# Health-Related Quality of Life and Mental Health in Autoimmune Thrombotic Thrombocytopenic Purpura Patients in the Caplacizumab Era

Julia Weisinger, Christina Tites, Laurent Gilardin, Aki Baba, Ygal

Benhamou, Elie Azoulay, Jean-François Augusto, Thomas Papo, Claire

Cartery, Olivier Moranne, et al.

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Julia Weisinger, Christina Tites, Laurent Gilardin, Aki Baba, Ygal Benhamou, et al.. Health-Related Quality of Life and Mental Health in Autoimmune Thrombotic Thrombocytopenic Purpura Patients in the Caplacizumab Era. Research and Practice in Thrombosis and Haemostasis, 2025, pp.103297. 10.1016/j.rpth.2025.103297. hal-05413767

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ORIGINAL ARTICLE

# Health-related quality of life and mental health in autoimmune thrombotic thrombocytopenic purpura patients in the caplacizumab era

Julia Weisinger<fnref n="1" />

<figure><img src="image_3.png" /></figure>

Christina Tites<fnref n="2" />

Laurent Gilardin<fnref n="2" />

Aki Baba<fnref n="3" />

Ygal Benhamou<fnref n="4" />

Elie Azoulay<fnref n="5" />

Jean-Francois Augusto<fnref n="6" />

Thomas Papo<fnref n="7" />

Claire Cartery<fnref n="8" />

Olivier Moranne<fnref n="9" />

Gabriel Choukroun<fnref n="10" />

Loïc Lièvre<fnref n="11" />

Jehane Fadlallah<fnref n="12" />

Pascale Poullin<fnref n="13" />

Arnaud Jaccard<fnref n="14" />

Claire Presne<fnref n="15" />

Bérangère Joly<fnref n="1" />, 16, 17

Agnès Veyradier<fnref n="1" />, 16, 17

Raida Bouzid<fnref n="1" />, 16

Paul Coppo<fnref n="1" />, 16

Correspondence

Paul Coppo, Service d'Hématologie et
Centre de Référence des
Microangiopathies Thrombotiques, AP-
HP.6; INSERM U1138, Centre de
Recherche des Cordeliers, Paris, France.
Email: paul.coppo@aphp.fr

Handling Editor: Prof Michael Makris

Abstract

**Background:** Despite improvement in acute care of immune-mediated thrombotic thrombocytopenic purpura (iTTP), numerous studies showed that patients with iTTP have inferior mental health and health-related quality of life (HRQoL). Caplacizumab led to shorter hospitalization, less plasma exchange, and improved survival in iTTP and might influence long-term HRQoL.

**Objectives:** We aimed to address the impact of iTTP on HRQoL, posttraumatic stress disease, depression, and anxiety, as well as the possible role of caplacizumab on improving these features.

<footnote n="1">¹Centre de Référence des Microangiopathies Thrombotiques, Service d'hématologie, Hôpital Saint Antoine, APHP et Sorbonne Université (AP-HP.6), Paris, France</footnote>

<footnote n="2">²Service de Médecine interne, Hôpital Jean Verdier, AP-HP. Hôpitaux Universitaires Paris Seine-Saint-Denis, Bondy, France</footnote>

<footnote n="3">³Service de Médecine interne, Hôpital Saint Antoine, AP-HP. Sorbonne Université, Paris, France</footnote>

<footnote n="4">⁴Service de Médecine Interne, CHU Charles Nicolle, Rouen, France</footnote>

<footnote n="5">⁵Médecine Intensive Réanimation, Hopital Saint Louis, APHP, Paris, France</footnote>

<footnote n="6">⁶Service de Néphrologie-Dialyse-Transplantation, CHU d'Angers, Angers, France</footnote>

<footnote n="7">⁷Service de Médecine Interne, Hopital Bichat, APHP, Paris, France</footnote>

<footnote n="8">⁸Service de Néphrologie, CH de Valenciennes, Valenciennes, France</footnote>

<footnote n="9">⁹Service de Néphrologie, Dialyses Apherese, Hopital Universitaire de Nimes, IDESP, Université de Montpellier, France</footnote>

<footnote n="10">¹⁰Service de néphrologie et de transplantation, CHU d'Amiens, Amiens, France</footnote>

<footnote n="11">¹¹Service de Néphrologie, Hopital Maison Blanche, Reims, France</footnote>

<footnote n="12">¹²Service d'Immunologie Clinique, Hôpital Saint-Louis, APHP, Paris, France</footnote>

<footnote n="13">¹³Service d'Hémaphérèse, Hôpital de La Conception, CHU de Marseille, Marseille, France</footnote>

<footnote n="14">¹⁴Service d'Hématologie et de Thérapie Cellulaire, CHU Limoges, Limoges, France</footnote>

<footnote n="15">¹⁵Department of Adult Nephrology, CHU d'Amiens, Amiens, France</footnote>

<footnote n="16">¹⁶INSERM Unité Mixte de Recherche (UMRS) 1138, Centre de Recherche des Cordeliers, Paris, France</footnote>

<footnote n="17">¹⁷Service d'Hématologie biologique, Hôpital Lariboisière, AP-HP.Nord, Université Paris Cité, Paris, France</footnote>
**Methods:** We conducted a survey among patients with iTTP enrolled in the French thrombotic microangiopathy registry: patients completed the Short Form (SF)-36 HRQoL, the Hospital Anxiety and Depression Scale screening for anxiety and depression, and the Posttraumatic Stress Disorder Checklist for DSM-IV post-traumatic stress disease questionnaires. Results were compared to those of a sample of the French general population.

**Results:** A total of 101 patients with iTTP in remission (45 patients previously treated with caplacizumab and 56 patients without caplacizumab) and 76 healthy controls were included. Patients with iTTP had significantly lower scores in all domains in the SF-36 survey and higher anxiety and depression scores than healthy controls. Advanced age was associated with improved SF-36 scores, lower anxiety scores and less severe anxiety cases. Furthermore, the use of caplacizumab led to a lower risk of severe anxiety.

**Conclusion:** Based on our results, HRQoL is decreased in patients with iTTP, and depression and anxiety are more prevalent. Caplacizumab treatment might influence long-term mental and psychological outcomes in iTTP by shortening the duration of treatment with plasma exchange.

## Health-Related Quality of Life and Mental Health in Autoimmune Thrombotic Thrombocytopenic Purpura Patients in the Caplacizumab Era

### Background

iTTP patients have inferior health-related quality of life (HRQoL) and mental health

Caplacizumab improves survival, leads to shorter hospitalization and less plasma exchange sessions, and thereby might influence HRQoL and mental health

### Patients

101 iTTP patients:
45 treated with caplacizumab
56 treated without caplacizumab

76 healthy controls

Questionnaires:

HRQoL - SF-36

Anxiety and depression - HADS

PTSD - PCL-S

### Results

#### HRQoL/SF-36

iTTP patients: decreased results

Advanced age: improved results in many domains

#### Anxiety and depression/HADS

iTTP patients: higher scores

Advanced age: lower anxiety scores and less severe anxiety

Caplacizumab: lower risk of severe anxiety

#### PTSD/PCL-S

No difference between patients treated with or without caplacizumab

### Conclusions

HRQoL is decreased in iTTP patients, and depression and anxiety are more prevalent

Caplacizumab influences long term mental outcomes

Psychological care and support are key in iTTP survivors

## KEYWORDS

caplacizumab, mental disorders, neurologic disturbances, quality of life, TTP

## Essentials

* Patients with iTTP have inferior mental health and HRQoL.

* We assessed HRQoL, depression, anxiety and PTSD in patients with iTTP.

* Patients with iTTP have decreased HRQoL and higher anxiety and depression scores.

* Caplacizumab was associated with less severe anxiety and might influence quality of life.
# 1 | INTRODUCTION

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare life-threatening disease caused by an immune, antibody-mediated, deficiency of the von Willebrand factor cleaving protease ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin-1 motifs, 13th member), leading to widespread microthrombi [1,2]. If left untreated, this condition is fatal in >90% of cases. Standard treatment consists in therapeutic plasma exchange (TPE), immunosuppression with glucocorticoids and the B cell-depleting monoclonal antibody rituximab, and targeting von Willebrand factor with the nanobody caplacizumab. With this regimen, the outcome of the acute phase improved substantially in the recent years, with survival rates of >95% [3]. However, the high burden of neurologic and mental health comorbidities in those patients has an important impact on patients' health-related quality of life (HRQoL) [4,5]. Many studies proved that HRQoL is inferior in patients with iTTP than that in the normal population, after the acute phase of TTP; furthermore, depression, anxiety, and post-traumatic stress disorder (PTSD) are more common [4-7]. In addition, HRQoL does not seem to improve with time from acute episode [4,5]. In the last decades, new therapies such as rituximab and, more recently, caplacizumab emerged and significantly improved both survival and the burden of care in iTTP. In particular, caplacizumab leads to a shorter hospitalization stay, especially in the intensive care unit; therefore, it might have a beneficial role on HRQoL [3,8]. So far, the possible effect of caplacizumab on long-term mental health and HRQoL only involved studies with a limited number of patients [9] and therefore deserves further investigation. Here, we addressed the impact of iTTP on HRQoL, PTSD, depression, and anxiety, as well as the possible role of caplacizumab on improving these features.

# 2 | METHODS

## 2.1 | Patients and recruitment

We assessed HRQoL, anxiety, depression, and PTSD in patients with iTTP and compared these findings to those of a healthy control group. The study was conducted using questionnaires submitted to patients with iTTP recruited in the Registry of the French National Reference Center for Thrombotic Microangiopathies (CNR-MAT, www.cnr-mat.fr). We included adult (≥18 years old) patients with a previous diagnosis of iTTP as defined by a severe, antibody-mediated ADAMTS-13 deficiency, in clinical remission at time of inclusion [10]. The recruitment period ranged from December 2007 and July 2020. Patients had to be able to read and understand French. Data on patients with a diagnosis of iTTP were collected according to a predefined computerized dataset [11,12]. Diagnostic criteria, remission, and relapse definitions were based on previous studies [10,13,14].

## 2.2 | Management

Treatment of iTTP in the acute phase was based on current national and international guidelines [13,15]. Briefly, acute phase treatment consisted of daily TPE started at diagnosis and carried out until clinical response. Patients received glucocorticoids (1 mg/kg/d and then tapered, for a total of 3 weeks). Rituximab has been routinely used since 2007, first as salvage therapy and then frontline when caplacizumab was approved for the treatment of iTTP; caplacizumab has been used routinely since September 2018 [8,15,16]. In the pre-emptive setting, rituximab was started after detection of a severe ADAMTS-13 deficiency (activity < 20%) [11,12].

## 2.3 | Questionnaires

The survey included 4 questionnaires. The first included general questions about previous episodes of anxiety or depression, previous health care consultation or medication for anxiety or depression, employment status before and after iTTP diagnosis, and difficulties for returning to work. The second questionnaire consisted of the Short Form (SF)-36 questionnaire that assesses HRQoL; it contains 36 items evaluating 8 domains: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. Scores range from 0 to 100 for each of the 8 domains and higher scores indicate better quality of life [17,18]. The physical composite score (PCS) and mental composite score (MCS) are calculated according to established country-specific algorithms to have the same mean and SD in each country (50 and 10). The raw scores were converted to a 0 to 100 scale and transformed to standardized z-scores for calculating the summary scores of MCS and PCS. The third questionnaire used was the Hospital Anxiety and Depression Scale (HADS), which can be used as a screening tool for anxiety and depression with a recall time of 1 week. It can be used in the hospital or the outpatient setting. The HADS has 2 scales with 7 items for anxiety and 7 for depression, with a total score range from 0 to 21 each. High screening scores indicate more severe symptoms, with scores from 15 to 21 classifying as severe, 11 to 14 moderate, 8 to 10 mild, and 0 to 7 being normal [19]. The last questionnaire was the French version of the Posttraumatic Stress Disorder Checklist for DSM-IV (PCL-S). PCL-S applies to describe reactions to a specific event that must be identified by the respondent [20]. The specific event in our study was linked to the patient's iTTP diagnosis and hospitalization; therefore, this questionnaire was only completed by patients with iTTP and not by the healthy controls. Participants received the questionnaires through mail or during their iTTP follow-up clinical visits. The healthy controls were recruited among the investigators' entourage and had to be 18 years or older, able to read, and understand French.
<figure><img src="image_4.png" /><figcaption>FIG URE 1 Study flow chart. HADS, Hospital Anxiety and Depression Scale; iTTP, immune-mediated thrombotic thrombocytopenic purpura; PCL-S, Posttraumatic Stress Disorder Checklist for DSM-IV; SF-36, Short form-36.</figcaption></figure>

## 2.4 | Statistical analysis

Data were summarized as counts and percentages. Medians and lowest and highest values or IQR were indicated. To compare variables, Fisher exact test or Mann-Whitney U-test were used. To assess risk factors, linear, robust linear, logistic and β regression models were performed, as applicable. Statistical power analysis and sample size calculation were performed (Supplementary Table 1). Analyses were performed using IBM SPSS statistical software (IBM SPSS Statistics for Windows; version 22.0; IBM Corp) and RStudio and R software 4.5.0 (R Foundation). Statistical significance was set at *P* < .05.

## 2.5 | Ethics

This study was part of the Thrombotic Microangiopathy program study approved by the Ethics Committee of Hospital Pitié-Salpêtrière (Paris, France; www.clinicaltrials.gov, NCT00426686), the Health Authority and the French Ministry of Health (P051064/PHRC AOM05012), and the French Data Protection Authority. Study procedures were performed in accordance with the Declaration of Helsinki.

# 3 | RESULTS

## 3.1 | Patients and baseline characteristics

In total, 184 eligible patients with iTTP were contacted between January and August 2021; among them, 101 patients (55%) from 21 centers responded to the survey and were analyzed in this study. All of them completed both the SF-36 and the HADS questionnaires, while 96 of them completed the PCL-S survey. Forty-five patients (44.5%) received caplacizumab. Ninety-one healthy controls were contacted; 76 completed the SF-36 and the HADS questionnaires (flow chart of the study detailed in Figure 1). Median time from iTTP diagnosis to the survey was 47 months (IQR, 29-84 months).

Baseline characteristics of patients with iTTP are detailed in Table 1. Significant differences were detected: in caplacizumab-treated patients, lactate dehydrogenase levels were higher (*P* = .03), the number of TPE was lower (*P* < .001), and rituximab use was more common (*P* = .009) than those in patients treated without caplacizumab [15]. As expected, follow-up was shorter in caplacizumab-treated patients (*P* < .001). The number of patients hospitalized in intensive care unit, as well as hospitalization in intensive care unit, was comparable between patients treated with and those without caplacizumab. No significant difference was detected regarding age, sex (ie, male or female), and self-reported previous anxiety and depression between patients with iTTP and healthy controls and between patients treated with iTTP and those without caplacizumab (Supplementary Table 2; Table 1).

## 3.2 | Health-related quality of life

Patients with iTTP had significantly lower scores in all domains in the SF-36 survey than healthy controls (*P* < .001 for all domains). Furthermore, MCS and PCS were significantly lower in patients with iTTP than those in the healthy controls (*P* < .001). No difference was observed between patients treated with caplacizumab and those without in the SF-36 survey (Table 2; Figure 2). Of note, age was a factor influencing significantly multiple domains of the SF-36 survey: advanced age was associated with improved general health perceptions, vitality, mental health, and MCS among patients with iTTP. Univariate and multivariate regression results for the SF-36 survey are detailed in Supplementary Tables 3–12.

## 3.3 | Anxiety and depression

The HADS questionnaire showed significant differences between patients with iTTP and healthy controls. Patients with iTTP had a higher median anxiety score (*P* < .001) and higher depression scores
<table><caption>TABLE 1 Characteristics of patients with iTTP.</caption><thead><tr><th>Characteristic</th><th>All iTTP (N = 101)</th><th>No caplacizumab (n = 56)</th><th>Caplacizumab (n = 45)</th><th>P</th></tr></thead><tbody><tr><td>Age (y)</td><td>51 (38-62)</td><td>51 (39-58)</td><td>51 (37-65)</td><td>.98</td></tr><tr><td>Female</td><td>76 (75)</td><td>44 (79)</td><td>32 (71)</td><td>.49</td></tr><tr><td>Previous health care visit due to mood disorder or stress</td><td>31 (31)</td><td>14 (25)</td><td>17 (38)</td><td>.28</td></tr><tr><td>Previous medication due to mood disorder or insomnia</td><td>15 (15)</td><td>6 (11)</td><td>9 (20)</td><td>.26</td></tr><tr><td>Acute phase</td><td></td><td></td><td></td><td></td></tr><tr><td>CNS involvement</td><td>65 (64)</td><td>35 (63)</td><td>30 (67)</td><td>.68</td></tr><tr><td>Cardiac involvement</td><td>41 (41)</td><td>19 (34)</td><td>22 (49)</td><td>.15</td></tr><tr><td>LDH, × ULN</td><td>4.48 (2.96-6.00)</td><td>4.12 (2.47-5.63)</td><td>5.24 (3.70-6.22)</td><td>.03</td></tr><tr><td>Platelet count (G/L)</td><td>14 (10-20)</td><td>13 (8-19)</td><td>16 (10-23)</td><td>.41</td></tr><tr><td>Hemoglobin (g/dL)</td><td>8.6 (7.4-9.8)</td><td>8.5 (7-9.9)</td><td>8.8 (7.7-9.8)</td><td>.22</td></tr><tr><td>Serum creatinine (µmol/L)</td><td>85 (70-117)</td><td>81 (69-114)</td><td>92 (70-120)</td><td>.36</td></tr><tr><td>TPE treatment</td><td>101 (100)</td><td>56 (100)</td><td>45 (100)</td><td>&gt;.999</td></tr><tr><td>No. of TPE per patients</td><td>6 (5-14)</td><td>12 (5-18)</td><td>5 (4-6)</td><td>&lt;.001</td></tr><tr><td>Corticosteroid treatment</td><td>95 (94)</td><td>53 (95)</td><td>42 (93)</td><td>&gt;.999</td></tr><tr><td>Rituximab treatment</td><td>76 (75)</td><td>36 (64)</td><td>40 (89)</td><td>.009</td></tr><tr><td>Hospitalization on ICU</td><td>72 (71)</td><td>37 (66)</td><td>35 (78)</td><td>.27</td></tr><tr><td>Days per patient on ICU</td><td>5 (3-9)</td><td>6 (3-12)</td><td>5 (3-8)</td><td>.47</td></tr><tr><td>Follow-up</td><td></td><td></td><td></td><td></td></tr><tr><td>Time from diagnosis to survey (mo)</td><td>47 (29-84)</td><td>71 (51-119)</td><td>29 (25-34)</td><td>&lt;.001</td></tr><tr><td>Clinical relapse</td><td>19 (19)</td><td>11 (20)</td><td>8 (18)</td><td>&gt;.999</td></tr><tr><td>ADAMTS-13 relapse</td><td>33 (33)</td><td>22 (39)</td><td>11 (24)</td><td>.200</td></tr></tbody></table>

Values are median (IQR) or n (%).

ADAMTS, A disintegrin and metalloproteinase with thrombospondin-1 motifs; CNS, central nervous system; ICU, intensive care unit; iTTP, immune-mediated thrombotic thrombocytopenic purpura; LDH, lactate dehydrogenase; TPE, therapeutic plasma exchange; ULN, upper limit of normal.

<table><caption>TABLE 2 Results of the Short-Form-36 questionnaire assessing health-related quality of life.</caption><thead><tr><th>Characteristics</th><th>iTTP (n = 101)</th><th>Healthy controls (n = 76)</th><th>P</th><th>iTTP, no caplacizumab (n = 56)</th><th>iTTP, caplacizumab (n = 45)</th><th>P</th></tr></thead><tbody><tr><td>Physical functioning (%)</td><td>75 (55-95)</td><td>95 (85-100)</td><td>&lt;0.001</td><td>78 (60-95)</td><td>75 (48-90)</td><td>.26</td></tr><tr><td>Role limitations due to physical problems (%)</td><td>50 (0-75)</td><td>100 (75-100)</td><td>&lt;0.001</td><td>50 (6-100)</td><td>25 (25-75)</td><td>.26</td></tr><tr><td>Role limitations due to emotional problems (%)</td><td>67 (0-100)</td><td>100 (67-100)</td><td>&lt;0.001</td><td>67 (67-100)</td><td>33 (33-100)</td><td>.37</td></tr><tr><td>Vitality (%)</td><td>45 (25-60)</td><td>65 (50-79)</td><td>&lt;0.001</td><td>45 (25-65)</td><td>45 (20-60)</td><td>.59</td></tr><tr><td>Mental health (%)</td><td>56 (40-76)</td><td>80 (60-88)</td><td>&lt;0.001</td><td>60 (44-76)</td><td>56 (40-76)</td><td>.97</td></tr><tr><td>Social functioning (%)</td><td>63 (50-88)</td><td>88 (50-100)</td><td>&lt;0.001</td><td>63 (50-100)</td><td>63 (44-88)</td><td>.26</td></tr><tr><td>Bodily pain (%)</td><td>58 (45-90)</td><td>100 (70-100)</td><td>&lt;0.001</td><td>68 (45-90)</td><td>55 (34-80)</td><td>.07</td></tr><tr><td>General health perceptions (%)</td><td>45 (33-65)</td><td>70 (60-90)</td><td>&lt;0.001</td><td>48 (31-65)</td><td>40 (33-60)</td><td>.48</td></tr><tr><td>MCS</td><td>37 (25-50)</td><td>54 (40-59)</td><td>&lt;0.001</td><td>39 (25-51)</td><td>32 (24-50)</td><td>.51</td></tr><tr><td>PCS</td><td>64 (60-66)</td><td>69 (66-72)</td><td>&lt;0.001</td><td>64 (59-67)</td><td>63 (60-66)</td><td>.44</td></tr></tbody></table>

Values are median (IQR).

iTTP, immune-mediated thrombotic thrombocytopenic purpura; MCS, mental composite score; PCS, physical composite score.
A

<figure><img src="image_5.png" /></figure>

B

<figure><img src="image_6.png" /></figure>

C

<figure><img src="image_7.png" /><figcaption>**FIGURE 2** Results of the SF-36 and the HADS surveys. (A) Comparison of SF-36 results of patients with iTTP and healthy controls. (B) Comparison of SF-36 results of patients with iTTP treated with caplacizumab and without caplacizumab (and healthy controls). (C) HADS anxiety and depression scores for healthy controls and patients with iTTP and for patients with iTTP treated with or without caplacizumab. HADS, Hospital Anxiety and Depression Scale; iTTP, immune-mediated thrombotic thrombocytopenic purpura; SF-36, Short Form-36.</figcaption></figure>

(P < .001) than healthy controls (Table 3; Figure 2). More than half of patients with iTTP had at least mild anxiety (n = 61, 60%), while 40 patients (40%) had at least mild depression. Severe anxiety and depression were observed in 17% and 4% of patients with iTTP, respectively.

Patients treated with caplacizumab had anxiety and depression scores comparable with those of patients treated without caplacizumab (P = .54 and P = .23, respectively). However, severe anxiety was more prevalent in patients treated without caplacizumab than that in patients treated with caplacizumab (P = .048).

We next assessed possible risk factors for depression and anxiety in patients with iTTP using multivariate regression models. Advanced age was associated with lower anxiety scores, and previous ADAMTS-13 relapses led to lower anxiety scores. However, the duration of ADAMTS-13 activity of ≥20% before study was not associated with anxiety scores. Accordingly, severe anxiety was

associated with younger age and no previous ADAMTS-13 relapses; furthermore, caplacizumab administration led to decreased risk of severe anxiety. Regarding depression scores, shorter time from diagnosis was associated with higher depression scores. Risk factors for severe depression could not have been calculated due to low event numbers. Detailed results of the regression models regarding the HADS questionnaires are added in Supplementary Tables 13–15.

## 3.4 | Posttraumatic stress disease

The median PTSD screening score was 42 (IQR, 24-52); 46 patients (48%) had a PCL-S score of ≥43, suggestive of PTSD. There was no significant difference in PCL-S scores between patients treated with caplacizumab and those treated without. No significant risk factors for PTSD could be identified among age, sex, neurologic or cardiac

<table><caption>**TABLE 3** Results of the Hospital Anxiety and Depression Scale.</caption><thead><tr><th>Scores</th><th>iTTP<br>(n = 101)</th><th>Healthy controls<br>(n = 76)</th><th>P</th><th>iTTP, no caplacizumab<br>(n = 56)</th><th>iTTP, caplacizumab<br>(n = 45)</th><th>P</th></tr></thead><tbody><tr><td>Anxiety score</td><td>9 (6-12)</td><td>6 (3-9)</td><td>&lt;.001</td><td>9 (6-13)</td><td>10 (5-12)</td><td>.52</td></tr><tr><td>Score 0-7 (normal)</td><td>40</td><td>47</td><td></td><td>22</td><td>18</td><td></td></tr><tr><td>Score 8-10 (mild)</td><td>20</td><td>16</td><td></td><td>11</td><td>9</td><td></td></tr><tr><td>Score 11-14 (moderate)</td><td>24</td><td>9</td><td></td><td>10</td><td>14</td><td></td></tr><tr><td>Score ≥15 (severe)</td><td>17</td><td>4</td><td></td><td>13</td><td>4</td><td></td></tr><tr><td>Depression score</td><td>6 (3-10)</td><td>3 (1-5)</td><td>&lt;.001</td><td>6 (2-9)</td><td>6 (4-10)</td><td>.23</td></tr><tr><td>Score 0-7 (normal)</td><td>61</td><td>64</td><td></td><td>37</td><td>24</td><td></td></tr><tr><td>Score 8-10 (mild)</td><td>21</td><td>6</td><td></td><td>8</td><td>13</td><td></td></tr><tr><td>Score 11-14 (moderate)</td><td>15</td><td>5</td><td></td><td>8</td><td>7</td><td></td></tr><tr><td>Score ≥15 (severe)</td><td>4</td><td>1</td><td></td><td>3</td><td>1</td><td></td></tr></tbody></table>

Values are median (IQR) or n.

iTTP, immune-mediated thrombotic thrombocytopenic purpura.
involvement, number of TPE, clinical or ADAMTS-13 relapses, and
length of intensive care unit hospitalization.

4 | DISCUSSION

Our findings present evidence of a significant deterioration in out-
comes reflecting quality of life in iTTP survivors compared with the
general French population, which is consistent with previous studies
[4,7,21,22]. Patients with iTTP experience higher rates of anxiety,
depression, more negative attitude to life, and low resilience than
healthy controls, which are also observed in as severely debilitating
diseases as sickle cell disease or in other critical illnesses including
severe sepsis [22-27]. A previous analysis in France assessing similar
aspects of HRQoL involved iTTP and patients with hemolytic uremic
syndrome with more severe disease presentation and intensive care
unit hospitalization, while the patient population in our study con-
sisted of well-characterized patients with iTTP, representing a
broader spectrum of disease severity and thereby a more represen-
tative iTTP population [4].

We could identify factors impacting HRQoL and mental health. First, age seemed to be the most universal factor influencing both HRQoL and anxiety; patients with more advanced age reported more favorable outcomes, which could result from more resilience in older patients [28]. Second, the use of caplacizumab during the acute phase could be associated with less severe anxiety in iTTP survivors, possibly because of the decrease in the burden of care provided by caplacizumab [15]. Lastly, previous ADAMTS-13 relapses were associated with less severe anxiety, possibly following a growing familiarization of patients with their disease, with the finding that pre-emptive treatment is efficient in preventing clinical relapses [11,12].

In our study, the incidence of anxiety was higher in iTTP than that in the whole French population: based on our results, 60% of patients had signs of anxiety on the HADS questionnaire, while the estimated incidence of anxiety disorders in the general French population is 21.6% [29]. Of note, the incidence of anxiety was higher in our healthy control group than that previously reported in the general population, but our results might have been affected by the COVID-19 pandemic [29]. Similarly, 40% of patients with iTTP showed signs of depression in our study, compared with 14% in our healthy control population, which is comparable with the French general population [30,31].

The causes resulting in neurocognitive impairment still remain debated, while their understanding is key to better prevent their occurrence. A role for cerebral infarctions was suggested previously from a prospective study, where half of patients with iTTP in clinical remission had silent cerebral infarction assessed by magnetic resonance imaging, along with higher rates of cognitive impairment, including severe cognitive impairment [32]. In that regard, the association between reduced (though detectable) ADAMTS-13 levels during remission and ischemic stroke in iTTP survivors [33] suggests that a more stringent control of ADAMTS-13 activity could decrease

the risk of ischemic stroke and thereby improve the cognitive status
and HRQoL of patients with iTTP. Further investigations are urgently
required to address more in detail this crucial aspect.

Our study has limitations. Selection bias might occur in case of
autoreported questionnaires, as patients with higher symptom
burden might be more motivated to response, whereas patients with
severe depression or patients with severely decreased daily func-
tioning might not respond. Educational level and French language
skills might also have influence. Data were not collected on race or
ethnicity from healthy controls and were not available for all patients
with iTTP; therefore, it was not assessed in this analysis. Second, the
questionnaires used in this study were validated as screening and not
diagnostic tools, and we have no certainty that patients who
screened positive would have fit an accurate diagnosis of PTSD or
depression in an extensive psychiatric evaluation. Lastly, due to low
event numbers, risk factors for severe depression could not been
assessed. Despite these limitations, the signal from our analysis is
clear in the sense that altered scores screening neurocognitive
dysfunction, even if autoreported, should alarm practitioners and
prompt further assessment by mental health professionals for an
adapted support early in the management.

As the landscape of iTTP treatment is evolving, new therapeutic approaches might influence long-term HRQoL and neurocognitive impairment. Recent studies, including the phase 3 MAYARI trial, suggested that TPE treatment might be omitted from the standard acute care in iTTP for many patients, reducing the burden of care [34,35]. This most likely will have an important effect on long-term mental health of patients with iTTP.

In conclusion, we confirm from a large cohort of well-
characterized population the high incidence of anxiety, depression,
PTSD, and decreased HRQoL in iTTP survivors. Furthermore, we
showed that caplacizumab is associated with decreased risk of severe
anxiety. Our results highlight the importance of more systematic
psychological care and support for patients with iTTP after the acute
phase of the disease. Further works are now needed to better un-
derstand their cause and prevent their occurrence.

ACKNOWLEDGMENTS

Figures were partially created with BioRender.com.

FUNDING

This work was partly funded by a grant from the French Ministry of Health (Projet Hospitalier de Recherche Clinique; P120118; AOM12259). This work was also supported by the National Plan for Rare Diseases of the French Ministry of Health (Direction Générale de l'Offre de Soin [DGOS]) and by funds of the EU MSCA project TOLERATE by the European Union (Grant Agreement No. 101072729). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Research Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.
## AUTHOR CONTRIBUTIONS

J.W. contributed to data collection, prepared the data file for sta-
tistical analysis, analyzed the data and wrote the first version of the
manuscript. C.T., L.G., and A.B. collected the data and prepared the
datafile. Y.B., E.A., J.-F.A., T.P., C.C., O.M., G.C., L.L., J.F., P.P., A.J., and
C.P. enrolled patients with iTTP and critically reviewed the manu-
script. R.B. coordinated data collection. B.J. and A.V. critically
reviewed the manuscript. P.C. initiated the study, edited the manu-
script, and supervised the work.

## RELATIONSHIP DISCLOSURE

P.C. is member of the Clinical Advisory Board for Alexion, Sanofi, and Takeda. A.V. is a member of the French clinical advisory board for Sanofi and Takeda. B.J. has participated in the advisory boards of Sanofi, Takeda, and Alexion. The other authors have no conflict of interest to declare.

## ORCID

Julia Weisinger https://orcid.org/0009-0003-8337-2925

X

Julia Weisinger @juliaweisinger

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SUPPLEMENTARY MATERIAL

The online version contains supplementary material available at
https://doi.org/10.1016/j.rpth.2025.103297.