How I Treat

How I treat immune-mediated thrombotic

thrombocytopenic purpura after hospital discharge
Frank Akwaa,1 Ana Antun,2 and Spero R. Cataland3

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1
Division of Hematology and Oncology, Department of Medicine, University of Rochester, Rochester, NY; 2Department of Hematology and Medical Oncology,
Emory University, Atlanta, GA; and 3Department of Medicine, The Ohio State University, Columbus, OH

Immune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired

ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of
ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids,
rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both
relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in
patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these
complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a
review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP
and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up
in the outpatient setting.

Introduction review of his peripheral blood smear showed an increased num-

Immune mediated thrombotic thrombocytopenic purpura (iTTP) is
an acute thrombotic microangiopathy that is mediated by an
acquired, antibody-mediated deficiency of the ADAMTS13 prote-
ase. Recent advances in our understanding of iTTP have shifted
the focus to improving recovery from an acute iTTP episode and
addressing long-term complications of the disease. iTTP is now
increasingly recognized as a chronic disease with long-term
sequelae. These sequelae include cardiovascular and neurocogni-
tive deficits that may be responsible for the decreased survival that
has been reported in patients with a previous diagnosis of iTTP.1,2
Case 1
A 36-year-old White man with a history of 3 prior acute iTTP epi-
sodes presented with abdominal pain, nausea for 3 to 4 days,
and a headache that began 24 hours earlier. His first iTTP epi-
sode occurred at age 29; since then, he has had 2 additional
episodes, with the most recent one occurring 3 years ago. His
previous episodes were treated with plasma exchange (PEX)
and steroids, but he received 4 weekly doses of rituximab (375
mg/m2) after the most recent episode. He was rapidly started
on PEX and corticosteroids for a clinical diagnosis of iTTP that
was confirmed with severely deficient ADAMTS13 activity
(,10%). He achieved a clinical response and was discharged
from the hospital at day 11 of hospitalization. During his first
outpatient visit, he had complaints of mild fatigue and was
found to have thrombocytopenia with a platelet count of 65 3
109/L and a lactate dehydrogenase level (LDH) that had
increased to more than 2 times the upper limit of normal. A
ber of schistocytes, consistent with an iTTP exacerbation.
Definition of exacerbation
The revised definition of clinical exacerbation, as proposed by an
international working group, is recurrent thrombocytopenia
(,150 3 109/L), with or without clinical evidence of new or pro-
gressive ischemic organ injury within 30 days of cessation of thera-
peutic plasma exchange or anti–von Willebrand factor (VWF)
therapy, in the absence of an alternative cause of thrombocytope-
nia.3 This diagnosis requires an initial clinical response with sus-
tained platelet count $150 3 109/L, normal LDH (,1.5 times the
upper limit of normal), and no clinical evidence of new or progres-
sive organ ischemia (Table 1). Thrombocytopenia in the first month
after stopping PEX may be caused by other clinical conditions,
including infection (catheter associated or not), consumptive coa-
gulopathy, including disseminated intravascular coagulation, drug-
induced thrombocytopenia, or even heparin-induced thrombocy-
topenia, but suspicion for an exacerbation of iTTP should be high.
This patient’s clinical picture is consistent with an exacerba-
tion of iTTP. Exacerbations are clinically significant events that
require reinitiation of PEX and intensification of immunosup-
pression, exposing patients to the potential morbidity and
even mortality related to the recurrent iTTP and the additional
treatment necessary to again achieve a clinical response.
Mechanism of exacerbations
Investigators have sought to identify risk factors for exacerba-
tions of iTTP, and the literature suggests that demographics and

438 blood® 4 AUGUST 2022 | VOLUME 140, NUMBER 5

Table 1. Clinical outcome definitions in iTTP
Initial clinical treatment end Clinical response
points
Exacerbation
Remission definitions Clinical remission
Complete ADAMTS13 remission
Partial ADAMTS13 remission
Relapse definitions Clinical relapse
ADAMTS13 relapse
Adapted from Cuker et al.3
ULN, upper limit of normal; LLN, lower limit of normal.
ADAMTS13 activity may play a role. A study conducted by Cata-
land et al showed that pretreatment ADAMTS13 activity was sig-
nificantly lower in patients who had an exacerbation, but after
accounting for race as a covariate of ADAMTS13 activity, the
difference was no longer significant, as Black patients
independently had an increased risk of iTTP exacerbation
(P 5 .046).4 Sui and colleagues also demonstrated that, whereas
pretreatment ADAMTS13 activity was not predictive of exacer-
bation, persistently low ADAMTS13 levels (,10 U/dL; hazard
ratio [HR], 4.4; P 5 .005) or higher anti-ADAMTS-13 IgG
(HR, 3.1; P 5 .016, measured 3 to 7 days after initiation of PEX
and immunosuppression, was predictive of exacerbation. Wu
et al reported similar findings where patients with more rapid
recovery of ADAMTS13 activity during PEX therapy did not
experience exacerbations.5 Similarly, a low ADAMTS13 level
(,10 U/dL; HR, 4.8; P 5 .002), low ADAMTS-13 antigen
(,25th percentile; HR, 3.3; P 5 .01), or high anti-ADAMTS13
IgG (.75th percentile; HR, 2.6; P 5 .047) at the time of clinical
response was predictive of exacerbation.6 Alterations in the titer
and potency of the anti-ADAMTS13 antibodies have also been
reported, despite daily PEX therapy and concurrent corticoste-
roid therapy, and could lead to both refractoriness to treatment
and an increased risk of exacerbation of iTTP.7 In the first capla-
cizumab study, 10 of 12 subjects also had severely deficient
ADAMTS13 activity (,10%) at the time they experienced an
exacerbation.8
Treatment to prevent exacerbations
The only treatment clearly shown to reduce exacerbation rates is
caplacizumab. Intensification of immunosuppressive therapy
may be expected to reduce exacerbations, but studies of cyclo-
sporine (CSA), steroids, and rituximab as adjuncts to PEX failed
to significantly reduce exacerbation rates.9,10 Caplacizumab
does not alter ADAMTS13 activity, inhibition, or function, but
rather blocks the formation of microthrombi by binding to the
A1 domain of VWF.8,11 In the initial caplacizumab study, when
the drug was stopped after 30 days without consideration of the
ADAMTS13 level, 7 of 8 patients developed recurrent iTTP in
the first 10 days after the last dose, suggesting that caplacizu-
mab protects patients from recurrent iTTP. Although the data
clearly support the efficacy of caplacizumab in preventing exac-
erbations, questions have been raised regarding the cost effec-
tiveness of the drug.12
HOW I TREAT iTTP AFTER HOSPITAL DISCHARGE
Sustained platelet count .150 3 109/L, LDH ,1.5 ULN, no new end
organ symptoms
After clinical response: platelet count ,150 3 109/L without other
explanation ,30 d after last PEX or anti-VWF therapy
Sustain clinical response for $30 d with no PEX or anti-VWF therapy
ADAMTS13 activity $ULN
ADAMTS13 activity $20% to LLN
After clinical remission, platelet count decreases to ,150 3 109/L
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without another explanation, and the need to start iTTP treatment
Confirmed by severe ADAMTS13 deficiency
After ADAMTS13 remission, ADAMTS13 activity decreases to #20%
Postdischarge follow-up and
exacerbation risk
The exacerbation rate after treatment with PEX and immune
suppression has been studied in 2 consecutive randomized, con-
trolled studies and is estimated to be between 28% and
38%.8,11 The consensus protocol of the United States Throm-
botic Microangiopathy (USTMA) Consortium institutions is to
evaluate patients weekly for the first 4 weeks after hospital dis-
charge to monitor for exacerbations that are most common in
the first 2 weeks.13 We monitor recovery of organ injury from
the acute iTTP episode clinically and with the following labora-
tory testing: complete blood count with differential, chemistry
panel, LDH level, and reticulocyte count. Prednisone is rapidly
tapered over the first 4 weeks after discharge. We use rituximab
in patients with newly diagnosed and relapsed iTTP to prevent
or delay relapses consistent with the recently published ISTH
TTP Guidelines.14 Rituximab may be initiated during hospitaliza-
tion concurrently with PEX, or alternatively, the first weekly dose
can be given soon after hospital discharge. The laboratory stud-
ies obtained at these initial follow-up visits and future visits are
shown in Figure 1. Patients treated with caplacizumab may
have weekly visits extended beyond 4 weeks to monitor the
ADAMTS13 level as they continue to receive therapy. Once
patients have safely achieved clinical remission of iTTP, we moni-
tor them monthly for 3 to 6 months followed by longitudinal
visits every 3 to 6 months. The unique monitoring of
caplacizumab-treated patients is discussed later.
Case 2
A 46-year-old Black woman was brought to the hospital by her
husband with symptoms of a headache and worsening confu-
sion over the past 2 days. She was found to have a platelet
count of 6 3 109/L and a peripheral smear that showed marked
fragmentation of red cells and confirmation of severe thrombo-
cytopenia. Clinical suspicion for a diagnosis of iTTP was high;
therefore, PEX was rapidly initiated in addition to prednisone at
a dose of 1 mg/kg daily orally with a plan to start a course of
4 weekly rituximab treatments before discharge from the hospi-
tal. Given the high clinical suspicion for a diagnosis of iTTP and
the absence of any bleeding symptoms, therapy with caplacizu-
mab was initiated concurrently with PEX, beginning on the
blood® 4 AUGUST 2022 | VOLUME 140, NUMBER 5 439
 Hospital discharge

Weekly follow-up for 4 weeks or

while on caplacizumab therapy

Monitor for:
1. Exacerbations of iTTP
2. Side effects of TTP treatment
including caplacizumab

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3. ADAMTS13 monitoring for
caplacizumab discontinuation
4. Tapering and discontinuation of
corticosteroids

Clinical remission Laboratory testing at each visit:

1. CBC with differential
2. Chemistry panel
Monthly follow-up for 3–6 months 3. Lactate dehydrogenase
with laboratory testing 4. Reticulocyte count
5. Bilirubin total/direct
6. ADAMTS13 activity with
inhibitor
Long-term follow-up

Clinic visits every 3–6 months

longitudinally to monitor:

1. ADAMTS13 activity for relapse

risk prediction
2. Development of long-term
complications in remission

Figure 1. Post–hospital discharge follow-up schedule. To monitor for exacerbations of iTTP and discontinuation of caplacizumab and long-term follow-up to predict
the risk for relapse and the development of long-term complications of iTTP.

second day. ADAMTS13 activity was reported to be ,10% on
the third day of hospitalization, confirming the diagnosis of iTTP.
After 6 daily PEX procedures, the platelet count and LDH level
normalized, and plans for postdischarge follow-up were made.
Exacerbation risk, caplacizumab, and
postdischarge follow-up
The addition of caplacizumab to PEX and steroids significantly
reduces the exacerbation rate, but without alteration of
the underlying immune-mediated clearance or blockage of
ADAMTS13 protease function. Increasingly, rituximab is added to
the initial therapy of iTTP to achieve a more durable suppression
of ADAMTS13 autoantibodies and safer discontinuation of capla-
cizumab. In the TITAN study, discontinuation of caplacizumab at
the end of the planned 30-day treatment led to disease
recurrence in 8 subjects, with 7 recurrences within a week of
cessation.8 Each of these 7 subjects had ADAMTS13 activity that
was persistently ,10%. This outcome to the treatment modifica-
tion in the HERCULES study that allowed for up to 4 weeks of
additional caplacizumab, whereas immune suppression was either
added or intensified to allow time for recovery of ADAMTS13
activity and for safer discontinuation of caplacizumab.11
In addition to prompting changes to the definition of exacerba-
tion of iTTP,3 these data have led to changes in the postdi-
scharge follow-up of patients treated with caplacizumab.
Although non–caplacizumab-treated patients have been seen
weekly for 4 weeks after hospital discharge to monitor for exac-
erbations, we still follow up caplacizumab-treated patients
weekly until they have discontinued caplacizumab after recovery
of ADAMTS13 activity. Expert consensus has been consistent in
using at least 2 weekly ADAMTS13 activity measurements
(obtained at least 1 week from the last PEX) of .20% as a
reasonable criterion to safely stop caplacizumab. However, a
retrospective analysis of 60 patients treated with caplacizumab
in Germany showed that, in 31 patients, stopping caplacizumab
before 30 days and before ADAMTS13 activity was $10% did
not result in an exacerbation of iTTP.15 Determinations of
length of therapy with caplacizumab must also take into account
bleeding complications.

440 blood® 4 AUGUST 2022 | VOLUME 140, NUMBER 5 AKWAA et al

Table 2. Long-term complications in survivors of iTTP
in remission
Cardiovascular complications1,2
Hypertension
Myocardial infarction
Cerebrovascular accidents
Neurocognitive injury45,47,49
Short-term memory issues (eg, finding words, processing
information, and retaining new memories)
Concentration skills
Chronic headaches46
Posttraumatic stress disorder50
Depression5,45,48,50
The patients in case 2 completed 4 weekly doses of rituximab at
a dose of 375 mg/m2 and at this writing is 7 weeks out from her
hospital discharge and has completed 8 weeks of caplacizumab
therapy. The most recent measurement of ADAMTS13 activity
showed persistently deficient activity of ,10% despite normal
complete blood count and LDH and serum creatinine levels.
Caplacizumab discontinuation without
recovery of ADAMTS13 activity
Although in most patients with acute iTTP, treatment with PEX,
corticosteroids, and rituximab corrects the severely deficient
ADAMTS13 level, there are patients in whom ADAMTS13 will
not recover after a 4-week course of rituximab.16,17 Although
severely deficient ADAMTS13 increases the risk of exacerbation
or relapse of iTTP, recovery is not necessary to achieve a sus-
tained clinical remission of iTTP. In the case of patients not
treated with rituximab, it would be reasonable to consider ther-
apy with rituximab. This therapy may be especially effective
in patients for whom this event was a relapse of previously
diagnosed iTTP.14
In the patient described in case 2 with newly diagnosed iTTP in
whom ADAMTS13 protease function did not recover after treat-
ment with rituximab, the decision to stop caplacizumab may not
be so straightforward. The best available data regarding the
timing of the recovery of ADAMTS13 activity after acute iTTP
treatment were reported by Scully et al where the first dose of
rituximab was given before the third day of hospitalization.9
When measured before the second rituximab infusion 1 week
later, median ADAMTS13 activity was 15%. After 8 weeks, the
median was .30%, increasing to a median of 45% after 3
months. These data suggest using a time frame of 8 to 12
weeks from the start of rituximab to assess its efficacy at improv-
ing ADAMTS13 activity. Interestingly, Barba et al reported data
on a subset of patients with iTTP in whom ADAMTS13 activity
failed to improve after an initial 4-week course of preemptive rit-
uximab (375 mg/m2). In this cohort, patients subsequently
received intensive rituximab therapy at a dose of 375 mg/m2
every 2 to 3 months for a median of 2 years (range, 1-6). Ten of
the 13 patients improved their ADAMTS13 activity a median of
56 days (range, 10 days to 2 years) after starting the intensive
regimen.18 In patients in whom their ADAMTS13 activity
HOW I TREAT iTTP AFTER HOSPITAL DISCHARGE
failed to improve after treatment with rituximab, additional
immunosuppressive therapies could be considered (see later
description of preemptive therapy). However, additional immu-
nosuppressive therapy after rituximab, such as CSA, bortezomib,
mycophenolate mofetil, and alemtuzumab, may require long-
term treatment or have potentially unfavorable side effects.19
There are unfortunately no published data to clearly guide physi-
cians. In these situations, our approach has been to consider
additional immunosuppressive therapy in those with a history of
relapses, where a relapsing clinical phenotype has been demon-
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strated and where the risk-benefit ratio may favor the addition of
another immunosuppressive therapy. A discussion about the
risks and benefits of additional immunosuppressive therapy
should be undertaken with patients in these situations. In the
event that caplacizumab is stopped without recovery of
ADAMTS13 activity, weekly or even biweekly labs should be
considered for at least the first 2 to 4 weeks to monitor for exac-
erbations of iTTP. Given that this was the initial iTTP episode,
caplacizumab was stopped after 8 weeks of therapy, and the
patient was monitored closely. Despite persistently deficient
ADAMTS13 activity in remission, she maintained a continuous
clinical remission and continued to be observed every 3 months.
The 36-year-old white man described in case 1 with a history of
chronic, relapsing iTTP was able to achieve a clinical remission
and a complete ADAMTS13 remission after 4 weekly infusions
of rituximab. He presented to the outpatient clinic 3 months
after completing rituximab to discuss his risk of relapse and any
measures that could be taken to reduce this risk. He also
had questions regarding persistent headaches and short-term
memory problems that he had recently noted.
Risk of relapse
Relapse is a major concern for patients with iTTP after recovery
from an acute iTTP episode.20 Approximately 50% or more
patients not treated with rituximab have at least 1 relapse within
5 years of initial diagnosis. Although prediction of relapse is
inexact, previous relapse of iTTP, severely deficient ADAMTS13
activity in remission, and anti-ADAMTS13 autoantibodies during
remission have been associated with an increased risk of iTTP
relapse.16,21-24 In addition, young age at presentation and previ-
ous episode of iTTP have been shown to be predictive of
relapse.21,22,25 Race may also be an important factor. A large
retrospective study of the USTMA Consortium database showed
that Black race was the strongest predictor of relapse.26 In
relapsed iTTP, relapse-free survival was significantly better in
White patients after rituximab, but treatment with rituximab did
not improve relapse-free survival in Black patients in this study.
These data suggest that race may differentially impact responses
to preemptive immunosuppressive therapy.
Prediction of relapse is clearly more complicated than
ADAMTS13 activity alone. Circulating ultralarge VWF multimers
correlated with severely deficient ADAMTS13 activity, but the
relationship was imprecise.27 Masias et al developed a multivari-
able model to predict relapses of iTTP in the following 3 months
after remission blood testing. Additional factors including age,
LDH, C3a, ADAMTS13 antigen, and the presence of ultralarge
multimers were able to improve the prediction of relapse over
blood® 4 AUGUST 2022 | VOLUME 140, NUMBER 5 441
ADAMTS13 activity alone, but the optimal clinical application of
this model requires further study.28
Monitoring ADAMTS13 activity
in remission
After achieving clinical remission of iTTP, the follow-up and moni-
toring strategy is then focused on the prevention of relapse.
Although the optimal monitoring schedule remains to be
defined, our practice is to monitor the complete blood count,
chemistry, and markers of hemolysis (LDH and haptoglobin) every
3 months for longitudinal follow-up.29 It is also our practice to
measure ADAMTS13 activity every 3 months to help assess the
risk of clinical and ADAMTS13 relapse (Figure 1).3 This schedule
was not developed from prospective study, but rather was
derived in part from a study by Jin et al that reported the risk of
relapse in the 3 months after measurement of ADAMTS13
activity.21 Experts have also agreed that monitoring ADAMTS13
every 3 months allows for sufficient time to intervene with pre-
emptive therapy, while not being overly onerous to patients.
After several years of continuous clinical and ADAMTS13 remis-
sion, it may be reasonable to alter the schedule to every 6
months for patients with difficulties keeping this rigorous follow-
up schedule, but maintaining a consistent follow-up plan is
very important. In addition, patients must be monitored for the
development of long-term complications of iTTP that have been
associated with premature death in at least 2 studies.1,2
ADAMTS13 activity threshold for
preemptive treatment
Although preemptive therapy with rituximab has been shown to
prevent or delay relapses of iTTP,16,17 there are no randomized,
prospective data to accurately define a specific threshold for
ADAMTS13 activity when preemptive immune suppression should
be initiated. Moreover, the development of severely deficient
ADAMTS13 activity does not uniformly lead to relapse and may
fluctuate in remission.21,23,30 Given the current knowledge of the
efficacy and favorable side effect profile of rituximab, the thresh-
old we typically use to initiate preemptive treatment has increased
from ADAMTS13 activity of #10% to a threshold of 20%. This
level is based on expert opinion regarding the increased risk of
relapse with decreasing ADAMTS13 activity and the need to allow
time for response to immunosuppressive therapy rather than pro-
spective data. Repeat measurement of ADAMTS13 activity in the
following 2 to 4 weeks is recommended for those with activity
.20% or those with a decrease from the previous measurement,
to establish a trend. In the absence of an absolute threshold to
initiate preemptive therapy, the risk and complications of an iTTP
relapse must be balanced against the risk of any preemptive ther-
apy. As stated previously, younger patients and patients with prior
relapses are likely to be at greater risk of relapse, which should
also factor into the decision making.
Preemptive treatment to prevent relapse
A detailed discussion of every preemptive agent reported is
beyond the scope of this manuscript, but preemptive therapies
that are commonly used and supported by data will be discussed.
The most common preemptive treatment used is rituximab, but
there are also data regarding the use of CSA and splenectomy
442 blood® 4 AUGUST 2022 | VOLUME 140, NUMBER 5
during remission to prevent relapse. There are reports of other
immunosuppressive therapies, including alemtuzumab, bortezo-
mib, cyclophosphamide, or mycophenolate, that have been used
to prevent relapse and could be considered, depending on the
individual circumstances of the patient.
Rituximab
The efficacy and safety of rituximab has been established in
several observational studies of patients with acute, refractory, or
relapsed iTTP.31-33 Reduction of relapses with the use of preemp-
tive rituximab has been demonstrated by several groups as
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well.31-33 The French Thrombotic Microangiopathy Reference
Center studied 92 patients with iTTP in remission with undetect-
able ADAMTS13 activity (,10%). During a follow-up period of
35.8 months, rituximab significantly decreased the median num-
ber of iTTP relapses (0 episodes per year vs 0.33 episodes per
year compared with historical controls).16 The optimal dose and
schedule of rituximab has not been determined in iTTP, but the
most common dose currently used is 375 mg/m2 per week for
4 weeks. The need for additional courses of rituximab beyond
the initial treatment should be guided by regular, serial measure-
ments of ADAMTS13 activity. Preemptive rituximab on a fixed,
regular schedule (every 3 months) without the guidance of serial
monitoring of ADAMTS13 activity is discouraged, as it could lead
to unnecessary rituximab therapy.14
CSA
Several reports have described the use of cyclosporine (CSA) for
iTTP including as a preemptive treatment to prevent relapse in
patients with severely deficient ADAMTS13 activity and a history
of multiple recurrences (.2).10,34-38 The dose administered for
prophylaxis was 2 to 3 mg/kg orally twice daily in divided doses
for a total of 6 months. Trough CSA levels were used in this study
to monitor for toxicity, but levels were not correlated with
response to therapy. At this lower dose, the CSA was well toler-
ated, but patients must be counseled regarding side effects that
include gingival hyperplasia, renal insufficiency, and increased
hair growth. Data from 19 patients indicated that that CSA is
effective in suppressing ADAMTS13 inhibitors and in improving
ADAMTS13 activity over the 6-month study, but 7 of 19 patients
relapsed after discontinuation of CSA, suggesting that the benefit
does not persist beyond the CSA treatment period.39,40 If used
preemptively, CSA is likely to be administered over a prolonged
period. As with rituximab, the level of ADAMTS13 activity should
be used to judge the efficacy of CSA with drug levels used only
to monitor for toxicity.
Splenectomy
A systematic review of 18 studies of splenectomy in iTTP demon-
strated that the relapse rate was reduced to 17% in a cohort of
patients with a chronic, relapsing phenotype. Despite the limita-
tions (no control groups and possible publication bias), the
response rate after splenectomy at 3 years ranged between 70%
and 80%.41 In another series of patients who underwent splenec-
tomy preemptively to prevent relapse, the relapse rate fell from
0.74 relapses per patient-year to 0.1 relapse per patient-year.42
Splenectomy, however, should not be considered in patients with
acute, refractory iTTP, given the greater risk for complications and
death.42 We believe that splenectomy could be considered a pre-
emptive treatment in remission to prevent relapse of iTTP after
considering other preemptive options and a thorough discussion
AKWAA et al
of the risks and benefits with the patient. ADAMTS13 activity after
splenectomy should be monitored as a measure of efficacy.
Long-term complications
It has been increasingly clear that a new diagnosis of iTTP is the
beginning of a long-term follow-up for a disease that is associated
with several long-term complications (Table 2). At least 2 studies
have demonstrated a shorter life expectancy in survivors of an
acute iTTP episode, with cardiovascular complications playing a
significant role.1,43 Published work by Upreti et al demonstrated a
fivefold increased risk for stroke in patients with iTTP (unrelated to
Another study from Chaturvedi et al, who used an online survey
tool, found that 80% of patients with iTTP in remission had at
least mild symptoms of depression.50 They also reported that
35% of patients with iTTP had a positive screening for posttrau-
matic stress disorder. It is presently unclear how to best screen
for these complications in patients with iTTP to allow for inter-
ventions to mitigate the morbidity and mortality associated with
them. We recommend referral to psychiatry or psychology for
detailed neurocognitive testing during follow-up when there are
possible signs or symptoms of mood or cognitive issues after a
diagnosis of iTTP.

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an acute iTTP episode) in remission during long-term follow-up,
with all of the patients who developed strokes having had lower-
than-normal (,70%) ADAMTS13 activity.44 These data support
the hypothesis that preemptive immunosuppressive therapy may
help to prevent stokes in patients with iTTP in remission. Given
these data, we have placed increased emphasis on addressing
modifiable risk factors for cardiovascular disease including blood
pressure, smoking cessation, and treatment of hypercholesterol-
emia, as indicated, to attempt to decrease the risk for cardiovas-
cular disease. We also commonly recommend referral to a
cardiologist for baseline evaluation and assessment of cardiovas-
cular risk after a diagnosis of iTTP and for consideration of the use
of antiplatelet therapy and other risk reduction strategies.
Although data on the efficacy of these measures in patients with
iTTP are lacking, antiplatelet therapy (aspirin, clopidogrel) seems
reasonable in patients with iTTP at risk for cardiovascular disease
as would be considered in similar nonpatients with iTTP.
Pregnancy and relapse
The question of pregnancy and the risk for relapse in patients
with a prior diagnosis of iTTP is understandably an important
issue for patients. Severely deficient ADAMTS13 activity in preg-
nancy is associated with an increased risk of relapse during
pregnancy.29 As a part of preconception counseling in a patient
with a history of iTTP, a discussion of this risk of relapse as well
as the potential need for prophylactic immunosuppressive ther-
apy is necessary. Regular monitoring of ADAMTS13 activity is
recommended every 2 to 3 months throughout the pregnancy,
using the trend in the ADAMTS13 activity to assess the need for
preemptive therapy to prevent relapse of iTTP.
Authorship
Contribution: F.A., A.A., and S.R.C. designed and wrote the manuscript.

Neurocognitive deficits that include short-term memory prob-
lems, mood disorders, headaches, and posttraumatic stress dis-
order are clearly recognized to be more common in patients
with iTTP in remission.1,45-50 In a study of select patients in iTTP
remission from The Ohio State University and the University Col-
lege London Hospitals (n 5 27), 63% of the patients studied
demonstrated neurocognitive impairment, particularly in the
areas of visual learning and memory.51 Deford et al also
reported that nearly 20% of the iTTP survivors in their study met
criteria for a diagnosis of major depression, which was signifi-
cantly greater than the expected population rate of 6%.1
Conflict-of-interest-disclosure: S.R.C. has received research funding and
consulting fees from Sanofi. F.A. and A.A. declare no competing financial
interests.
Correspondence: Spero R. Cataland, Department of Hematology, The
Ohio State University, 1150F Lincoln Tower, 1800 Cannon Dr, Columbus,
OH 43210; e-mail: spero.cataland@osumc.edu.
Footnote
Submitted 20 October 2021; accepted 14 March 2022; prepublished online
on Blood First Edition 6 June 2022. DOI 10.1182/blood.2021014514.

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