 domain of VWF [112]. In that small trial, 7 patients
were treated prior to its discontinuation due to financial constraints so
no data regarding efficacy could be ascertained. Development of the
agent has not continued, however, due to the favorable safety profile
second generation aptamers targeted towards VWF platelet interactions
have emerged. A novel aptamer TAGX-0004, also targeting the A1
domain of VWF, inhibits thrombus formation with comparable efficacy
to caplacizumab [113]. Additionally, another aptamer in development,
BT200, prevents arterial thrombosis in non-human primates as well as
inhibition of human VWF in vitro. [114] As new therapies are developed
further multi-center collaborative trials are warranted to optimize the
acute therapy approach for patients with TTP.
Therapies targeting plasma cells such as bortezomib [115,116] and
daratumumab [117] have also been reported to effectively suppress
anti-ADAMTS13 antibodies but need to be evaluated in clinical trials.
2. Conclusion and future perspectives
The past several decades have seen major developments in our un­
derstanding of iTTP pathogenesis, treatment and survivorship. Future
research on the antibody repertoire in acute iTTP as well as in remission
may facilitate the development of novel assays that help with diagnosis
as well as longitudinal monitoring. Indeed, the development of novel
therapies such as caplacizumab and rADAMTS13 highlight the need to
focus on rapid and reliable ADAMTS13 assays that are widely available.
Since most patients with iTTP now survive their acute episode, there is
an increasing focus on survivorship. It is clear that iTTP survivors are at
risk for a plethora of adverse outcomes separate from iTTP relapse,
which range from cognitive impairment, depression and poor quality of
life to hypertension, stroke and shorter survival. There is a critical need
to investigate risk factors and mechanisms underlying these adverse
outcomes in order to improve long term outcomes of iTTP.
Conflict of interest statement
S.C. has served on advisory boards for Alexion, Sanofi-Genzyme, and
6
Thrombosis Update 5 (2021) 100062
Takeda. The other authors have no relevant conflicts to disclose.
Declaration of competing interest
The authors declare the following financial interests/personal re­
lationships which may be considered as potential competing interests:
S.C. has served on advisory boards for Alexion, Sanofi-Genzyme, and
Takeda. The other authors have no relevant conflicts to disclose.
Acknowledgments
E.G. is supported by the ASH Global Research Award 2020. S.C. is
supported by National Institutes of Health (NIH), Heart, Lung and Blood
Institute grant K99HL150594 and ASH Scholar Award.
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