Introduction
Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare and severe disorder that can be life-threatening and recurring. It results from a deficiency of ADAMTS13, a von Willebrand factor (vWF)-cleaving protease that leads to microvascular thrombosis in various organs [
1]. To manage iTTP effectively, accurate diagnosis and comprehensive care from a team of specialists trained in managing bleeding disorders are crucial, along with access to ongoing treatment [
2].
The cornerstone of life-saving therapy in iTTP has been therapeutic plasma exchange (TPE) combined with immunomodulatory strategies. Caplacizumab was approved for treating iTTP in August 2018 after favorable results from the TITAN and HERCULES clinical trials [
3,
4]. It is a nanobody that inhibits the interaction between ultra-large von Willebrand factor multimers and platelets [
5]. Patients who received caplacizumab in addition to standard care showed a significantly shorter time to platelet count normalization, a reduction in duration of TPE, and a reduction of days of hospitalization compared to those who received a placebo [
3,
4]. However, high rates of relapses may occur, and refractory disease with fatal outcomes still occurs [
6]. In this context, rituximab, a B-cell-depleting therapy, has represented the second breakthrough in iTTP management [
7]. Recently, rituximab has been proposed as part of a first-line strategy for patients with unfavorable outcomes under standard care [
8].
While these treatments have been successful, it’s essential to consider the long-term complications of iTTP [
9,
10] Survivors of iTTP may experience neurological issues and depression as a common mental long-term complication, which can lead to a decrease in health-related quality of life (HRQoL) and reduced resilience. All these aspects, including cognitive impairment, anxiety, and depression disorders, are equally essential to be considered in managing patients with iTTP, both evaluating the long-term implications of previous acute episodes and providing psychological support to those who need it [
2]. Although previous efforts have addressed these factors, limited understanding remains regarding the impact of new therapeutic approaches on HRQoL and mental health.
The primary objective of this study was to compare the long-term HRQoL of iTTP patients with that of the general population. Secondary objectives were to evaluate how the addition of caplacizumab and rituximab to standard treatment affects HRQoL domains and explore the impact of depression and anxiety on treatment outcomes. Additionally, a cognitive evaluation was conducted.
Discussion
Advancements in therapeutic approaches have significantly improved patients’ prognoses with iTTP, enabling them to achieve long-term survival rates [
7,
22]. However, survivors frequently experience chronic problems that can have a remarkable effect on the psychological and cognitive well-being of the individual [
23].
Very few studies have reported data on long-term HRQoL and the mental status of iTTP patients [
2,
24‐
29]. As the first objective, the present study indicates that the HRQoL profile after a median follow-up of eight years from the iTTP occurrence is lower than that of the general population. This finding is consistent with previous studies that have reported a high prevalence of depression and anxiety, a more negative attitude toward life, and low resilience among iTTP patients. Resilience was also found to be negatively correlated with the severity of the depression [
2].
While it is true that advancements in iTTP treatment have reduced hospitalizations and improved hematological recovery, the survivors are at increased risk of multiple adverse health outcomes, including higher than all-cause mortality rates [
10]. In fact, according to the Oklahoma iTTP registry, iTTP patients may experience comorbidities such as an increase in body mass index, hypertension, and other autoimmune conditions like systemic lupus erythematosus, as well as depression [
9]. Studies have also suggested that iTTP patients with ischemic brain lesions detected by magnetic resonance imaging may experience cognitive impairment [
27,
30]. Our study revealed that patients without any neurological or autoimmune conditions generally had enhanced HRQoL and lower levels of fatigue, indicating that the early detection and treatment of underlying conditions that may have adverse effects on their cognitive and psychological health is crucial.
In our secondary endpoint, we found that the vast majority of our patients reported anxiety, depression, and impaired mental profiles, regardless of the type of treatment received. Although the post-HERCULES study did not provide conclusive findings on the long-term effects of iTTP on HRQoL and cognitive function [
31], we found that patients who received caplacizumab treatment did not experience stable or slightly improved cognitive functioning and HRQoL. While rituximab may reduce the risk of iTTP relapse [
7,
32], our study found that it did not lead to higher HRQoL scores, even when used as a first-line treatment. Surprisingly, patients who did not receive rituximab reported better mental profiles. This aligns with similar observations in using rituximab for immune thrombocythemia, where there was no clear link between the drug’s response and improved HRQoL [
33]. The lower scores observed in patients treated with rituximab may be due to the drug being reserved for more severe presentations or relapses of the disease, which could inevitably affect their quality of life.
A web-based survey tool, consisting of demographic and clinical data and two validated self-administered questionnaires, was utilized to gather information from a cohort of 236 TTP patients to estimate the prevalence of symptoms related to post-traumatic stress disorder (PTSD) and depression in iTTP survivors [
34]. PTSD is an adverse reaction to traumatic experiences that results in patients repeatedly reliving the traumatic event (such as through recurring thoughts or nightmares), avoiding anything that reminds them of the event, and experiencing hyperarousal symptoms (like irritability and difficulty sleeping), which cause adverse effects on their cognitive ability and functioning. All of these factors contribute to a lower quality of life. The study revealed a high incidence of PTSD and depression in iTTP survivors. This is because patients who were previously in good health have experienced a traumatic, life-threatening event and now face an uncertain future, including the risk of recurrence [
34]. Our findings confirm that a majority of patients exhibit significant symptoms of anxiety and depression based on their responses to the HADS questionnaires, highlighting the need for psycho-educational strategies [
25].
Additionally, as reported in Fig.
2, the mental component scores in the areas of VT, SF, and RE were lower than those of the general population, indicating the need for further support and interventions to improve the patient’s mental health. A study by Riva and colleagues involved 35 patients with acquired iTTP. The objective was to evaluate the long-term neuropsychological effects of the condition at a minimum of three months after their last acute iTTP episode [
25]. The neuropsychological assessment results indicated below-average direct, indirect, and deferred memory scores. Despite receiving plasma exchange and immunosuppressive therapy during the acute phase of iTTP, patients continue to experience long-term neurological complications and impaired HRQoL even years after the acute phase [
25]. Lewis et al. confirmed that persistent cognitive problems and impaired HRQoL are common among iTTP survivors and suggested that defining these mental abnormalities could help develop targeted rehabilitation techniques. This, in turn, would enable better adaptation and emotional support for patients, addressing their concerns about feeling neglected due to the lack of acknowledgment and treatment for their health problems [
24]. In our study, we utilized the FACT-Cog questionnaire to analyze cognitive impairment, and our findings indicate a strong correlation between the score obtained in the questionnaire and HRQoL, particularly in the mental domain. The results in Fig.
3 demonstrate a strong relationship between the various areas examined by FACT-Cog and the different aspects analyzed by SF36, particularly those related to mental health. Using simple questionnaires to assess cognitive status, clinicians could identify patients requiring further evaluation. Combining these tools could further enhance these patients’ quality of care and well-being.
Although our study provides valuable information, it has some limitations. First, the number of patients enrolled in a single institution was small. Second, the patients included in the study had different stages of the disease, such as diagnosis, relapse, or follow-up, which could result in bias. However, considering the rarity of this disease, the data we have gathered still hold significant importance. They could help facilitate more targeted supportive care interventions.
In conclusion, our research shows that although cutting-edge drugs have greatly improved the course of iTTP, they still report HRQoL impairments compared to their peers in the general population. We collected an average follow-up of almost 8 years and used multidimensional PRO that were closely related to each other. It seems that anxiety and depression were commonly observed, along with a more widespread impairment of mental and cognitive functions.
We used FACT-Cog for the first time in iTTP, which showed significant agreement with other questionnaires. The findings indicate that FACT-Cog could help evaluate the cognitive function of patients with iTTP. It is an effective method for assessing the cognitive sphere in these individuals. The sustained presence of impairments during long-term follow-up highlights the necessity for consistent monitoring and support for those affected by the disease.
Finally, it appears essential to rephrase the treatment approach for these patients. The new approach should focus on engaging multiple specialists, such as hematologists, neurologists, psychiatrists, psychologists, and rehab experts, in managing the patients. This multitasking approach should consider not only the patient’s physical health but also their psychological well-being to ensure psychophysical rehabilitation.
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