Clinical Review & Education

JAMA | Review

Immune Thrombotic Thrombocytopenic Purpura

A Review
Allyson M. Pishko, MD, MSCE; Ang Li, MD, MS; Adam Cuker, MD, MS

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IMPORTANCE Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening CME at jamacmelookup.com
thrombotic microangiopathy that presents with microangiopathic hemolytic anemia (MAHA)
and thrombocytopenia. Worldwide annual incidence of iTTP is 2 cases per million to 6 cases
per million.

OBSERVATIONS Immune TTP is caused by an autoantibody to a disintegrin and

metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13), an enzyme that cleaves
von Willebrand factor (vWF). With severely low ADAMTS13 activity (<10%), large multimers
of vWF accumulate and bind platelets, forming microvasculature thromboses that cause
ischemic organ injury (eg, myocardial infarction and stroke). The incidence of iTTP is higher in
adults than children (incident rate ratio [IRR], 31.62 per million person-years [95% CI,
14.68-68.10]), females than males (IRR, 3.19 [95% CI, 2.65-3.85]), and Black compared with
non-Black individuals (IRR, 7.09 [95% CI, 6.05-8.31]). Common presenting symptoms are
neurologic (eg, headache, confusion, or seizures [39%-80%]) and abdominal pain
(35%-39%). For patients presenting with MAHA and thrombocytopenia, clinical prediction
scores for iTTP using laboratory data, such as platelet count less than 30 × 109/L and
creatinine level less than 2.0 mg/dL (176.8 μmol/L), can help guide empirical treatment
initiation for iTTP before ADAMTS13 results are available. Prompt initiation of therapy with
therapeutic plasma exchange, corticosteroids, and rituximab improves survival with iTTP
from almost zero to approximately 93%. Caplacizumab, a synthetic small antibody
(nanobody) that blocks platelet binding to vWF, administered concurrently with
immunosuppression and therapeutic plasma exchange and continued until ADAMTS13
recovery, reduces the time to normalization of platelet count and decreases the risk of early
recurrence (defined as within 30 days of completing therapeutic plasma exchange)
compared with placebo (risk difference [RD], −29% [95% CI, −42 to −14%]) but increases
bleeding risk (RD, 17% [95% CI, 4%-30%]). After obtaining clinical remission (defined as at
least 30 days of sustained normalization of platelet count, decreased serum lactate
dehydrogenase level, and absence of new or progressive ischemic organ injury without
therapeutic plasma exchange or caplacizumab), 16% of patients have at least 1 relapse of
iTTP. Regular monitoring of ADAMTS13 activity in remission and administration of rituximab
when ADAMTS13 activity is less than 20% reduces risk of relapse (odds ratio, 0.09 [95% CI,
0.04-0.24]).

CONCLUSIONS AND RELEVANCE Immune TTP is a rare immune-mediated disorder that

presents with thrombocytopenia and MAHA and may cause life-threatening thrombosis.
Treatment with therapeutic plasma exchange, corticosteroids, and rituximab is associated
with 30-day survival rates of more than 90%. Addition of caplacizumab shortens time to Author Affiliations: Department of
normalization of platelet count and reduces recurrences while receiving the drug but Medicine, Perelman School of
increases bleeding risk. Monitoring ADAMTS13 activity in survivors and initiation of rituximab Medicine, University of Pennsylvania,
Philadelphia (Pishko, Cuker); Section
for those with low ADAMTS13 activity reduces the risk of clinical relapse.
of Hematology-Oncology, Baylor
College of Medicine, Houston, Texas
(Li); Department of Pathology and
Laboratory Medicine, Perelman
School of Medicine, University of
Pennsylvania, Philadelphia (Cuker).
Corresponding Author: Allyson M.
Pishko, MD, MSCE, Department of
Medicine, Perelman School of
Medicine, University of Pennsylvania,
3400 Spruce St, Dulles Bldg,
Third Floor, Philadelphia, PA 19104
JAMA. doi:10.1001/jama.2025.3807 (Allyson.Pishko@pennmedicine.
Published online May 19, 2025. upenn.edu).

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 Clinical Review & Education Review Immune Thrombotic Thrombocytopenic Purpura: A Review

I
mmune thrombotic thrombocytopenic purpura (iTTP) is a life-
threatening thrombotic microangiopathy with hemolytic ane- Box. Commonly Asked Questions About iTTP
mia and thrombocytopenia that is caused by an acquired se-
vere deficiency of a disintegrin and metallopeptidase with How Is iTTP Distinguished From Other Thrombotic
thrombospondin type 1 motif 13 (ADAMTS13) (<10%), which nor- Microangiopathies?
A clinical prediction score, such as the PLASMIC or FRENCH score,
mally cleaves ultralarge multimers of von Willebrand factor (vWF).1,2
can be used to predict the likelihood of iTTP. The pathognomonic
Microangiopathic thrombosis associated with iTTP may cause com- finding of iTTP is thrombotic microangiopathy with ADAMTS13
plications such as stroke, myocardial infarction, and kidney injury.3 activity less than 10%, although patients with ADAMTS13 activity
This review highlights the epidemiology of iTTP and clinical predic- of 10% to 20% may have iTTP.
tion scores for the diagnosis of TTP in adults; reviews evidence for
What Are the Benefits and Risks of Caplacizumab for iTTP?
treatment of acute iTTP and prevention of relapse; and discusses For patients with iTTP, the addition of caplacizumab to treatment
potential long-term complications of iTTP (Box). with therapeutic plasma exchange, corticosteroids, and rituximab
shortens time to normalization of platelet count and reduces risk
of recurrence while receiving the drug but does not reduce relapse
risk (beyond 30 days of caplacizumab discontinuation). The major
Methods adverse effect of caplacizumab is bleeding.

We searched PubMed for English-language studies on the epidemi- How Should Patients With iTTP Be Monitored Long Term?
ology, pathophysiology, diagnosis, treatment, and prognosis of iTTP After recovery from an initial episode of iTTP, patients are at risk
from January 1, 2010, to April 2, 2025. We manually reviewed the for relapse of the disease. Monitoring ADAMTS13 activity at regular
reference lists of selected articles and reviews for other relevant intervals and administering rituximab if ADAMTS13 activity falls
below 20% decreases the risk of relapse.
sources such as earlier studies of therapeutic plasma exchange, cor-
ticosteroids, and splenectomy. Of the 1841 articles reviewed, we in- Abbreviations: ADAMTS13, a disintegrin and metallopeptidase with
thrombospondin type 1 motif 13; iTTP, immune thrombotic
cluded 76 articles, composed of 4 randomized clinical trials; 2 single-
thrombocytopenic purpura.
group clinical trials; 53 retrospective or observational studies; 5 meta-
analyses; 8 society guideline or recommendation, working group
guidance, or expert consensus documents; 4 narrative reviews. tation (1%), or drugs (eg, ticlopidine, quinine, gemcitabine, and cal-
cineurin inhibitors [1%]).6

Diagnosis of iTTP
Discussion
Clinical Presentation and Initial Laboratory Findings
Pathophysiology Common presenting features of iTTP include neurologic symptoms
TTP results from severe deficiency of the enzyme ADAMTS13, which (eg, headache, confusion, vision changes or seizures [39%-80%]), ab-
normally cleaves vWF. Without ADAMTS13, large multimers of vWF dominal pain or nausea (35%-39%), and fever (10%-35%).9-11 Less
accumulate and bind platelets, leading to the formation of thrombi than 10% of patients exhibit the full “pentad” of TTP manifestations
in the microvasculature.4 These thrombi shear red blood cells and (hemolytic anemia, thrombocytopenia, fever, kidney and neurologic
cause ischemic organ injury, such as stroke and myocardial infarc- dysfunction) at presentation.6,12
tion (Figure 1).In iTTP, autoantibodies (typically IgG) result in the in- Key laboratory findings in iTTP are thrombocytopenia (typical
hibition or clearance of ADAMTS13.2 Severe deficiency in ADAMTS13 platelet count <30 × 109/L) and microangiopathic hemolytic ane-
activity (<10%) is necessary for development of TTP, but some pa- mia (MAHA). MAHA is hemolytic anemia, diagnosed by elevated se-
tients with iTTP may have extended periods of severe deficiency of rum lactate dehydrogenase (LDH) and indirect bilirubin levels; re-
ADAMTS13 prior to presenting with clinical relapse.5 ticulocyte count above the upper limits of normal; serum haptoglobin
level below the lower limits of normal; and a negative result from
Epidemiology Coombs testing for anti–red cell antibody or complement. With
TTP is a rare disease, with a worldwide annual incidence of 2 to 6 MAHA, schistocytes are the prominent red blood cell morphologic
cases per million.6-8 The incidence rate of iTTP is higher in adults abnormality on a peripheral blood smear, at a frequency of 1% of red
than children (incident rate ratio [IRR] for adults vs children, 31.62 blood cells or greater.13 Daily blood smear examination should be per-
per 100 000 person-years [95% CI, 14.68-68.10]), females than formed in patients with high clinical suspicion for iTTP because schis-
males (IRR, 3.19 per 100 000 person-years [95% CI, 2.65-3.85]), tocytes may not be present initially.13 Coagulation tests (prothrom-
and Black individuals compared with non-Black individuals (race bin time, activated partial thromboplastin time) are typically normal
assigned by investigators) (IRR, 7.09 per 100 000 person-years or only mildly prolonged with iTTP. In a study of 363 patients with
[95% CI, 6.05-8.31]).7 Most cases of TTP in adults (>95%) are iTTP, acute kidney injury occurred in up to 48% of patients (creati-
immune-mediated from autoantibodies to ADAMTS13 (iTTP), with nine level ⱖ1.5 mg/dL [to convert creatinine values to μmol/L, mul-
the remaining 3% to 5% due to congenital deficiency of tiply by 88.4]), but only 14% have a serum creatinine level 2.5 mg/dL
ADAMTS13.6 A cross-sectional analysis of a FRENCH cohort of 939 or greater.10 Only 5% had kidney failure, defined as either a serum
adult patients with TTP reported associated conditions of autoim- creatinine level increasing by 0.5 mg/dL or more per day for 2 days
mune disease (eg, severe systemic lupus erythematosus or cata- or a serum creatinine level 4.0 mg/dL or greater plus dialysis within
strophic antiphospholipid syndrome [14%]), infection (eg, HIV 7 days of the diagnosis.10 A diagnostic and initial treatment work-
[13%]), pregnancy (7%), disseminated malignancy (4%), transplan- flow is summarized in Figure 2.

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 Immune Thrombotic Thrombocytopenic Purpura: A Review Review Clinical Review & Education

Figure 1. Pathophysiology of Immune Thrombotic Thrombocytopenic Purpura

Normal von Willebrand factor (vWF) secretion Immune thrombotic thrombocytopenic purpura (iTTP)
and cleavage
vWF is secreted by the
Weibel-Palade body.
vWF
ENDOTHELIAL CELL

ARTERIOLE LUMEN

Glycoprotein
ADAMTS13 1b-IX-V complex

Sequestered platelets
bound to ultralarge vWF

Circulating vWF
platelet

Anti-ADAMTS13 antibodies bind and inhibit

or increase clearance of ADAMTS13.

ADAMTS13 protease cleaves ultralarge multimers of vWF

secreted by endothelial cells, limiting platelet binding Thrombocytopenia
and thrombosis when vascular injury is not present.

In iTTP, severe deficiency of ADAMTS13 causes ultralarge multimers

of vWF to accumulate, bind platelets, and promote thrombus formation.

Platelet microthrombus

Platelet
Shearing of red blood cells
into fragments (schistocytes)

Microangiopathic hemolytic anemia

Ischemic organ injury

Complications may include
stroke, myocardial infarction,
or kidney dysfunction.

ADAMTS13 indicates a disintegrin and metallopeptidase with thrombospondin type 1 motif 13.

ADAMTS13 Activity Testing and Interpretation ADAMTS13 activity is most commonly measured by a fluores-
Patients with MAHA and thrombocytopenia without another clear cence resonance energy transfer assay or a chromogenic enzyme-
etiology for thrombotic microangiopathy, such as active malig- linked immunosorbent assay.16 Plasma samples for ADAMTS13 ac-
nancy, transplantation, severe sepsis, or disseminated intravascu- tivity should ideally be obtained prior to therapeutic plasma
lar coagulation,14 should undergo testing of ADAMTS13 activity. The exchange, because the levels may be falsely elevated by ADAMTS13
diagnosis of TTP is made in patients with MAHA, thrombocytope- in the donor plasma. A study of 19 patients with iTTP reported the
nia, and ADAMTS13 activity less than 10% (lower limit of normal sensitivity of detecting severe deficiency (ADAMTS13 activity <10%)
for ADAMTS13 activity varies by method and assay, generally at 89% within 1 day of therapeutic plasma exchange initiation, 83%
40%-60%).15-17 Patients with ADAMTS13 activity of 10% to 20% and within 2 days, and 78% within 3 days of therapeutic plasma ex-
high suspicion for iTTP should undergo repeat ADAMTS13 activity change initiation.18 Due to the need for technical expertise to per-
testing to avoid missing iTTP, and treatment should be initiated for form these assays, ADAMTS13 testing is often sent to reference labo-
those deemed likely to have iTTP.14 ratories, and reporting of results typically takes more than 72 hours.

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 Clinical Review & Education Review Immune Thrombotic Thrombocytopenic Purpura: A Review

Figure 2. Initial Diagnostic Workflow for Patients With Suspected Thrombotic Thrombocytopenic Purpura

Patient presents with new-onset thrombocytopenia and anemia

Symptoms at presentation vary but may include neurologic symptoms, abdominal pain, and fever
<10% of patients present with full “pentad” of TTP characteristics (microangiopathic
hemoytic anemia [MAHA], thrombocytopenia, fever, and kidney and neurologic dysfunction)

Evaluate for presence of MAHA and thrombocytopenia

• Blood smear confirming thrombocytopenia and presence of schistocytes (repeat daily blood smear in patients with high suspicion for immune-mediated TTP [iTTP])
• Elevated lactate dehydrogenase (LDH), decreased haptoblogin, elevated indirect bilirubin, and elevated reticulocyte count
• Direct coombs negative for anti–red cell antibody or complement

MAHA and thrombocytopenia confirmed

Evaluate for alternate etiology of thrombotic microangiopathy

• Signs of severe sepsis • History of solid organ or bone marrow transplant • Severe valvular disease or malignant hypertension Treat as
• Elevated D-dimer and • Pregnancy in later second or third trimester • Features consistent with catastrophic Non-TTP appropriate for
international normalized ratio with typical features of preeclampsia antiphospholipid syndrome etiology alternate etiology
consistent with disseminated or hemolysis, elevated liver enzymes, • Medication associated with
intravascular coagulation and low platelets syndrome (HELLP) thrombotic microangiopathy

High clinical concern for TTP or no obvious etiologya

Calculate clinical risk score (PLASMIC or FRENCH) and order ADAMTS13 activity assay

PLASMIC or FRENCH clinical risk score ADAMTS13 activity assay

Initial empiric action taken on clinical risk score while waiting for • Fluorescence resonance energy transfer assay
ADAMTS13 test results to confirm or modify therapeutic actions • Chromogenic enzyme-linked immunosorbent assay (ELISA)
Plasma sample should be obtained before starting plasma exchange

Intermediate or ADAMTS13 ADAMTS13 ADAMTS13

Low risk for TTP
high risk for TTP activity <10% activity 10%-20% activity >20%

Consider alternate diagnosis Confirmed TTP Consider repeat testing TTP unlikely
and evaluation diagnosis diagnosis
• Further evaluate for iTTP with repeat
• Consider complement-mediated • Evaluate for iTTP ADAMTS13 activity and inhibitor • Consider stopping
thrombotic microangiopathy (atypical testing with high clinical suspicion empiric TTP-directed
hemolytic uremic syndrome [HUS]) • Continue TTP-directed treatment treatment if initiated
if rapidly worsening kidney function if high clinical concern for iTTP
• Evaluate for HUS if bloody diarrhea • Consider non-TTP etiology
• Observe closely

Initiate iTTP-directed treatmentb Reflex testing to detect auto-antibody to ADAMTS13

• Plasma exchange • Caplacizumabc • ADAMTS13 functional inhibitor assay

• Corticosteroids Consider initiation with high risk for TTP • ADAMTS13 IgG antibody ELISA
Start immediately • Rituximab
with intermediate Consider addition with confirmation Antibody detected Antibody not detected
or high risk for TTP of severe ADAMTS13 deficiency

Confirmed iTTP diagnosis Repeat ADAMTS13 activity assay in remission

• If ADAMTS13 activity <10% without detectable inhibitor,
consider congenital TTP and send for gene sequencing

b
ADAMTS13 indicates a disintegrin and metallopeptidase with thrombospondin Prompt hematological consultation to evaluate for initiation of empirical
type 1 motif 13; TTP, thrombotic thrombocytopenic purpura. treatment for TTP for PLASMIC score 5 or higher or FRENCH score 1 or higher.
a c
If atypical or severe features of another etiology are present (eg, severe International Society on Thrombosis and Haemostasis guidelines suggest using
neurologic symptoms with preeclampsia), consider proceeding with risk score caplacizumab in all patients with immune TTP (confirmed by ADAMTS13 activity
calculation and ADAMTS13 testing. <10% or high pretest suspicion with ADAMTS13 results available within 72 hours).
Some experts reserve it for cases of severe illness and/or refractory disease.

Hospitals with on-site testing can provide results within 6 to 24 hours, Anti-ADAMTS13 Antibody Testing
but testing is often batched and only offered during business hours.9 To confirm the diagnosis of iTTP, patients with low ADAMTS13 ac-
To address diagnostic delays, rapid ADAMTS13 assays have been de- tivity (predefined by the laboratory performing ADAMTS13 test-
veloped that can be performed in less than 60 minutes, although ing, generally 10%-30%) should undergo anti-ADAMTS13 anti-
these rapid assays have not been widely validated.16,19-22 body testing using a functional inhibitor assay (mixing study) and/or

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 Immune Thrombotic Thrombocytopenic Purpura: A Review Review Clinical Review & Education

Table 1. Differential Diagnosis and Features of Thrombotic Microangiopathies

Platelet Key
count, Creatinine level,
a b
Diagnosis Hemolysis ×109/Lc mg/dLc Featuresd Therapies
Thrombotic thrombocytopenic purpura Yes <30 <2 ADAMTS13 Immune: therapeutic plasma exchange,
deficiency immune suppression, caplacizumab
(<10%-20%) Congenital: donor plasma or
recombinant ADAMTS13
Complement-mediated thrombotic Yes >30 >2 Complement Complement inhibitors
microangiopathy dysregulation
<100
Infection
Shiga toxin producing Escherichia coli Yes Variable Variable Variable Supportive care
(O157:H7) Disease-specific antivirals/
Advanced HIV infection antimicrobials
Sepsis
Autoimmune
Systemic lupus erythematosus Yes Variable Variable Variable Corticosteroid with-without other
immunosuppressant
Catastrophic antiphospholipid syndrome
Anticoagulation with/without
therapeutic plasma exchange
Pregnancy
Preeclampsia Yes Variable Variable Variable Delivery of fetus

HELLP syndrome (hemolysis, elevated

liver enzyme levels, low platelet count)
Cardiac
Malignant hypertension Yes Variable Variable Variable Treatment of hypertension or valvular
disease
Malfunctioning mechanical valve
Cancer
Disseminated cancer Yes Variable Variable Variable Treatment of cancer
Transplant
Hematopoietic cell Yes Variable Variable Variable Treatment of rejection or graft-vs-host
disease, supportive care, stop offending
Solid organ drugs
Drugs
Quinine Yes Variable Variable Variable Stop offending drug
Ticlopidine
Tacrolimus
Gemcitabine
Mitomycin
b
Abbreviation: ADAMTS13, a disintegrin and metallopeptidase with Hemolysis: low hemoglobin level, high reticulocyte counbt/serum lactate
thrombospondin type 1 motif 13. dehydrogenase level/indirect bilirubin, low haptoglobin levels.
c
SI conversion factor: To convert creatinine values to μmol/L, multiply by 88.4. Common laboratory values at presentation, although patients may differ.
a d
Common etiologies are listed, although the list is not meant to be exhaustive. All thrombotic microangiopathies can have neurologic, cardiac, and abdominal
features due to involvement of microvasculature.

an enzyme-linked immunosorbent assay for ADAMTS13 IgG anti- Differential Diagnoses

body, preferably on a sample drawn before therapeutic plasma The differential diagnosis of iTTP (Table 1) includes complement-
exchange.18 While 67% to 97.8% of patients with iTTP have a de- mediated thrombotic microangiopathy (also known as atypical he-
tectable ADAMTS13 antibody, absence of an antibody does not ex- molytic uremic syndrome), although iTTP typically presents with
clude the diagnosis of iTTP.9 When using a functional inhibitor as- more severe thrombocytopenia (platelet count <30 × 109/L) and
say, weak inhibitors or antibodies that cause increased clearance of relatively mild kidney dysfunction (creatinine level <2 mg/dL)
ADAMTS13 may not be detected.16 Furthermore, in 1 cohort of 191 (Table 1).25 During pregnancy, the most common etiologies of throm-
patients with TTP without detectable anti-ADAMTS13 antibody on botic microangiopathy presenting in the second or third trimester
presentation, 21% had detectable antibody at subsequent is HELLP syndrome (preeclampsia hemolysis, elevated liver en-
follow-up.23 If ADAMTS13 activity remains less than 10% during clini- zyme levels, and low platelet count). However, in patients with
cal remission with no detectable anti-ADAMTS13 antibody, congen- thrombotic microangiopathy presenting earlier in pregnancy or with
ital rather than immune-mediated deficiency of ADAMTS13 may be other atypical features (eg, neurologic features or cardiac ische-
present.9 The diagnosis of congenital TTP can be confirmed by ge- mia), a severely low ADAMTS13 activity level (<10%-20%) distin-
netic sequencing of the ADAMTS13 gene.24 guishes TTP from these other pregnancy-specific conditions.26

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 Clinical Review & Education Review Immune Thrombotic Thrombocytopenic Purpura: A Review

Table 2. Components and Operating Characteristics of Clinical Prediction Scores for Severe ADAMTS13 Deficiency in Patients
With Microangiopathic Hemolytic Anemia and Thrombocytopenia

PLASMICa FRENCH score (modified)b

Components (points) Platelet count <30 × 109/L (+1) Platelet count <30 × 109/L (+1)
Creatinine <2 mg/dL (+1) Creatinine <2.26 mg/dL (+1)
Hemolysis (indirect bilirubin >2 mg/dL or reticulocytes >2.5%
or undetectable haptoglobin) (+1)
INR <1.5 (+1)
MCV <90 fL (+1)
No active cancer (+1)
No history of solid-organ or stem-cell transplant (+1)
Probability of severe Score ≥5: sensitivity, 99% (95% CI, 91%-100%); specificity, Score ≥1: sensitivity, 98.8%;
ADAMTS13 deficiency 57% (95% CI, 41%-72%)29 specificity, 48.1%30
b
Abbreviations: ADAMTS13, a disintegrin and metallopeptidase with The FRENCH score was derived in patients with microangiopathic hemolytic
thrombospondin type 1 motif 13; INR, International Normalized Ratio; MCV, anemia (+schistocytes, +thrombocytopenia) for whom ADAMTS13 activity
mean corpuscular volume. testing was sent and after exclusion for known associated condition (including
a
The PLASMIC score was derived in patients with microangiopathic hemolytic active cancer, transplantation, severe sepsis, and disseminated intravascular
anemia (+schistocytes, +thrombocytopenia) for whom ADAMTS13 activity coagulation). The performance metric was estimated after exclusion of
testing was sent by the treating physician. It should only be used in patients antinuclear antibody testing. The performance reported was estimated from
with schistocytes and clinical suspicion for thrombotic thrombocytopenic initial derivation cohort without validation (N = 160/214 with ADAMTS13
purpura. deficiency).

Additionally, anemia from severe vitamin B12 deficiency (average should occur for patients with a thrombotic microangiopathy with
hemoglobin level <5.5-6.1 g/L), with thrombocytopenia and he- no obvious secondary cause and a FRENCH score of 1 or higher.
molysis from ineffective erythropoiesis, can present similarly to In a study of 75 patients with iTTP and 57 with other causes of
MAHA but typically is associated with elevated mean corpuscular thrombotic microangiopathy, the sensitivity of a PLASMIC score of
volume (mean, 109 fL), very high serum LDH level (mean, 3539 U/L 5 or higher for diagnosis of iTTP was 91.4% for patients aged 18 to
[59.1 μkat/L]), low reticulocyte count (mean, 0%-4%), and near- 39 years, 78.3% for those aged 40 to 59 years, and 76.9% for those
normal bilirubin level (mean, 1.6 mg/dL [27.37 μmol/L]).27,28 60 years or older.31 The sensitivity of a FRENCH score of 1 or higher
for diagnosis of iTTP was 100% for patients aged 18 to 39 years,
Clinical Prediction Scores 96.2% for those aged 40 to 59 years, and 76.9% for those 60 years
Clinical prediction scores are useful to estimate the likelihood of se- or older. No clinical risk score has been derived or validated for throm-
vere ADAMTS13 deficiency because treatment should begin ur- botic microangiopathy diagnosis during pregnancy.26
gently in patients with iTTP, often before the results of ADAMTS13
activity are available (Table 2; Figure 2).9 Natural History of iTTP and Outcome Definitions
The most commonly used prediction score is the PLASMIC score Figure 3 outlines the 2021 International Working Group outcome
(Table 2).25 A systematic review that included 13 validation cohort definitions for iTTP and implications for management.12 Most
studies with 970 patients with thrombotic microangiopathy (de- early morbidity and mortality associated with acute iTTP is due to
fined as platelet count <150 × 109/L and presence of schistocytes microvascular thrombosis leading to ischemic organ injury, such as
on peripheral smear) found that a PLASMIC score of 5 or higher had myocardial infarction and stroke. A clinical response to acute iTTP
a sensitivity of 99% (95% CI, 91%-100%) and specificity of 57% treatment is characterized by normalization of platelet count, a
(95% CI, 41%-72%) for the diagnosis of iTTP.29 Prompt hemato- decrease in serum LDH level, and absence of new or progressive
logic consultation to evaluate for initiation of empirical treatment ischemic organ injury.12 Patients who achieve clinical response may
for TTP prior to return of an ADAMTS13 activity result should be ob- still have persistent deficiency of ADAMTS13 activity less than 10%
tained for patients with a PLASMIC score of 5 or higher. caused by anti-ADAMTS13 autoantibodies, and up to 38% have an
The French Thrombotic Microangiopathy Reference Center iTTP exacerbation (a recurrence within 30 days of stopping thera-
score, derived from patients with MAHA and ADAMTS13 levels, in- peutic plasma exchange and caplacizumab).32,33 Patients who are
cludes only the platelet count, serum creatinine level, and anti- 30 days post therapeutic plasma exchange and caplacizumab
nuclear antibody test result, after excluding persons with known as- therapy with sustained clinical response have obtained clinical
sociated secondary causes of microangiopathy such as active remission; if ADAMTS13 increases to at least 20%, they have
malignancy, transplantation, severe sepsis, and disseminated intra- achieved an ADAMTS13 remission.12 Similar to other autoimmune
vascular coagulation.30 A score of 1 or higher has a sensitivity of diseases, the ADAMTS13 autoantibody may recur, and patients can
98.8% (95% CI, 96.9%-100%) and specificity of 48.1% (95% CI, have clinical or ADAMTS13 relapse years after recovery, with
38.9%-59.3%) for the diagnosis of iTTP.30 A modified FRENCH score relapse occurring in approximately 30% of patients (16% clinical
excluding antinuclear antibody (which is not readily available at pre- relapse, 13% ADAMTS13 relapse only) at 5-year follow-up.5
sentation in most patients) performed similarly in the derivation
study and is more commonly used.30 No meta-analysis of valida- Treatment of an Initial iTTP Episode
tion studies is available for the FRENCH score. Prompt hemato- For a first acute episode, the 2020 International Society on Throm-
logic consultation to evaluate for initiation of empirical treatment bosis and Hemostasis (ISTH) guidelines recommend first-line

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 Immune Thrombotic Thrombocytopenic Purpura: A Review Review Clinical Review & Education

Figure 3. Immune Thrombotic Thrombocytopenic Purpura Outcome Definitions and Implications for Management

Initial immune thrombotic thrombocytopenic purpura (iTTP) episode

Treatment
• Daily therapeutic plasma exchange • Rituximaba
• Corticosteroids • Caplacizumaba

Clinical response Refractory disease (4%-14% of patients)

Sustainedb platelet count ≥150× 109/L and lactate dehydrogenase (LDH) Lack of sustainedb platelet count increment with other causes of
<1.5× upper limit of normal (ULN) and no clinical signs of new or thrombocytopenia excluded or platelets <50 × 109/L after 5 days of
progressive ischemic organ injury plasma exchange or persistently raised LDH level (>1.5 × ULN)

Management, monitoring, and counseling Continued treatment and escalation of therapy

• Discontinue therapeutic plasma exchange • Continue therapeutic plasma exchange
• Caplacizumab continued until ADAMTS13 recovery (>10%-20%) • Start caplacizumab if not given previously
• Close laboratory monitoring after treatment (complete blood cell count, LDH, • Start rituximab if not given previously
basic metabolic panel, ADAMTS13 activity, and anti-ADAMTS13 antibody) • Consider increasing immunosuppression
• Counsel patients on symptoms of TTP recurrence

Clinical remission Exacerbation (38% of patients)

Sustained clinical response with either no therapeutic plasma Prior to obtaining remission, platelet count decreases to <150 × 109/L (other causes
exchange and no caplacizumab for ≥30 days or with attainment of thrombocytopenia excluded) with or without progressive ischemic organ injury,
of partial or complete ADAMTS13 remission (ADAMTS13 ≥20%) within 30 days of stopping therapeutic plasma exchange or caplacizumab

Continued monitoring and counseling

• Complete blood cell count, LDH, basic metabolic panel, ADAMTS13 activity,
and anti-ADAMTS13 antibody (every 1-3 monthsc)
• Counsel patients on clinical symptoms of relapse (eg, fatigue and neurologic symptoms)

ADAMTS13 relapse (30% of patients at median 5-year follow-up) Preventive treatment

After ADAMTS13 remission, ADAMTS13 activity decreases <20% • Prophylactic rituximab to prevent clinical relapse

Clinical relapse (16% of patients at median 5-year follow-up)

Platelet count decreases to <150 × 109 /L with or without clinical evidence
of new ischemic organ injury and confirmed severe ADAMTS13 deficiency

Boxes with headings in gray or purple are the 2021 International Working Group ADAMTS13 activity <10% or high pretest suspicion). Others reserve if for severe
for Thrombotic Thrombocytopenic Purpura outcome definitions.12 Other boxes illness and/or refractory diseases.
outline steps in management. ADAMTS13 indicates a disintegrin and b
Sustained platelet count was not defined by working group. In our practice, we
metallopeptidase with thrombospondin type 1 motif 13. consider the patient to have achieved a clinical response when they have met
a
Rituximab and caplacizumab are suggested by International Society on the International Working Group criteria for clinical response for at least 3 days.
Thrombosis and Haemostasis guidelines (conditional recommendation). Some c
Interval for monitoring has not been studied.
experts advocate for caplacizumab use in all patients with iTTP (confirmed by

treatment of iTTP as the combination of therapeutic plasma ex- estimated amount of plasma in a person’s body) removed and re-
change and corticosteroids (strong recommendation) along with ri- placed with donor plasma per procedure and continued daily until
tuximab and caplacizumab (conditional recommendation) (Table 3).35 clinical response (sustained platelet count ⱖ150 × 109/L) or an al-
ternate diagnosis has been established (ie, iTTP ruled out by
Therapeutic Plasma Exchange ADAMTS13 activity >20%). Therapeutic plasma exchange requires
Therapeutic plasma exchange removes the antibody to ADAMTS13 apheresis catheter insertion, which is associated with procedural risks
and provides ADAMTS13 via donor plasma.40,41 Therapeutic plasma of bleeding, arterial injury, and pneumothorax42 as well as central
exchange decreases mortality during an acute episode of iTTP from line infection and thrombosis.43 There is also a risk of plasma-
more than 90% to 9% to 20% and should be started promptly, prior related transfusion reactions, occurring in 12% of patients with TTP
to the reporting of ADAMTS13 results, in patients with intermedi- in 1 cohort, including life-threatening anaphylaxis.10 For patients
ate or high clinical suspicion for TTP (Figure 2).9,35 Therapeutic awaiting emergent transfer to a center capable of performing thera-
plasma exchange is initiated with 1 to 1.5 plasma volumes (the total peutic plasma exchange, plasma infusion (with infusion volume

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 E8
Table 3. First-Line Therapies in Addition to Therapeutic Plasma Exchange for an Initial Episode of TTP
Time to Incidence
normalization Incidence of TTP Incidence
Therapy type Medication and dosing Mechanism of platelet count, d of refractory TTP exacerbation of TTP relapse Overall mortality Adverse eventsa
Immunosuppression Prednisone (1 mg/kg/d orally) Decrease NR NR NR NRb Corticosteroids: Infection: NR
or methylprednisolone (1000 auto-antibody 7.9% (5/63)35 Hyperglycemia: 9%36
mg intravenously daily ×3 d) production Control: 20%
for severe features such as Fluid retention: 9%36
(8/40)35
neurologic symptoms Mood disorders: NR
Absolute risk
effect: 176 fewer Hypertension: NR
per 1000 (from Gastric irritation: NR
Clinical Review & Education Review

195 fewer to 111

fewer)35 Weight gain: NR
Insomnia: 9%36
Myopathy: NR
Decreased bone density (>6 wk of use)

JAMA Published online May 19, 2025 (Reprinted)

Glaucoma (>6 wk of use)
Rituximab (375 mg/m2 weekly Deplete CD20+ B NR NR NR Rituximab: Rituximab: Infections: 19%-63%34
×4 doses)c cells to decrease 22/13937 8/26337 Infusion reactions: 12%-77%34
auto-antibody Control: 74/22637 Control: 28/26237
production Hypogammagloublinemia: 51%-72%34
OR, 0.4 (95% CI, OR, 0.41 (95% CI, Lymphocytopenia: 48%34
0.19-0.85)37 0.18-0.91)37
Hepatitis B reactivation (screen and give
antiviral prophylaxis)

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Serum sickness: <1%34
Progressive multifocal
leukoencephalopathy: <1%34
Anti-vWF Caplacizumab (11 mg Nanobody blocks Caplacizumab Caplacizumab: 0% Caplacizumab: Caplacizumab: Caplacizumab: Any bleeding: 58.5%38
intravenously prior to binding of platelets (median days): (0/108)39e 5.6% (6/108)39e 15.7% (17/108)39e 0.93% (1/108)39e Serious bleeding: 11.3%38
therapeutic plasma exchange, to A1 domain of von 2.75 (95% CI, Placebo: 8.0% Placebo: 34.8% Control: 2.7% Control: 4.5%
then 11 mg subcutaneously for willebrand factor 2.53-2.87)38e Fatigue: 15.1%38
(89/112)39e (39/112)39e (3/112)39e (5/112)39e
30 d following therapeutic Placebo (median Headache: 20.8%38
plasma exchange Pooled risk Pooled risk Pooled risk Pooled risk
days): 3.51 difference: −8% difference: −29% difference: 14% difference: −4% Nausea: 15.1%38
administration or until (95% CI,
ADAMTS13 recovery)d (95% CI, −13% to (95% CI, −42% to (95% CI, (95% CI, −8% to Urticaria: 14.2%38
2.88-3.86)38e −2%)39e −14%)39e 0%-27%)39e 1%)39e
Pooled mean Pyrexia: 13.2%38
difference (days): Parasthesias: 12.3%38
−0.66 (95% CI, Constipation: 11.3%38
−0.90 to −0.43)39e
Insomnia: 10.3%38
Injection site reactions: 3%-6%38
c
Abbreviations: ADAMTS13, a disintegrin and metallopeptidase with thrombospondin type 1 motif 13; NR, not Off-label use, indication not approved by the US Food and Drug Administration.
reported; OR, odds ratio; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor. d
The clinical trial reported using caplacizumab (10 mg), but a posttrial dose-recovery study showed that the mean
a
Adverse events from studies specifically of patients with thrombotic thrombocytopenic purpura. When dose that can be withdrawn from the vial and reconstituted is 11 mg. Thus, labeling of the commercial product
unavailable, incidence of adverse events of medication reported from product labeling. labeling is 11 mg, which is equivalent to the dose used in the study.
b e
While some observational studies have reported relapse risk with corticosteroid use as per International Society Only data from randomized trials included.
on Thrombosis and Haemostasis treatment guideline panel, overall quality of evidence is very low, supported by
only small studies with a heterogenous population and varied interventions. Thus, relapse risk with
corticosteroids is not reported.

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 Immune Thrombotic Thrombocytopenic Purpura: A Review Review Clinical Review & Education

dependent on cardiac and volume status) can be considered as a which caplacizumab (10 mg) was administered intravenously once
temporizing measure to replace ADAMTS13.40,44 Table 3 reviews ad- prior to therapeutic plasma exchange and continued subcutane-
junctive therapies that current ISTH guidelines recommend or sug- ously following daily therapeutic plasma exchange for at least 30
gest in the first-line setting with therapeutic plasma exchange.35 days, found that patients treated with caplacizumab had a shorter
time to platelet count recovery (mean difference, 0.7 days [95% CI,
Corticosteroids 0.4-0.9]) and decreased mortality (1/108 [0.9%] vs 5/112 [4.5%] in
For patients with iTTP, corticosteroids help suppress production of the standard-care group; risk difference [RD] of death from any
autoantibodies to ADAMTS13.35,36 The ISTH guideline panel com- cause, −4% [95% CI, −8% to 1%]; relative risk, 0.21 [95% CI,
bined data from 2 comparative observational studies (103 pa- 0.05-1.74]).39 Individuals who received caplacizumab during the first
tients) and estimated an absolute risk reduction of 176 fewer deaths 30 days after therapeutic plasma exchange cessation had a signifi-
per 1000 patients (95% CI, 111-195) with corticosteroids plus thera- cant decrease in iTTP exacerbations (RD, −29% [95% CI, −42% to
peutic plasma exchange vs therapeutic plasma exchange alone, al- −14%]) and refractory iTTP (RD, −8% [95% CI, −13% to −2%]) com-
though the quality of evidence was considered very low due to the pared with standard care.39 However, caplacizumab treatment was
small sample size with heterogenous populations in the 2 studies.35 associated with an increase in relapse risk beyond 30 days after thera-
The ISTH guidelines do not recommend a specific corticosteroid, peutic plasma exchange (RD, 14% [95% CI, 0%-27%]).39 This in-
dose, or duration, although oral prednisone (1 mg/kg daily) is com- creased risk of relapse may occur because caplacizumab does not
monly used. Some experts suggest treating high-risk iTTP (severe affect anti-ADAMTS13 antibody production, so iTTP may recur if se-
neurologic features or elevated troponin level) with intravenous vere ADAMTS13 deficiency persists after drug cessation. In a retro-
methylprednisolone (1000 mg/d for 3 days).35 Adverse effects of spective multicenter cohort study, 1015 patients who received ca-
corticosteroids may include hyperglycemia, mood disorders (eg, de- placizumab along with therapeutic plasma exchange and
pression, mania, insomnia), and increased risk of infection. Corti- immunosuppression (corticosteroids with or without rituximab)
costeroids are generally continued during therapeutic plasma ex- showed improved outcomes compared with 510 historic controls
change and until ADAMTS13 activity increases to more than 10% to who received only therapeutic plasma exchange and immunosup-
20%, then doses are rapidly tapered to limit toxicity (duration of ta- pression (corticosteroids with or without rituximab).52 Caplaci-
per has not been studied).44,45 zumab was associated with higher 3-month survival (98.5% vs 94%,
P < .001), lower rates of refractory iTTP (1% vs 10%, P < .001), and
Rituximab fewer exacerbations (4% vs 32%, P < .001).52 In the phase 3 clini-
Rituximab, an anti-CD20 monoclonal antibody that depletes B lym- cal trial, caplacizumab was continued for 30 days following cessa-
phocytes, reduces autoantibody production to ADAMTS13 and helps tion of therapeutic plasma exchange and could be extended up to
restore ADAMTS13 activity.37 ISTH guidelines do not specify dos- an additional 28 days if severe ADAMTS13 deficiency persisted, with
ing, but most studies of rituximab used 4 weekly infusions of 375 immunosuppression adjusted accordingly to increase ADAMTS13
mg/m2,46,47 although lower doses and different schedules have been levels.33 Subsequent observational studies used ADAMTS13 recov-
described.48 There are currently no randomized trials of rituximab ery (>10%) to guide discontinuation (prior to 30 days) or extension
in combination with corticosteroids and therapeutic plasma ex- of caplacizumab (beyond 30 days).53 Current recommendations are
change as first-line therapy for iTTP. A 2019 meta-analysis (6 co- for use of caplacizumab with immunosuppression (corticosteroid and
hort studies, 365 patients) reported a lower rate of clinical relapse rituximab)35 and therapeutic plasma exchange, but use of caplaci-
with rituximab administration during an acute iTTP episode (22 re- zumab and immunosuppression (corticosteroid with or without ri-
lapses among 139 patients) compared with no rituximab (74 re- tuximab) without therapeutic plasma exchange is under investiga-
lapses among 226 patients; odds ratio, 0.40 [95% CI, 0.19-0.85])37. tion (NCT05468320). A retrospective analysis of 41 patients treated
Rituximab is associated with increased risk of viral infections, initially with caplacizumab without therapeutic plasma exchange
including hepatitis B reactivation. Prior to initiation of rituximab, pa- showed clinical response in all but 4 patients (9.5%) who then
tients should be tested for total hepatitis B core antibody and hepa- initiated therapeutic plasma exchange.54
titis B surface antigen and, if positive, should receive antiviral pro- Bleeding is the major adverse effect of caplacizumab due to im-
phylaxis (eg, entecavir or tenofovir).49 Other anti-CD20 therapies, paired platelet adhesion to vWF.38 In the 2 clinical trials, treatment-
such as ofatumumab and obinutuzumab, have been used as an al- emergent bleeding occurred in 65 of 106 patients (61%) in the ca-
ternative treatment in patients with rituximab infusion–related re- placizumab groups vs 49 of 110 patients (45%) in the standard-
actions or serum sickness.50 care groups (RD, 17% [95% CI, 4%-30%]), although major bleeding
events were not significantly increased (RD, 2% [95% CI, −2% to
Caplacizumab 7%]).39 With clinically significant bleeding, caplacizumab was held
Caplacizumab is a nanobody (synthetic small antibody) that binds until resolution or permanently discontinued, and 1 patient was
to the A1 domain of vWF with high affinity and blocks binding of the treated with vWF concentrate.32 Patients with clinically active bleed-
platelet glycoprotein 1b-IX-V complex. By inhibiting platelet bind- ing or high risk of bleeding (other than thrombocytopenia) were ex-
ing, caplacizumab prevents formation of microvascular thrombo- cluded from clinical trials of caplacizumab.32,33 A retrospective co-
sis in patients with an acute episode of iTTP.32,33 Caplacizumab was hort study of 85 patients treated with caplacizumab suggested that
approved by the US Food and Drug Administration in 2019 for adult patients with iTTP complicated by stroke may be a group at high risk
patients with iTTP in combination with therapeutic plasma ex- for intracranial bleeding with caplacizumab treatment (occurring in
change and immunosuppression, such as corticosteroids and 2% in this cohort).55 In a cohort of 1015 patients treated with cap-
rituximab.51 A meta-analysis of 2 clinical trials (220 patients)32,33 in lacizumab, major bleeding occurred in 2% (0.3% intracranial

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 Clinical Review & Education Review Immune Thrombotic Thrombocytopenic Purpura: A Review

Table 4. Preemptive Therapies Used During Clinical Remission to Prevent iTTP Relapse

Clinical relapse rate (relapses per patient-year)

Preemptive No. of
therapy Source (No.) patients No preemptive therapya With preemptive therapya
Rituximab Hie et al,63 2014 30 Median, 0.57 Median, 0 (IQR, 0-0.81)
(IQR, 0.46-0.7)
Jestin et al,61 2018 92 Median, 0.33 Median, 0 (IQR, 0-1.32)
(IQR, 0.23-0.66)
64
Splenectomy Crowther et al, 1996 6 Mean, 2.3 (SD, 2.0) Mean, 0.1 (SD, 0.1)
Kappers-Klunne et al,65 33 Mean, 0.74 Mean, 0.10
2005
Aqui et al,66 2003 14 Mean, 1.0 Mean, 0.3
Outschoorn and Ferber,67 10 Mean, 0.60 Mean, 0.27
2006 a
Data from observational studies
Veltman et al,68 1995 5 Mean, 1.5 Mean, 0 reporting relapse rate prior to
initiation of preemptive therapy to
Cyclosporin A Comparon et al,69 2023 14 Median, 1 (IQR, 0.5-1) Median, 0 (IQR, 0-0.2)
prevent relapse.

hemorrhage).52 Patients with bleeding events were older than pa- causing ADAMTS13 deficiency.12 Thus, patients with persistent
tients without bleeding events (median age, 57 years vs 45 years; ADAMTS13 deficiency (<10%) remain at risk of recurrence on ces-
P < .001).52 sation of these therapies.12 With an exacerbation of iTTP, therapeu-
tic plasma exchange should be reinitiated.57 Similar to use in the re-
Refractory iTTP fractory iTTP setting, caplacizumab initiated at time of iTTP
Refractory iTTP is defined by lack of sustained platelet count incre- exacerbation (if not used on initial presentation) had a high re-
ment or platelet count less than 50 × 109/L with persistently in- sponse rate (13/14 patients [93%]) in a retrospective cohort study.56
creased serum LDH level (>1.5 times the upper limit of normal) af-
ter 5 or more therapeutic plasma exchange sessions (Figure 3).12 A Clinical Remission
retrospective study of 122 patients with iTTP reported refractory iTTP A clinical remission is defined by a sustained clinical response (plate-
in 14.1% of patients receiving therapeutic plasma exchange plus im- let count ⱖ150 × 109/L) without therapeutic plasma exchange or ca-
munosuppression (100% corticosteroids and 84% rituximab) and placizumab for 30 days and ADAMTS13 activity of 20% or greater.12
in 4.5% of patients receiving caplacizumab in addition to therapeu- For patients with iTTP who are in clinical remission, expert opin-
tic plasma exchange and immunosuppression (100% corticoste- ion suggests that regular laboratory monitoring (including com-
roids and 68% rituximab).56 Because refractory iTTP is relatively un- plete blood cell count, LDH level, and basic metabolic panel) at least
common, other etiologies of persistent thrombocytopenia, such as every 1 to 3 months.45 An optimal schedule for ADAMTS13 monitor-
infection (typically related to the apheresis catheter) or drug- ing during clinical remission has not been established, but expert
induced thrombocytopenia, should be considered.57 opinion is to monitor once monthly in the first year after an initial
In a cohort study of 22 patients with refractory TTP or exacer- episode and then every 3 to 6 months thereafter.45 Patients in clini-
bation (6 with refractory TTP, 16 with exacerbations) who were not cal remission from iTTP should be also informed about potential signs
treated with rituximab at initial presentation, addition of rituximab and symptoms of relapse such as petechiae, headaches, and fa-
after lack of response to therapeutic plasma exchange or after an tigue and instructed to seek medical attention immediately if these
exacerbation shortened time to platelet count recovery compared symptoms arise.
with historical controls, with remission achieved by day 35 in all ri- During clinical remission, a decrease in ADAMTS13 activity be-
tuximab-treated survivors compared with 78% of controls.58 If ca- low 20% (ADAMTS13 relapse) may be an early sign of impending
placizumab was not initially used, retrospective data suggest that clinical relapse. In a French cohort of 23 patients with iTTP in clini-
starting caplacizumab in patients with refractory iTTP has a high re- cal remission whose ADAMTS13 activity was persistently less than
sponse rate (18/19 patients [95%]).56 For patients unresponsive to 10%, the incidence of clinical relapse was 74% at 7 years after the
therapeutic plasma exchange, corticosteroids, and rituximab, in- initial TTP episode.61 The time from ADAMTS13 relapse to clinical re-
creased doses of corticosteroids, cyclosporine, cyclophospha- lapse is highly variable. Data from the Oklahoma TTP registry re-
mide, vincristine, daratumumab, bortezomib, and splenectomy have ported a median time to clinical relapse of 5.4 (range, 0.3-9.5) years
been used, but data are limited to case studies and small case after a first ADAMTS13 activity less than 10% during remission.62
series.57,59,60
Prevention of Relapse During Clinical Remission
Exacerbation For patients in clinical remission who have low ADAMTS13 activity,
In up to 38% of patients, iTTP recurs in the days to weeks after dis- ISTH guidelines suggest preemptive therapy with rituximab to in-
continuation of therapeutic plasma exchange or after discontinua- crease the ADAMTS13 activity and reduce the risk of clinical relapse.35
tion of therapeutic plasma exchange and caplacizumab.32,33 Termed A threshold of ADAMTS13 activity below 20% is used by many ex-
exacerbations, these early recurrences (within 30 days of discon- perts for preemptive rituximab.45 In a UK study, 96% of patients with
tinuing therapeutic plasma exchange or caplacizumab) occur be- ADAMTS13 relapse in clinical remission experienced an increase in
cause therapeutic plasma exchange and caplacizumab are tempo- ADAMTS13 activity to 20% or greater after treatment with ritux-
rizing measures that do not treat the underlying autoimmunity imab at a median of 21 days (IQR, 14-21 days).5 A meta-analysis of 2

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 Immune Thrombotic Thrombocytopenic Purpura: A Review Review Clinical Review & Education

cohort studies (163 patients) demonstrated a reduction in clinical or with Glasgow coma scale of 14 or less (20% vs 2.0%, P < .001)
relapse when rituximab was prescribed to patients in clinical remis- on presentation.73
sion with ADAMTS13 activity less than 10% compared with no ri- Survivors of an initial iTTP episode have higher mortality rates
tuximab (17 relapses among 122 patients vs 24 relapses among 41 than an age-, sex-, and race-standardized reference US population
patients; odds ratio, 0.09 [95% CI, 0.04-0.24])37 (Table 4). (2228.3 deaths per 100 000 person years vs 1273.8 per 100 000
For patients with an ADAMTS13 relapse only (no symptoms at- person years).74 In a US cohort study of 222 patients with iTTP fol-
tributable to ongoing thrombotic microangiopathy) who do not have lowed up for a median of 4.5 years (IQR, 0.4-11.5 years), cardiovas-
an ADAMTS13 response (ADAMTS13 activity ⱖ20%) with ritux- cular diseases including sudden cardiac death, ischemic heart dis-
imab or who do not tolerate rituximab, observation or other pre- ease, and stroke were the leading non-TTP cause of death in survivors
emptive therapies may be considered, although evidence for these of an initial TTP episode (29 died after surviving an initial episode
treatments is limited to case series (Table 4).64-69 Splenectomy re- of TTP).74 Another cohort study of 137 survivors of an acute iTTP epi-
moves splenic ADAMTS13-specific memory B cells but is currently sode reported that ischemic stroke occurred in 13% during clinical
infrequently performed for relapse prevention of iTTP.66-68,70 remission, a 5-fold higher rate than expected based on an age- and
sex-matched general population.75
Clinical Relapse
A clinical relapse is defined by thrombocytopenia (platelet count Immune TTP and Pregnancy
<150 × 109/L) with or without clinical evidence of new ischemic or- In a cohort of 280 female patients with TTP younger than 45 years,
gan injury after clinical remission of iTTP.12 In the UK TTP registry of 42 (15%) had their first TTP episode during pregnancy or postpar-
443 patients with iTTP (54% of whom received rituximab at initial tum (76% iTTP and 24% congenital TTP).76 Treatment of an iTTP
presentation) with a median follow-up of 8 years, 16% of patients episode during pregnancy includes corticosteroids and therapeu-
had 1 or more clinical relapses at least 6 months after the initial TTP tic plasma exchange, and treatment response rates are similar to
episode.5 While most relapses occur in the first few years, relapses those for nonpregnant individuals.26,77 Rituximab is generally re-
have been described more than 10 years after the initial episode, and served for refractory cases after risk-benefit discussion due to its abil-
some patients have frequent relapses (ⱖ0.5 episodes per year).5 ity to cross the placenta and potentially cause neonatal adverse
events such as lymphopenia and infection.26,78Caplacizumab is not
Treatment of an iTTP Clinical Relapse recommended during pregnancy due to potential risks of maternal
Clinical relapse (ADAMTS13 activity <10%-20% with thrombocyto- and fetal hemorrhage.26
penia with and without signs of organ injury) is treated similarly to
an initial iTTP episode, with ISTH guidelines strongly recommend- Limitations
ing therapeutic plasma exchange and corticosteroids and condition- This review has several limitations. First, the literature search was
ally recommending use of rituximab and caplacizumab.35 A retro- limited to articles in English. Second, there are few randomized clini-
spective single-center analysis of 35 initial TTP episodes vs 76 cal trials of patients with iTTP, and the reported benefit of some
relapsed TTP episodes found no significant differences in clinical re- therapies may be confounded by use of historical controls or incom-
sponse, exacerbation, refractory TTP, or death.71 plete data from registry studies. Third, this review does not ad-
dress management of congenital TTP.
Prognosis and Long-Term Complications
An analysis from the multicenter US TMA registry of 770 patients
with an acute TTP episode reported overall iTTP mortality within 30
Conclusions
days of 6.6%, a rate which has declined from 14% over the past 3
decades.3 In a French cohort study (281 patients in the derivation Immune TTP is a rare immune-mediated disorder that presents with
cohort and 66 in the validation cohort, all enrolled prior to 2011), in- thrombocytopenia and MAHA and may cause life-threatening throm-
dependent predictors of 30-day mortality during iTTP episodes were bosis. Treatment with therapeutic plasma exchange, corticoste-
neurologic features on presentation (headache, stupor, seizure, or roids, and rituximab is associated with 30-day survival rates of more
focal deficit), age (especially 60 years or older), and serum LDH lavel than 90%. Addition of caplacizumab shortens time to normaliza-
more than 10 times the upper limit of normal.72 Another, more re- tion of platelet count and reduces recurrences while receiving the
cent, retrospective study of 292 patients in the UK TTP registry re- drug but increases bleeding risk. Monitoring ADAMTS13 activity in
ported higher mortality in patients presenting with troponin levels survivors and initiation of rituximab for those with low ADAMTS13
elevated above the upper limit of normal (12.1% vs 2.0%, P = .04) activity reduces the risk of clinical relapse.

ARTICLE INFORMATION receiving royalties from UpToDate for an article on contact Kristin Walter, MD, at kristin.walter@
Accepted for Publication: March 10, 2025. heparin-induced thrombocytopenia; and serving on jamanetwork.org.
an advisory board on gene therapy for Biomarin LLC
Published Online: May 19, 2025. outside the submitted work. Dr Cuker reported REFERENCES
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and Sanofi Genzyme; receiving speaking honoraria Submissions: We encourage authors to submit
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papers for consideration as a Review. Please ADAMTS13, induced by antibodies, is a biomarker

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