Thrombotic Thrombocytopenic Purpura Survivors Research Articles

Shades of Grey-The brain in TTP.

In their paper, Hannan etal. suggest that new approaches to the management of the acute and remission phases of thrombotic thrombocytopenic purpura should be considered to address white matter changes seen in patients undergoing magnetic resonance imaging. Timely intervention may have significant implications for the long-term physical and mental health of patients. Commentary on: Hannan etal. Cognitive decline in thrombotic thrombocytopenic purpura survivors: The role of white matter health as assessed by MRI. Br J Haematol 2024;204:1005-1016.

Cognitive decline in thrombotic thrombocytopenic purpura survivors: The role of white matter health as assessed by MRI.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities.

Thrombotic Thrombocytopenic Purpura (TTP) Survivors Exhibit Impaired Stress Perfusion on Cardiac MRI

Introduction: Thrombotic thrombocytopenic purpura (TTP) survivors have increased rates of cardiovascular morbidity and mortality when compared with the general population. In this prospective pilot study, we sought to further characterize the long-term cardiovascular sequelae of TTP survivors through pharmacologic stress cardiac magnetic resonance imaging (CMR). Stress CMR has been increasingly utilized to detect clinical and subclinical structural and functional changes. A CMR biomarker of myocardial remodeling is extracellular volume (ECV); an increase in ECV may indicate the development of interstitial myocardial fibrosis. ECV was chosen for structural assessment as it has been implicated with diastolic dysfunction and other cardiac issues in other hematologic diseases, like sickle cell anemia. Methods: Adult patients (age ≥18 years of age) with TTP (immune-mediated or congenital) in the Ohio State University (OSU) TTP registry were prospectively consented and enrolled from March 2023 through July 2023 to undergo adenosine stress CMR at standard clinical dosing. All patients in the TTP cohort had confirmed diagnosis based on ADAMTS13 activity &amp;lt;15% during an acute episode and were in clinical remission at the time of CMR testing. Standard baseline and stress CMR parameters were obtained and compared with an age and sex matched control population, selected from patients without TTP who underwent identical stress CMR protocol for other indications and demonstrated normal stress perfusion. Patients in the control cohort predominantly had diagnoses of arrhythmia, stable angina, or heart failure. We collected data on patient demographics, details of TTP history, and underlying comorbidities. On CMR standard structural measurements were evaluated, and ECV was calculated (normal range 25.3 ± 3.5%). Perfusion was measured per standard protocols via global myocardial blood flow (MBF) as ml/min/g. Differences between the TTP and control populations were tested using the Fischer's exact test for categorical variables and Mann-Whitney U test for continuous variables. Results: A total of 10 TTP patients (9 immune-mediated, 1 congenital) were enrolled between March and July 2023. Median age at enrollment was 44.5 years (IQR 40.8-49.5) and 80% (8/10) were female. Patients were in documented clinical and ADAMTS13 activity remission with median ADAMTS13 activity of 68% (64.0-84.5), excluding the activity level of the congenital patient. Median time from initial diagnosis was 15 years (range 0.5 - 41 years) and median number of acute TTP episodes was 2 (IQR 1.0-4.5). Characteristics of the study (n= 10) and control cohort (n = 13) are summarized in Table 1. There were no significant differences in the TTP and control cohorts with respect to age, sex, race, and presence of hypertension or diabetes. Patients in the TTP cohort had significantly higher BMI (median 34.5 mg/m 2 vs 26.5 mg/m 2, p = .012), diastolic blood pressure (94 mmHg vs 82 mmHg, p = .003), and a lower rate of known cardiac disease (10% vs 85%, p&amp;lt;.001). Stress CMR showed reduced myocardial perfusion in TTP survivors: Nine out of 10 (90%) TTP survivors had evidence of structural or perfusion deficits on CMR. The median ECV in the TTP cohort (28.5%, 24.8 - 31.5) was increased compared with controls (26%, 23.5 - 27.5) though it did not reach significance (p = .08). There were no significant differences in median global MBF at rest in the TTP group (1.30, 1.16 - 1.37) compared with controls (1.18, 1.07 - 1.31, p = .210). However, TTP survivors had significantly reduced stress MBF (3.28, 2.21 - 3.53) vs controls (4.1, 3.88 - 4.22, p &amp;lt;.001) with adenosine. Reductions in quantitative stress perfusion in the TTP cohort was primarily noted in the subendocardium as shown in Figure 2. Conclusion: Asymptomatic structural changes and reduction in quantitative perfusion are common in TTP survivors. The study is ongoing to recruit more patients to ensure clinical significance and generalizability of these preliminary findings. Stress CMR may detect subclinical myocardial damage in TTP survivors who otherwise do not exhibit overt cardiovascular symptoms until a later time and may provide the basis to understand increased cardiovascular morbidity and mortality in this population.

Preferences for Accessing Patient Reported Outcomes and Health Information Among Thrombotic Thrombocytopenic Purpura Survivors

Introduction: Our previous qualitative studies of immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors revealed that patients did not communicate to their hematologists about residual cognitive and fatigue issues. A way to overcome this communication barrier is implementation of patient-reported outcomes (PROs) in routine care. Integration of PROs into the clinical care of other diseases has resulted in improved patient-provider communication, symptom management, quality of life and overall patient satisfaction. However, decisions about the mode of administration are challenging. Although 92% of the United States population has access to the internet, studies have shown minorities prefer alternative modes of administration. Given that iTTP disproportionately affects Black women, understanding patient preference is critical for integrating PRO instruments into routine care. The primary study goal was to determine the preferred mode of administration of PRO instruments in iTTP. Furthermore, many individuals use the internet as a source of medical information/advice. A study of iTTP literacy reported that only 34% of survivors correctly identified disease relapse risk factors suggesting a critical knowledge gap. A secondary goal was to describe iTTP survivors' behaviors regarding using the internet for medical information or support.Methods: We utilized a cross-sectional study design. iTTP survivors were recruited from August 2019 until present. Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Multi-center recruitment of survivors included: Oklahoma University, Ohio State University, University of Minnesota, Johns Hopkins University, University of Rochester, University of Pennsylvania, University of Alabama at Birmingham, University of Utah and the University of Vermont. Following informed consent, survivors were administered the PROMIS ® cognitive function ability, anxiety and fatigue instruments via their preferred mode (online, telephone, or self-administered). Typical internet usage, behaviors regarding searching for health information online and demographics were also obtained.Results: To date, 94 survivors have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). A majority (54%) preferred completing PROMIS ® surveys online vs. self-administered or telephone administered. However, among Black survivors, only 38% preferred online administration and among survivors aged ≥65 years only 22% preferred online administration. Interestingly, there was an overall shift in a preference toward online administration following the onset of the COVID-19 pandemic (45% (21/47) preferred online pre vs 66% (31/47) preferred online post).Ninety-one percent (86/94) of survivors reported at least occasional internet use vs 8 (9%) reported none. Similarly, 82% (70/85) had searched the internet for health/medical information for themselves in the past year. Also 62% (53/86) of the survivors selected ‘strongly agree’ or ‘agree’ to the statement that the internet helps them determine if symptoms are important enough to see a doctor. Likewise, 62% used the internet to interpret doctor's recommendations. Additionally, 47% (40/86) ‘strongly agree/agree’ the internet helped determine if they would take a medication/seek alternative treatment.Moreover, 64% (55/86) agreed the internet was a good way to find others experiencing similar health problems. However, when asked about behaviors over the past year, only 42% (36/85) used online social networking sites like Facebook to look for health information or find others with iTTP and only 36% (31/85) had actually participated in online iTTP support groups.Conclusions: Overall iTTP survivors preferred online PRO administration; however, Black and older survivors preferred other methods. Recognizing these preferences is a vital step toward integrating PROs into routine care. Furthermore, iTTP survivors are using the internet as a source of medical support and information. Therefore, it is critical to not only educate iTTP survivors about credible online resources but also to create additional content. Also, future studies are needed to further explore the impact of the COVID-19 pandemic on online health behaviors. DisclosuresTerrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Cuker: Spark Therapeutics: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy. Chaturvedi: Dova: Other: Advisory board member; UCB: Other: Advisory board participation; Argenx: Other: Advisory board member; Alexion: Other: Advisory board member; Sanofi Genzyme: Other: Advisory board member. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria. Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Cataland: Alexion: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy.

Cardiovascular Disease Is a Leading Cause of Death in Thrombotic Thrombocytopenic Purpura (TTP) Survivors

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially lethal thrombotic microangiopathy; however, prompt therapy with plasma exchange and immunosuppression leads to survival in over 90% of patients. Though TTP survivors were previously thought to return to baseline levels of health, recent reports suggest that TTP survivors have high rates of adverse health sequelae including hypertension, stroke, cognitive impairment, and poor quality of life as well as higher mortality rates compared with an age, race, and sex matched controls population. We conducted this multi-center cohort study to evaluate long term mortality and causes of death in patients that survived their first TTP episode. Methods: All available patients in The Ohio State University and Johns Hopkins Hospital Thrombotic Microangiopathy (TMA) registries were reviewed. Patients with confirmed iTTP based on ADAMTS13 activity &amp;lt;10% during an acute episode were included for analysis. A total of 238 patients met inclusion criteria, with 38 experiencing death during follow up. We evaluated primary and secondary cause of death where applicable. We also collected data on patient demographics, details of TTP history, and comorbidities including hypertension, diabetes, obesity, heart failure, hyperlipidemia, autoimmune conditions, chronic kidney disease, smoking, etc. Mortality was compared with an age, sex and race standardized US population using indirect standardization methods. A multivariable cox regression analysis was used to evaluate risk factors for reduced survival. Results: A total of 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries between 2003 and 2020, of which 70.3% were female, and median age at enrollment was 42 (IQR [interquartile range] 29, 55) years. There were 38 deaths over a median follow up of 4 (IQR 0, 11) years (and a total of 1318 patient years of follow up). Characteristics of the study cohort are summarized in Table 1. Of the 38 patients that died, 9 died during their first episode of TTP and 29 died after surviving the first TTP episode. Median age at death among those that survived the first TTP episode was 49 (IQR 39, 65) years. Among survivors of acute TTP, cardiovascular disease was the leading primary cause of death (27.6%) followed by relapsed TTP (27.6%), malignancy (20.7%), infection (13.8%), and other/unknown causes (10.3%) (Table 2). Cardiovascular disease was the primary or secondary cause of death in 31% (9 of 29) patients. Cardiovascular causes of death included myocardial infarction, arrhythmia, decompensated heart failure, stroke, and hypertensive emergency. The median age of death from any cardiovascular cause (primary or secondary) was 49 years. Among TTP survivors, male sex [HR 4.39 (95% CI 1.83-10.52, P=0.001), age [HR 1.03 (95% CI 1.01-1.06), P=0.039] and number of TTP episodes [HR 1.12 (96% CI 1.05-1.21), P=0.001] were risk factors for mortality in a Cox regression model also adjusted for hypertension [HR 0.60 (95% CI 0.26-1.37), P=0.228], CKD [HR 1.38 (95% CI 0.61-3.13, P=0.436] and SLE [HR 1.26 (95% CI 1.04-1.21), P=0.771]. The mortality rate in TTP survivors was significantly higher than the expected mortality rate from an age and sex standardized reference US population (2228.3 per 100,000 person years versus 1273.8 per 100,000 person years, P = 0.007) (Figure 1). The median age at death was also lower in TTP survivors compared with the general population (49 versus 78.7 years). Conclusions: TTP survivors have two-fold higher mortality rate than expected rates from a reference US population, adjusted for age, sex and race. Cardiovascular disease is a leading cause of death in patients that survive their first episode of TTP. This may be due to higher rates of cardiovascular risk factors such as hypertension in TTP survivors. Reduced ADAMTS13 activity is a risk factor for all cause and cardiovascular death in the general population (Sonneveld et al.Arterioscler Thromb Vasc Biol. 2016) and may contribute to cardiovascular death in TTP survivors. Our results highlight the need to screen and aggressively manage cardiovascular risk factors in TTP survivors, and for prospective studies examining the vascular sequelae of TTP. Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Chaturvedi:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Impact of Residual Effects and Complications of Thrombotic Thrombocytopenic Purpura (TTP) on Daily Living: A Qualitative Study

Introduction: Adverse health outcomes following recovery from thrombotic thrombocytopenic purpura (TTP) are under-recognized. The Oklahoma (OK) TTP Registry has documented that patients have residual complications following recovery. TTP survivors have an increased prevalence of major depression, decreased quality of life, minor cognitive impairment, and a decreased life expectancy compared to the general population. Additionally, Chaturvedi et. al (2017), reported that 32% of TTP survivors met the provisional diagnosis of post-traumatic stress disorder related to their TTP. Yet studies have failed to assess the significance of residual complications from the survivor's perspective. The goal of this study was to determine from the survivor's perspective, long-term outcomes that impact daily activities during remission. Patients: TTP survivors were recruited from the OK Registry and the Ohio State University (OSU) TTP Research Program. Eligibility included: 1) age &amp;gt;18 years, 2) documented ADAMTS13 deficiency, 3) in clinical remission from TTP, and 4) able to read and understand English. A non-probabilistic purposive sampling approach was utilized to select survivors from whom the most could be learned. To understand the full range of health challenges during remission, we intentionally included &amp;gt; 1 person who had experienced a TTP relapse in each focus group. Methods: Qualitative focus groups were conducted using a semi-structured discussion guide to facilitate and standardize the discussion. Prior to use, the discussion guide was pilot-tested and revised accordingly. All the focus groups were conducted in-person and moderated by the first author. During the focus group, TTP survivors described symptoms following recovery. All of the mentioned symptoms were transferred to index cards and given to each person. Patients individually sorted the cards into 'high', 'medium', and 'low' impact on daily living. Next, patients discussed views on what makes a symptom high, medium, or low impact. Additionally, patients were asked to list their top 3 symptoms on an index card (regardless of if it had been previously mentioned). Patients were also asked about discussions with their physicians regarding these symptoms. Frequencies were calculated for quantitative responses. Qualitative data were analyzed for themes. Results: Focus groups (4 in OK; 3 in OSU) were conducted from May-Oct. 2018, were 54-94 minutes, and digitally recorded. Overall, there were 25 patients (76% female, 52% black, median age 46 years) (Table 1). Eighty percent of patients were &amp;gt;5 years from their last episode, 52% had experienced a TTP relapse. The top 2 symptoms listed on the cards were: cognitive impairment 19/25 (76%) and fatigue 17/25 (68%). These symptoms were ranked as high in patients who were both &amp;lt; and &amp;gt;5 years from their last episode. High-impact symptoms occurred daily and negatively affected self-esteem, relationships, and careers. In 6/7 focus groups, survivors described high-impact symptoms caused feelings of being a burden, embarrassment, depression, and anxiety. Fatigue kept survivors from activities with loved ones and the hobbies they enjoyed prior to TTP. Cognitive impairment was described as difficulty 'getting the right words out', forming complete thoughts, and problems with memory and concentration. Cognitive impairment often resulted in arguing and frustration with loved ones. In 4/7 focus groups, memory and concentration problems were detrimental to marriages/long-term relationships. In 5/7 focus groups, cognitive impairment significantly impacted a person's ability to do their job. In 1 focus group, patients who worked in healthcare stated they changed careers because they feared their memory problems would negatively impact the health of others. Yet, many patients were hesitant to discuss these symptoms with a physician because they: 1) did not want to complain, 2) did not want to be prescribed additional medication, and 3) did not think these symptoms were relevant to their 'blood doctor'. Conclusion: Cognitive impairment and fatigue have serious impacts on daily living even &amp;gt;5 years after TTP. Yet, patients were often hesitant to discuss the issues with their doctor and failed to connect these symptoms with the TTP recovery process. Phase II of this study is currently underway, the goal is to identify from the TTP survivor's perspective, preferred ways to assess and manage these symptoms. Disclosures Terrell: National Institutes of Health: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Panepinto:NIH: Research Funding.

Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors

AbstractWith timely and effective treatment, most patients with thrombotic thrombocytopenic purpura (TTP) survive the acute TTP episode. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities, including hypertension, depression, and mild cognitive impairment. We conducted this retrospective-prospective cohort study to determine the incidence and prevalence of stroke after recovery from acute TTP and to test the hypothesis that lower ADAMTS13 activity after recovery from TTP is associated with an increased risk of stroke during remission. Of 170 consecutive patients treated for TTP at The Johns Hopkins Hospital from 1995 through 2018, 14 (8.2%) died during the index episode and 19 were observed for less than 1 month after recovery. Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years, which is fivefold higher than the expected prevalence of 2.6% from an age- and sex-matched reference population (P = .002). ADAMTS13 activity during remission was measured in 52 patients and was >70% in 44.2%, 40% to 70% in 23.1%, 10% to 39% in 25%, and <10% in 7.7%. Stroke after recovery from acute TTP occurred in 0% (0 of 22) of patients with normal remission ADAMTS13 activity (>70%) and in 27.6% (8 of 29) of patients with low ADAMTS13 activity (≤70%; P = .007). In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission.

Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura.

The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)-platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF-platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF-glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.

Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor-induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity. The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (IDS-SR) and mental performance (FLei). We received answers of 104 individual TTP patients and 55 of them participated in both surveys. Seventy-one of the 104 responding TTP patients (68%) suffered from depression and the severity of depression was similar in both surveys performed 1year apart. Furthermore, TTP patients had considerably lower cognitive performance than controls. There was no correlation between prevalence of depression and cognitive deficits and the number and the severity of acute episodes. Impairment of mental performance correlated with the severity of depression (rs =0.779). The prevalence of depression and cognitive deficits was significantly higher in TTP patients. Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes.

Post-traumatic stress disorder and depression in survivors of thrombotic thrombocytopenic purpura

IntroductionSurvivors of thrombotic thrombocytopenic purpura (TTP) have high rates of chronic morbidities including neurocognitive complications and depression. There is limited information regarding the psychological consequences of TTP. We conducted this cross sectional study to estimate the prevalence of symptoms of PTSD and depression in survivors of TTP. MethodsAn online survey tool comprising demographic and clinical information and two validated self-administered questionnaires, the PTSD checklist for DSM-5 (PCL-5) and Beck Depression Inventory-II (BDI-II), was distributed to individuals with TTP. Multivariable regression was used to identify clinical and demographic associations of depression and PTSD. ResultsA total of 236 individuals completed either the BDI II or PCL-5 and were included in the analysis. Median age was 44years and 87.3% were female. Median time from diagnosis was 80months. BDI-II scores >13 indicating at least mild depressive symptoms were present in 80.8% individuals (15.8%, 28.2%, and 36.8% with mild, moderate and severe symptoms, respectively) and 35.1% had a positive screen for PTSD (PCL-5 score≥38). A previous diagnosis of depression [OR 3.65 (95% CI 1.26–10.57); p=0.017] and unemployment attributed to TTP [OR 5.86 (95% CI 1.26–27.09); p=0.024] were associated with depression. Younger age (p=0.017), a pre-existing anxiety disorder [OR 3.57 (95% CI 1.76–7.25), p<0.001], and unemployment attributable to TTP [OR 6.42 (95% CI 2.75–415.00), p<0.001] were associated with PTSD. ConclusionWe report a high prevalence of PTSD and depression in TTP survivors. These results are concerning and indicate a need for further investigation to better define this association and its consequences.

Post Traumatic Stress Disorder and Depression in Survivors of Thrombotic Thrombocytopenic Purpura

Background and objective: Recent data suggests that patients with thrombotic thrombocytopenic purpura (TTP) have higher rates of chronic morbidities including neurocognitive complications and depression. There is limited information regarding the psychological consequences of this disorder. TTP is conceivably an emotional trauma with a risk of post-traumatic stress disorder (PTSD). We conducted this cross sectional study to estimate the prevalence of symptoms of PTSD and depression in survivors of TTP.Methods: We developed an online survey tool based on two validated questionnaires: the PTSD checklist for DSM-5 (PCL-5) and Beck Depression Inventory-II (BDI-II). We also collected information regarding patient demographics clinical features and experiences. Surveys were distributed through email in collaboration with AnsweringTTP, a patient support organization. Survey responses were managed in RedCap. Associations of clinical and demographic variables with a positive screen for PTSD were first evaluated by the chi-square test and t-test, and then in a multivariable regression model. Prevalence of PTSD and depression were compared with a general primary care population. A p-value of 0.05 was considered significant for all analyses.Results: Three hundred and sixteen patients responded to the survey (response rate 27.5%). Of these, 290 completed consent to participate in the study, and 236 completed either the PCL-5 (n=231) or BDI-II (209) and were included in the analysis. Median age was 44 years and 206 (87.3%) were female. A pre-existing diagnosis of depression, anxiety disorder and PTSD was present in 97 (41.1%), 81 (34.3%) and 37 (15.7%) respondents, respectively. Median time from initial diagnosis of TTP was 80 months (interquartile range 37 to 132 months).BDI-II scores >13 indicating at least mild depressive symptoms were present in 169 (80.8%) patients. Thirty-three (15.8%), 59 (28.2%) and 77 (36.8%) had mild, moderate and severe depressive symptoms, respectively. Eighty-one (35.1%) individuals had a positive screen for PTSD (PCL-5 score >= 38), and 75 (32.4%) met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria of presence of cluster B, C, D and E symptoms. Compared to an age and sex adjusted primary care population, TTP survivors had a higher prevalence of PTSD (32.4% versus 3.5%) and depression (80.9% versus 10.5%). On multivariable analysis, a previous diagnosis of depression [odds ratio (OR) 3.65 (95% CI 1.26 - 10.57); p=0.017] and being unemployed due to TTP [OR 5.86 (95% CI 1.26 - 27.09); p = 0.024] were identified as significant predictors of depression. A positive screen for PTSD was associated with younger age (p = 0.017), a pre-existing diagnosis of anxiety disorder [OR 3.57 (95% CI 1.76 - 7.25), p < 0.001], and being unemployed for reasons attributable to TTP [OR 6.42 (95% CI 2.75-415.00), p < 0.001).Conclusion: We found a high prevalence of PTSD (32.4%) and depression (80.8%) in survivors of TTP. While responder bias may lead to overestimation of prevalence in this study, these results are concerning and indicate a need for further investigation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased Morbidity during Long Term Follow up of Survivors of Thrombotic Thrombocytopenic Purpura

Background and Objective: The advent of plasma exchange has led to a dramatic improvement in the survival of patients with thrombotic thrombocytopenic purpura (TTP). Recovery from TTP is usually complete, but may be complicated by a significant rate of relapse, particularly in the first year after the acute episode. Recent reports also suggest that survivors of TTP may have a poorer health related quality of life than previously estimated. We followed a cohort of 100 patients diagnosed with TTP to estimate the burden of chronic renal impairment, hypertension, diabetes, stroke, depression and other psychiatric and neurologic conditions in this group.Patients and Methods: A total of 100 consecutive patients treated for TTP at the Cleveland Clinic from January 2000 to March 2012 were identified. Nine patients died and the remaining 91 patients were followed until death or date of last clinical contact. The point prevalence of chronic kidney disease, hypertension, diabetes, stroke, major depression and other neurologic and psychiatric conditions was compared to expected values in the reference US population [based on National Health and Nutrition Examination Survey (NHANES) data] adjusted for age and sex.Results: Of the 91 patients who survived a first episode of TTP, 69 (75.8%) were female, with an age range of 16 to 79 years (median 44 years). Fifty one percent of patients were Caucasian, 45% African American and 2% Hispanic. Sixty three percent of cases occurred without predisposing conditions while 12.1% were associated with autoimmune disease (5 with SLE, 2 with rheumatoid arthritis, one with SLE and rheumatoid arthritis, and one each with Sjogren’s syndrome, dermatomyositis and mixed connective tissue disorder), 8% with pregnancy or the postpartum state, 6.6% with cancer and 5.5% with solid organ transplant.The median follow up time was 59 months (range 1-117 months). During this period, 18 patients suffered relapses (11 patients had 1 relapse, 6 patients had 2 relapses, and 1 had three relapses). Compared to the reference US population, survivors of TTP had a higher prevalence of hypertension (61.5% versus 29.8%), chronic renal disease (26.4% versus 16.8%) and stroke (12.1% versus 1.87%). TTP survivors also had a high prevalence of neurologic disorders including migraines (n=9), multiple sclerosis (n=1), fibromyalgia (n=1) and restless leg syndrome (n=2). There was a five-fold higher incidence of major depression requiring pharmacologic treatment compared to the reference population (26.4% versus 5.4%). We also noted a significant prevalence of other mental health disorders such as anxiety disorders (n=15), bipolar disorder (n=2), adjustment disorder (n=1) and conversion disorder (n=1). The incidence of diabetes was lower than seen in the reference population (6.6% versus 14.4%).Conclusion: Survivors of TTP are at higher risk for poor health outcomes including chronic cardiovascular disease, neurologic disease and psychiatric conditions, all of which impair quality of life. These may be related to persistent organ damage from microvascular dysfunction during the acute episode of TTP, or from co-morbid conditions such as auto-immune diseases that are independent risk factors for poor outcomes. Our results highlight the importance of continued follow up in order to address the long-term health problems associated with TTP survivorship. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk-Predictors of Mortality in Hospitalized Patients with Thrombotic Thrombocytopenic Purpura: Nationally Representative Data from 2007-2011

▪Introduction: Survivors of Thrombotic Thrombocytopenic Purpura (TTP) hospitalizations have been proposed to be at higher risk for long term poor clinical outcomes and premature death. Patients with TTP have a high risk for in-hospital morbidity and mortality as well. However, there is a paucity of data on the predictors of adverse outcomes including death in hospitalized patients with TTP.Methods: A weighted analysis of 5 years (2007-2011) using data from the Nationwide Inpatient Sample, a stratified probability sample of 20% of all hospital discharges among community hospitals in the United States (approximately 1100 hospitals/year), was performed. Hospitalizations with TTP as the primary admitting diagnoses were identified using the ICD-9 discharge code 446.6. Univariate and stepwise multivariable logistic regression analyses with elimination were used for statistical analysis. Based on results of univariate analysis, the significant variables were added in a stepwise manner in a multivariable model. All variables selected for the multivariable model were tested for interaction with a significance threshold level of p<0.2. Except for this, all hypothesis testing was two tailed and p<0.05 was considered significant. Receiver Operator Characteristics (ROC) curve was constructed using risk factors on multivariate analysis.Results: The all-cause mortality rate was 8.7% (918/10615) among admissions with primary diagnosis of TTP (0.5% pediatric, 65.9% female, 58.2% Caucasian, 27.2% African-American). Table 1 lists the risk factors by univariate analysis and includes a) factors with significantly higher odds of mortality and b) other putative factors which were not statistically significant predictors.Table 2: In stepwise multivariable logistic regression analysis: arterial thrombosis (adjOR 5.1 95%CI=1.1-31.7), acute myocardial infarction (adjOR 2.8, 95%CI=1.6-4.9), non-occurrence of either intervention: plasmapheresis or fresh frozen plasma infusion (adjOR 2.0, 95% CI=1.4-2.9) 4) requirement of platelet transfusions during hospitalization (adjOR 2.0, 95%CI= 1.3-3.2) and every ten year increase in age (OR 1.4 95%CI=1.3-1.6) were independently predictive of mortality in TTP patients (area under the curve for ROC 74%, Figure 1).Conclusion: We present a set of independent risk factors that may potentially be used in a predictive model of mortality in TTP. Early and targeted aggressive therapy based on these factors should guide the management of hospitalized patients with TTP for improved outcomes. Table 1Unadjusted odds of in-hospital mortality.Significant predictors of mortality for TTP on univariate analysisOdds Ratio95% Confidence LimitsArterial Thrombosis10.92.254.6AMI3.72.16.2STROKE4.93.07.9Platelet Transfusion2.31.53.6Bleeding event1.71.12.6Plasmapheresis (No vs. Yes)1.61.22.3plasmapheresis or plasma infusion(not performed)2.21.53.1Every 10 years increase in age1.51.31.6PRBC transfusion1.71.22.3Caucasian versus African American1.91.32.8Asian versus African American3.31.29.1V ariables not significant predictors of mortality for TTP on univariate analysis.Odds Ratio95%Confidence LimitsVenous Thrombosis/Thromboembolism1.90.84.4FEMALE versus male gender1.00.71.4Hypertension Yes vs. no0.90.61.2Diabetes Yes vs. no0.90.61.4Chronic Kidney Disease Yes vs. No1.40.92.2End Stage Renal Disease Yes vs. No0.90.41.9Overweight/Obese Yes vs. No0.70.41.5Variables meeting criteria for inclusion in multiple logistic regression model are in boldface type.Table 2Multivariable Predictors for In Hospital Mortality in patients with primary diagnosis of TTPAdjusted Odds Ratio95% Confidence LimitsArterial Thrombosis6.01.230.5Acute myocardial infarction2.81.64.8No Plasmapheresis/Plasma infusion2.01.42.9Platelet Transfusion2.11.43.2Age (per 10 year higher)1.41.31.6Female versus Male1.20.81.7TTP = Thrombotic Thrombocytopenic PurpuraStep 0: Using arterial thrombosis [Display omitted] Step 1: Adding acute myocardial infarctionStep 2: Adding plasmapheresis /fresh frozen plasma infusionStep 3: Adding platelet transfusionsFinal model: Adding every ten year increase in age. DisclosuresNess:Terumo BCT: Consultancy.

Thrombotic Thrombocytopenic Purpura (TTP) Patient Attitudes Regarding Depression Management: a Qualitative Study

▪Introduction: Recovery from an acute episode of TTP was previously thought to be complete except for a risk for relapse. However, the Oklahoma TTP-HUS Registry has documented that patients have multiple health problems that persist following recovery, including an increased prevalence of major depression (Blood122:2023;2013). Untreated major depression impacts daily functioning, quality of life and is a risk factor for suicide. Recognizing depression and establishing effective treatment should be a critical part of TTP follow-up care. The objective of our study was to identify TTP patient attitudes regarding treatments for depression.Methods: The study was based on the theoretical framework of the Theory of Planned Behavior (TPB). The theory suggests that intention is the immediate predictor of behavior. Intention is determined by 3 factors: attitude toward a behavior, subjective norms, and perceived behavioral control. This study focused on attitude; therefore, patients were primarily asked if there were any advantages or disadvantages of treating depression with either pharmacotherapy or counseling.One-on-one semi-structured interviews were conducted by the first author. Interviews were transcribed verbatim and content analysis was conducted by 3 qualitative researchers and facilitated by using the NVivo 10 software. A codebook was developed to guide the data analysis. Similar beliefs were grouped into themes and key ideas.Patients: Registry patients whose initial episode was associated with severe ADAMTS13 deficiency (<10%), 1995-2012, and who had major depression on at least 1 screening evaluation from 2004-2012. Qualitative purposeful sampling was used instead of random sampling. Patients were stratified by previous/current or no pharmacotherapy treatment regardless of counseling history.Results: Fifty-six ADAMTS13-deficient patients in clinical remission had been screened for depression; 50 patients were alive in 2013; 24 had a score of major depression at least once. Of the 24 patients, 12 (50%) had taken pharmacotherapy for their depression and 12 (50%) patients had never taken pharmacotherapy.Data saturation was achieved after interviewing 16 patients (9 pharmacotherapy; 7 no pharmacotherapy). Fourteen patients (88%) were women, 9 (56%) were black, and the median age was 49 years (range 28-69). Patients were a median of 8.5 years from their most recent TTP episode (range 2-17 years), 5 (31%) had relapsed, and 7 (44%) had been treated with rituximab.Interviews among all patients revealed that a TTP diagnosis was 'life-altering’ and 'traumatic’. Many patients felt the residual effects of TTP (a fear of relapsing, fatigue, and mild cognitive impairment) were related to their depression. A major theme across groups was that patients had a positive attitude toward counseling and believed counseling could be an effective way to treat depression. However, a history of a negative counseling experience seemed to discourage many patients from continuing counseling. Additionally, regardless of previous counseling experience, a key idea across groups was mistrust toward the mental healthcare provider’s ability. However, this mistrust was only a perception among those who had never tried counseling. Within the pharmacotherapy group, patients believed that medication was an effective way to treat depression; however, many patients reported side effects (feeling 'sluggish’ and 'not caring about anything’) as the reasons for stopping the medication. On the contrary, among the non-pharmacotherapy group patients were unsure if pharmacotherapy actually worked-'Uh, I guess it kind of would keep you steady-minded I guess’. The fear of side effects and the fear of addiction were the biggest barriers among the non-pharmacotherapy group for using pharmacotherapy.Conclusion:Hematologists need to recognize that TTP is a long-term life-altering diagnosis following recovery. Identifying and managing depression is a critical issue that can save lives. TTP patients seem to have a positive attitude toward counseling and a mixed attitude toward pharmacotherapy. Whether these fears are valid is beyond the scope of this study; however, it is imperative that hematologists discuss the issue of depression in depth with their patients and address the barriers to acceptance of treatment. This study is a first step in identifying barriers to depression treatment in TTP survivors. DisclosuresNo relevant conflicts of interest to declare.

Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura

AbstractRecovery from acute episodes of thrombotic thrombocytopenic purpura (TTP) appears complete except for minor cognitive abnormalities and risk for relapse. The Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry enrolled 70 consecutive patients from 1995 to 2011 with ADAMTS13 activity <10% at their initial episode; 57 survived, with follow-up through 2012. The prevalence of body mass index (BMI), glomerular filtration rate (GFR), urine albumin/creatinine ratio (ACR), hypertension, major depression, systemic lupus erythematosus (SLE), and risk of death were compared with expected values based on the US reference population. At initial diagnosis, 57 survivors had a median age of 39 years; 45 (79%) were women; 21 (37%) were black; BMI and prevalence of SLE (7%) were greater (P < .001) than expected; prevalence of hypertension (19%; P = .463) was not different. GFR (P = .397) and ACR (P = .793) were not different from expected values. In 2011-2012, prevalence of hypertension (40% vs 23%; P = .013) and major depression (19% vs 6%; P = .005) was greater than expected values. Eleven patients (19%) have died, a proportion greater than expected compared with US and Oklahoma reference populations (P < .05). TTP survivors may have greater risk for poor health and premature death.

Thrombotic thrombocytopenic purpura.

This overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS-13 deficiency as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS-13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS-13 structure and function are reviewed. The complex, initially devised assays for ADAMTS-13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73-amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS-13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and--if untreated--frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody-mediated ADAMTS-13 deficiency. The pathogenesis of cases without severe deficiency of the VWF-cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS-13 activity. Survivors of acute TTP, especially those with autoantibody-induced ADAMTS-13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo-plasia and several drugs, usually have normal or only moderately reduced ADAMTS-13 activity, with the exception of ticlopidine-induced TMA. Diarrhea-positive-hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D- HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS-13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and--given prophylactically every 2-3 weeks--prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients.