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Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a microangiopathy often characterized by acute neurological involvement including ischemic stroke (IS). The characteristics of IS in iTTP remain largely unknown., Aims: To evaluate the epidemiology, neuroimaging patterns and risk factors of IS in iTTP patients., Methods: We performed a cross-sectional study of patients enrolled in the Milan TTP Registry presenting with neurological signs/symptoms and underwent neuroimaging evaluation during their first acute iTTP episode., Results: Seventy-eight patients were enrolled, the majority of patients were female (72 %), with a median age of 46 years. Computed tomography (CT) was performed in all patients, and magnetic resonance (MRI) was performed in 38 % of patients. IS was confirmed in 18 out of 78 patients (23 %), most of whom (70 %) showed a non-lacunar pattern with multifocal involvement. In the subgroup of patients who had MRI (n = 30), IS was identified in 12 patients (40 %) and of them 6 (50 %) had a false negative result with CT scan. Patients with IS were slightly older than those without, whereas the prevalence of cardiovascular risk factors and iTTP-related parameters were comparable between the two groups., Conclusion: 23 % of patients presenting with neurological manifestations at their first acute TTP episode, showed brain IS. As expected, MRI showed higher sensitivity in detecting ischemic lesions underscoring its usefulness over CT in this setting. An unexpected prevalence of non-lacunar and multifocal stroke patterns warrants further investigation. Cardiovascular risk factors and iTTP-related clinical and laboratory parameters were similarly distributed in patients with and without IS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P. Agosti, A. Artoni, and B. Ferrari received honoraria for participating as a speaker at educational meetings organized by Sanofi; I. Mancini received honoraria for participating as a speaker at educational meetings organized by Werfen and Sanofi; F. Peyvandi has received honoraria for participating as a speaker in education meetings organized by Sanofi, Spark and Takeda and she is member of scientific advisory boards of CSL Behring, Biomarin, Roche, Sanofi, Sobi. The other authors do not have any conflict of interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Objectives: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course., Methods: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected., Results: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable., Conclusion: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients., Competing Interests: Competing interests: GN received speaker fees from Novartis, Amgen, Galapagos and BMS. AV is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments and Takeda. XM received fees from BMS, Galapagos, GSK, Novartis and Pfizer. PC is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma and Takeda. IB received speaker fees from Galapagos. BSJ received speaker fees from Sanofi, Takeda and LFB-Biomédicaments. JL, LG and RB declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare autosomal recessive, life-threatening disorder caused by a severe deficiency of the plasma enzyme, ADAMTS13. The current estimated prevalence of hTTP in different regions of the world, 0.5 to 2.0 patients per million, is determined by the frequency of diagnosed patients. To evaluate more accurately the worldwide prevalence of hTTP, and also the prevalence within distinct ethnic groups, we used data available in exome and genome sequencing of 807 162 (730 947 exomes, 76 215 genomes) subjects reported recently by the Genome Aggregation Database (gnomAD-v4.1). Among 1 614 324 analyzed alleles in the gnomAD population we identified 6321 distinct ADAMTS13 variants. Of these, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). In total 10 154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7759 (77%) with previously reported variants. Considering all 758 pathogenic variants and also only the 140 previously reported variants, we estimated a global hTTP prevalence of 40 and 23 cases per 106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 106). The estimated prevalences of other populations were: Finnish, 32 per 106; non-Finnish Europeans, 28 per 106; Admixed Americans, 19 per 106; Africans/African Americans, 6 per 106; and South Asians, 4 per 106. The lowest prevalences were Middle Eastern, 1 per 106 and Ashkenazi Jews, 0.7 per 106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many patients with hTTP may not be diagnosed or may have died during the neonatal period., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Pregnancy-onset thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disease of which diagnosis and management requires experienced multidisciplinary teams. The mechanisms responsible for a deficiency in the disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) leading to pregnancy-onset TTP may be congenital or acquired, and studying ADAMTS13 conformation could be of interest. The differential diagnosis between TTP and other pregnancy-associated thrombotic microangiopathies (TMA) is often challenging. Our retrospective multicenter study highlights the significance and the challenges associated with pregnancy-onset TTP and childbirth in terms of diagnosis, obstetric management, and follow-up aspects. Among 1174 pregnancy-onset TMA enrolled in the French Registry for TMA from 2000 to 2020, we identified 108 pregnancy-onset TTP: 52 immune-mediated TTP (iTTP, 48.1%), 27 acquired TTP of unidentified mechanism (uTTP, 25%), and 29 congenital TTP (cTTP, 26.9%). Data show that maternal outcome is good (survival rate: 95%) and fetal outcome is linked to the gestational age at the onset of the disease (survival rate: 75.5%). Three distinct entities with different natural histories emerged: pregnancy-onset iTTP appears similar to idiopathic iTTP, with an open ADAMTS13 conformation, and is marked by a relapse risk independent of subsequent pregnancies; pregnancy-onset uTTP appears to have a different pathophysiology with an unexpected open ADAMTS13 conformation and a very low relapse risk independent of subsequent pregnancies; finally, pregnancy-onset cTTP is characterized by the necessity of pregnancy as a systematic and specific trigger and a need for prophylactic plasmatherapy for subsequent pregnancies. This trial was registered at www.clinicaltrials.gov as #NCT00426686, and at the Health Authority and the French Ministry of Health (P051064/PHRC AOM05012)., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known., Aim: The prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and Shiga toxin-producing Escherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study., Methods: Univariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions., Results: Among 73 TMA cases (mean age 46.9 ± 16 years (range 21-87 years) with iTTP (n = 57) or HUS (n = 16), one-third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, three factors predicted the occurrence of acute ischemic lesions on cerebral MRI: (1) the presence of old infarcts on cerebral MRI, (2) the level of blood pulse pressure, (3) the diagnosis of iTTP., Conclusion: At the acute phase of iTTP or HUS, both symptomatic and covert ischemic lesions are detected in one third of cases on MRI. Diagnosis of iTTP and the presence of old infarcts on MRI are associated with the occurrence of such acute lesions as well as increased blood pulse pressure, that may represent a potential target to further improve the therapeutic management of these conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by widespread microthrombosis that can predispose to multiple organ failure. The literature is sparse on the outcomes of critically ill patients with TTP managed in intensive care units (ICUs). We aimed to determine the mortality of ICU patients admitted with TTP and evaluate the predictors of survival. We also compared the incidence of nosocomial infection among those who did or did not receive plasma exchange (PE). Methods We conducted a retrospective study in a tertiary ICU. Two authors screened patients for eligibility from the hospital information system based on peripheral smear reports. Adult critically ill TTP patients managed in ICU were included. Patients with a diagnosis of haemolytic uraemic syndrome, autoimmune causes of haemolysis and pregnancy-related conditions, etc. were excluded. Two authors extracted data from medical charts. No imputation of missing variables was done. Non-parametric statistics were used to report data. Statistical analyses were performed using Stata version 16. Results Of the 535 records that were screened, 33 patients were deemed eligible. Mortality among TTP patients was 14 (42%). The women to men ratio was 7:3. At admission, greater degree of anaemia, thrombocytopenia, and higher lactate dehydrogenase levels were observed in non-survivors compared to survivors (5.4 g/dl [4.8-7.1] v. 7.6 g/dl [6.1-8.9], p=0.05; 17x103 μl v. 21x103 μl, p=0.63; and 2987 (1904-3614) U/L v. 2126 U/L (1941-3319), p=0.71; respectively]. Nineteen (57%) patients had acute kidney injury (AKI), of which 11 survived: 6 recovered completely from renal failure and 5 progressed to end-stage renal disease. Nosocomial infection rates were not different among those receiving and not receiving PE therapy (7 [33%] v. 3 [25%], respectively). Conclusion TTP is more common in women and has a high mortality. Older age, low haemoglobin and higher platelet transfusions are predictors of poor survival. Nosocomial infection rates were similar irrespective of receiving PE therapy.

Immuno Thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially fatal disorder characterized by systemic microvascular thrombosis because of a severe deficiency of ADAMTS13. It is difficult to generate knowledge about TTP because of its low incidence and the lack of clinical trials. Most of the evidence on diagnosis, treatment, and prognosis has been generated from real-world data registries. In 2004, the Spanish Apheresis Group (GEA) implemented the Spanish registry of TTP (REPTT) with 438 patients suffering 684 acute episodes in 53 hospitals up to January 2022. REPTT has studied several aspects of TTP in Spain. The iTTP incidence in Spain our country is 2.67 (95 % CI 1.90-3.45) and the prevalence is 21.44 (95 % CI % 19.10-23.73) patients per million inhabitants. The refractoriness incidence is 4.8 % and exacerbation incidence was 8.4 %, with a median of follow-up of 131.5 months (IQR: 14-178 months). In a 2018 review, the mortality in the first episode due to TTP was 7.8 %. We have also found that de novo episodes require fewer PEX procedures than relapses. Since June 2023, REPTT will involve Spain and Portugal, with a recommended sampling protocol and new variables to improve the neurological, vascular and quality of life evaluation of these patients. The main strength of this project will be the involvement of a combined population of more than 57 million inhabitants, which implies an annual incidence of close to 180 acute episodes per year. This will allow us to provide better answers to questions like treatment efficacy, associated morbidity and mortality, and the possible neurocognitive and cardiac sequelae., Competing Interests: Declaration of Competing Interest MEMC, CPI and JDRG have not conflict of interest for this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The outcomes and characteristics of acquired thrombotic thrombocytopenic purpura (TTP) in adolescents is poorly understood due to an absence of studies focused on this population. To better understand the life-threatening disorder in this age, we performed an analysis of adolescent patients (ages 10-21) with TTP in the Pediatric Health Information Systems database from 2009 to 2020. The primary outcomes evaluated were in-hospital mortality and rate of TTP relapse. Secondary outcomes included rates of hemorrhagic and thrombotic complications during hospitalizations for TTP. Patients were included if they had a thrombotic microangiopathy diagnostic code, ADAMTS13 lab obtained, and received therapeutic plasmapheresis. Patients that received treatment for other non-TTP microangiopathies were excluded. A total of 99 patients with 123 hospitalizations for TTP treatment were identified. In-patient mortality occurred in 6 % (n = 6) and TTP relapse in 20 % (n = 20) of the cohort. Median time from initial admission to relapse was 33 days (IQR 15, 92). A hemorrhagic complication was identified in 29 % (n = 36) and thrombotic complication in 15 % (n = 19) of the cohort. The presence of underlying comorbidities was not associated with TTP relapse and only a diagnosis of cancer was associated with increased mortality. The rate of mortality and relapse in adolescent TTP is lower than that seen in adult registries. Long term prospective studies are needed to understand the long-term consequences of adolescent onset acquired TTP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Utilizing the comprehensive Nationwide Inpatient Sample (NIS) database, we examined the impact of thrombotic thrombocytopenic purpura (TTP) on the outcomes of patients with coronavirus disease-19 (COVID-19), emphasizing the potential role of the ADAMTS13 enzyme in disease pathogenesis and evolution. We analyzed extensive data from the NIS database using STATA v.14.2 and accounted for potential confounders using multivariate regression analysis to uphold the validity and reliability of the study. Among 1 050 045 adult patients hospitalized with COVID-19, only 300 (0.03%) developed TTP. These patients were younger (mean age 57.47 vs 64.74, P < .01) and exhibited a higher prevalence of preexisting conditions, such as congestive heart failure (13.33% vs 16.82%, P value not provided) and end-stage renal disease (3.33% vs 3.69%, P value not provided). On multivariate regression analysis, COVID-19 patients with concomitant TTP demonstrated a significant increase in mortality (adjusted odds ratio [AOR] 3.99, P < .01), venous thromboembolism (AOR 3.33, P < .01), acute kidney injury (AOR 7.36, P < .01), gastrointestinal bleeding (AOR 10.75, P < .01), intensive care unit admission (AOR 14.42, P < .01), length of hospital stay (17.42 days, P < .01), and total hospitalization charges ($298 476, P < .01). Thrombotic thrombocytopenic purpura in COVID-19 patients elevates the risk of mortality and complications, likely driven by the thrombotic nature of TTP. Our data underline the potential significance of ADAMTS13 in COVID-19 and TTP pathophysiology, suggesting its possible role as a therapeutic target., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Comparing the characteristics of thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome patients at admission will allow early differentiation of TTP from TTP-like syndrome and help tailor initial treatment. The medical records of 78 patients with suspected TTP in the Emergency Department of Peking University People's Hospital in the past 5 years were retrospectively analyzed and divided into TTP and TTP-like syndrome groups based on ADAMTS13 activity and ADAMTS13 antibody titer. There were 25 and 53 patients in the TTP group and the TTP-like syndrome group, respectively. The neutrophil-to-lymphocyte ratio (P = 0.025) was tremendously higher, and albumin (P = 0.002) was lower in the TTP-like syndrome group, indicating a more severe inflammation. Compared with the TTP-like syndrome group, the TTP group had an approximately two-fold to three-fold higher prevalence of central nervous system dysfunction (P < 0.001). Also, hemolysis was more substantial in the TTP group as evidenced by higher schistocytes (P < 0.001), reticulocyte (P < 0.001), total bilirubin (P = 0.002), indirect bilirubin (P < 0.001), lactate dehydrogenase (P = 0.007) and cell-free hemoglobin (P < 0.001), simultaneously lower platelet (P < 0.001), haptoglobin (P = 0.044), and ADAMTS13 activity (P < 0.001). The Kaplan-Meier survival analysis showed that the TTP group significantly predicted poor prognosis (log-rank test: X 2  = 5.368, P = 0.021). TTP and TTP-like syndrome are two kinds of distinct phenotypes with different hemolysis statuses and illustrated differentiated inflammatory reactions, target organ damage (TOD), and the clinical outcome., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Thrombotic microangiopathies (TMA) are serious medical conditions requiring a prompt diagnosis to adapt treatment. The determination of ADAMTS-13 activity enables discriminating thrombotic thrombocytopenic purpura (TTP) from other forms of TMA. The purpose of this study was to provide an estimate of the incidence of TTP and TMA in the Canadian Quebec province using data collected from a laboratory centralizing ADAMTS-13 testing for the whole province., Results: From 2012 to 2019, 846 patients were evaluated for plasma ADAMTS-13 activity due to a suspicion of TMA. TTP was identified in 147 patients. Of these, 118 patients with a median age of 51.5 years and a male-female ratio of 1:1.4 had their first episode of TTP during the study period. The number of ADAMTS-13 tests performed and the number of patients with suspected TMA increased annually by 19% and 21% respectively. While the incidence of non-TTP TMA increased annually, that for TTP remained unchanged. This averaged 10.2 (95% CI 5.9-14.4) per million persons per year for suspected non-TTP TMA and 1.8 (95% CI 1.3-2.4) for confirmed TTP. The incidence rate of TMA other than TTP was higher in the age group 70-79 years (21.8; 95% CI 5.4-38.1) for females and in the age group 80-89 years (24.4; 95% CI 7.2-41.7) for males compared to other age groups. The incidence rate of TTP was higher in the age group 40-49 years (4.0; 95% CI 2.0-5.9) for women and in the age group 60-69 years (3.4; 95% CI 1.1-5.6) for men compared to other age groups., Conclusion: The analysis of centralized data measuring ADAMTS-13 activity allowed us to adequately establish the incidence rate and demographic characteristics of TMA, particularly TTP, in Quebec. TTP incidence remained stable while suspected non-TTP TMA steadily increased from 2012 to 2019., (© 2022. The Author(s).)

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region., Methods: We perfomed a cohort study in the frame of the project "Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis", including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h., Results: Forty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity < 10% vs ≥ 10%: median difference of -27 × 10 9 /l, 95% CI - 37 to - 3). PEX treatment was initiated in all patients, but soon discontinued in cases without severe ADAMTS13 deficiency. In this group, the mortality rate was higher and no episode exacerbations or relapses within 6 months occured. The estimated average annual incidence of acute acquired TTP events was 1.17 [0.78-1.55] per million people., Conclusions: Severe ADAMTS13 deficiency distinguished two groups of patients with largely overlapping clinical features but different treatment and disease course. This study provides a feasible model implemented in a large Italian region for the practical clinical approach to TMAs and underlines the importance of urgent ADAMTS13 activity testing for an accurate differential diagnosis and therapeutic approach., (© 2022. The Author(s).)

Background: Thrombotic thrombocytopenic purpura (TTP) is a clinically rare thrombotic cardiovascular and microvascular disease. The purpose of this study was to observe the clinical efficacy and safety of plasma exchange in the treatment of TTP., Methods: A total of 16 TTP patients who underwent plasma exchange from January 2015 to December 2020 were selected. The clinical data of all patients were collected for retrospective analysis. The effective rate of treatment, the changes of blood cell count before and after treatment, and adverse reactions during treatment were analyzed., Results: A total of 50 plasma exchanges were performed in 16 TTP patients. After plasma exchange treatment, there were 4 invalid and 12 improved patients. The total effective rate of plasma exchange in patients with TTP was 75.0%. After treatment, platelet count (PLT) and hemoglobin (Hb) levels were significantly increased in TTP patients. Compared with before treatment, lactate dehydrogenase (LDH), indirect bilirubin (IBIL), total bilirubin (TBIL), and broken red blood cells were significantly reduced. In addition, 3 adverse reactions occurred in 50 plasmapheresis procedures, and the incidence of adverse reactions was 6.0%., Conclusion: Plasma exchange therapy has a good therapeutic effect on TTP and can significantly improve abnormal blood cell count in patients with high safety., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Zhilan Pan et al.)

Objectives: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare life-threatening thrombotic microangiopathy affecting adults with unpredictable disease onset and acute presentation. This study aimed to describe the health-related quality of life (HRQoL), cognitive functioning and work productivity of survivors following acute episode(s) of iTTP in the United Kingdom (UK)., Methods: An online survey was developed in collaboration with the TTP Network. Descriptive statistics were calculated for the health questionnaire Short Form Survey-36 Version 2 (SF-36v2), the Hospital Anxiety and Depression Score (HADS), the PROMIS Cognitive Function Abilities Subset - Short Form 6a (PROMIS CFAS - SF6a), and the Work Productivity and Activity Index: Specific Health Problem (WPAI-SHP), along with several iTTP-specific bespoke questions., Results: Fifty participants were recruited between July-November 2019. The mean (standard deviation [SD]) standardized SF-36v2 physical and mental component scores were 42.16 (9.59) and 33.61 (12.34), lower than population norms. The mean (SD) standardized PROMIS CFAS - SF6a score was 39.69 (7.86), lower than population norms. HADS mean (SD) scores of 12.18 (3.14) and 11.78 (2.36) indicated moderate levels of anxiety and depression, respectively. Of those employed (58%), approximately 42.73% of participants reported work productivity loss due to their iTTP. Participants also reported experiencing flashbacks, fatigue interference in family, social and intimate life, and fears of relapse., Discussion and Conclusion: Regardless of recency of the last acute episode, participant scores signified impairments in all domains. Remission from an acute episode of disease does not signify the conclusion of care, but rather the requirement for long-term healthcare particularly focused on psychological support.

Background: Upshaw-Schulman syndrome (USS) is an autosomal recessive disease characterized by thrombotic microangiopathies caused by pathogenic variants in ADAMTS13. We aimed to (1) curate the ADAMTS13 gene pathogenic variant dataset and (2) estimate the carrier frequency and genetic prevalence of USS using Genome Aggregation Database (gnomAD) data., Methods: Studies were comprehensively retrieved. All previously reported pathogenic ADAMTS13 variants were compiled and annotated with gnomAD allele frequencies. The pooled global and population-specific carrier frequencies and genetic prevalence of USS were calculated using the Hardy-Weinberg equation., Results: We mined reported disease-causing variants that were present in the gnomAD v2.1.1, filtered by allele frequency. The pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics criteria. The genetic prevalence and carrier frequency of USS were 0.43 per 1 million (95% CI: [0.36, 0.55]) and 1.31 per 1 thousand population, respectively. When the novel pathogenic/likely pathogenic variants were included, the genetic prevalence and carrier frequency were 1.1 per 1 million (95% CI: [0.89, 1.37]) and 2.1 per 1 thousand population, respectively., Conclusions: The genetic prevalence and carrier frequency of USS were within the ranges of previous estimates., (© 2021. The Author(s).)

Objectives: To describe short- and long-term neurologic prognosis of patients with thrombotic thrombocytopenic purpura and to identify clusters associated with evolution., Design: Prospective French cohort., Setting: ICU in a reference center., Patients: All consecutive patients with newly diagnosed thrombocytopenic purpura., Intervention: Comprehensive clinical, biological, and radiological evaluation at admission. Neurocognitive recovery was assessed using Glasgow Outcome Scale (range 1-5, with 1 representing death and 5 representing no or minimal neurologic deficit)., Measurements and Main Results: Among the 130 newly diagnosed patients with thrombocytopenic purpura, 108 (83%; age 43 [30-52]; 73% women) presented with neurologic signs, including headaches (51%), limb weakness, paresthesia, and/or aphasia (49%), pyramidal syndrome (30%), decreased consciousness (20%), seizure (19%), cognitive impairment (34%), cerebellar syndrome (18%), and visual symptoms (20%). A hierarchical cluster analysis identified three distinct groups of patients. Cluster 1 included younger patients (37 [27-48], 41 [32-52], and 48 [35-54], in clusters 1, 2 and 3, respectively; p = 0.045), with a predominance of headaches (75%, 27%, and 36%; p < 0.0001). Cluster 2 patients had ataxic gait and cerebellar syndrome (77%, 0%, and 0%; p < 0.0001) and dizziness (50%, 0%, and 0%; p < 0.0001). Cluster 3 included patients with delirium (36%, 0%, and 9%; p < 0.0001), obtundation (58%, 0%, and 24%; p < 0.0001), and seizure (36%, 0%, and 14%; p < 0.0001). Acute kidney injury was 32%, 68%, and 77%, in clusters 1, 2, and 3, respectively (p < 0.0001). The three clusters did not differ for other biological or brain imaging. After a median follow-up of 34 months (12-71 mo), 100 patients (93%) were alive with full neurocognitive recovery (i.e., Glasgow Outcome Scale score 5) in 89 patients (89%). Patients from cluster 1 more frequently exhibited full recovery (Glasgow Outcome Scale score of 5) compared with clusters 2 and 3, (44 [98%], 13 [65%], and 21 [60%] at 3 mo; p < 0.0001), (44 [100%], 15 [68%], and 23 [69%] at 6 mo; p < 0.0001), and (40 [100%], 15 [79%], and 20 [57%] at 1 yr; p < 0.0001)., Conclusions: Initial clinical neurologic evaluation in thrombocytopenic purpura patients distinguishes three groups of patients with different clinical and functional outcomes., Competing Interests: Dr. Zafrani’s institution received funding from a grant from Jazz Pharmaceuticals. Drs. Valade, Darmon, and Azoulay received funding from Gilead. Drs. Valade and Azoulay received funding from Pfizer and Sanofi. Dr. Darmon received funding from MSD and Astelas. Dr. Azoulay’s institution received funding from Fisher & Payckle, Gilead, and Pfizer; he received funding from Baxter and Alexion. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Plasma exchange (PEX) using fresh frozen plasma has considerably reduced the mortality rate in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP). However, some patients still do not survive even with treatment, but little information is available regarding which treatment these patients received. This study was conducted to obtain this information in 240 patients who met the current iTTP diagnostic criteria and completed at least 30 days of follow-up except for deceased cases. These patients were divided into three groups: survivors (n = 195), TTP-related deaths (n = 32), and other cause of death (n = 13). In the TTP-related death group, 26 of 32 patients experienced sudden death, mostly following radical hypotension and bradycardia. The median follow-up time after admission was 5.0 days, and the median number of PEX sessions was 2.5. Nine patients underwent autopsy and had cardiac microvascular thrombi in arterioles. Levels of lactate dehydrogenase, total bilirubin, serum creatinine, and D-dimer were significantly higher in the TTP-related death group than in the survivors group. Frequent PEX (> 20 sessions) was not associated with TTP-related death. In the acute phase of iTTP, patients with substantial organ damage caused by microthrombi have a greater mortality risk, even after just a few PEX sessions., (© 2021. Japanese Society of Hematology.)

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by the presence of anti-ADAMTS13 autoantibodies. Achieving accurate information on incidence and customary disease management is important to provide appropriate diagnostic and therapeutic resources. The aim of this study was to determine the incidence and outcomes of iTTP in Spain., Study Design and Methods: A cross-sectional survey was carried out among Spanish hospitals, focused on iTTP patients ≥16 years old attended between 2015 and 2017, and those at follow-up before that interval. Incidence, prevalence, mortality, refractoriness, exacerbations, treatment complications, relapses, and sequelae were estimated., Results: Forty-two hospitals covering roughly 20 million inhabitants answered the survey and reported 203 episodes (138 newly-diagnosed and 65 relapses), of which 193 (95.1%) were treated. Incidence was 2.67 (95% CI 1.90-3.45) patients per million inhabitants per year and prevalence 21.44 (95% CI% 19.10-23.73) patients per million inhabitants. At diagnosis, ADAMTS13 activity and anti-ADAMTS13 autoantibody were measured in 97% and 84.3% of reported episodes, respectively. Fifteen patients (7.4%) died as a direct consequence of iTTP, 6 of them before receiving any iTTP-specific treatment. Thirty-one (16.1%) of the 193 treated episodes were refractory to plasma exchange and corticosteroids, and 51 (26.4%) suffered at least one exacerbation., Conclusion: iTTP incidence and prevalence were somewhat higher than those documented in neighboring countries. Together with data on treatments and outcomes, this information will allow us to better estimate what is needed to improve diagnosis and prognosis of iTTP patients in Spain., (© 2021 Wiley Periodicals LLC.)

Congenital thrombotic thrombocytopenic purpura (cTTP), known as Upshaw-Schulman syndrome, is an ultrarare thrombotic disorder caused by ADAMTS13 gene mutations; however, its long-term outcomes have not been widely studied. A questionnaire survey was administered to physicians of patients in the Japanese cTTP registry to characterise these outcomes. We analysed 55 patients in remission, with 41 cases receiving prophylactic fresh frozen plasma (FFP; median dosage: 13·2 ml/kg per month) and 14 receiving on-demand FFP. Patients receiving prophylactic FFP were considered as having a more severe form of the disease and had lower platelet counts and higher serum creatinine levels than those receiving on-demand FFP (median 138 × 10 9 /l vs. 243 × 10 9 /l, P = 0·003 and 0·71 mg/dl vs 0·58 mg/dl, P = 0·009, respectively). Patients who received prophylactic FFP more commonly developed organ damage, including renal impairment, cerebral infarctions, and cardiac hypofunction, than those who did not. Adverse FFP-related events were seen in 78% of the prophylactic FFP group, with allergic reactions being most common. Since current protocols for FFP administration to the prophylactic FFP group in Japan may be insufficient for preventing cumulative organ damage, a higher dosage of ADAMTS13 supply using recombinant ADAMTS13 agent is needed in these patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in patients with hTTP is largely lacking. This study reports prospective data on 87 patients from the Hereditary TTP Registry (clinicaltrials.gov #NCT01257269) for survival, frequency, and severity of acute episodes from enrollment until December 2019. The 87 patients, followed up for a median of 4.2 years (range, 0.01-15 years), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and 18 years (range, 0.0-70 years for both), respectively. Forty-three patients received regular plasma prophylaxis, whereas 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes, of which 91 (69%) occurred in patients receiving regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95% confidence interval [CI], 0.29-0.44) with regular plasma treatment and of 0.41 (95% CI, 0.30-0.56) without regular plasma treatment. More than one-third of acute episodes (n = 51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients aged >40 years (1.18 [95% CI, 0.88-1.55] vs 0.14 [95% CI, 0.08-0.23]). The prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, and caregivers, patients, and their guardians are reluctant to start regular plasma infusions, from which children particularly would benefit., (© 2021 by The American Society of Hematology.)

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally., (© 2021 by The American Society of Hematology.)

Introduction: Thrombotic microangiopathies are a group of disorders that are mainly related to endothelial dysfunction. This category of endothelial dysfunction results of several imbalances between platelets, endothelium and immune system, also cytokine production., Aim of This Study: To report cases with thrombotic thrombocytopenic purpura (TTP) and COVID-19 and review COVID-19 endothelial dysfunction literature., Methods: Primary laboratory data, peripheral blood smear, ADAMTS13 antigen activity level, and antibody ordered for each of these four patients. Treatments for COVID-19 administered for all patients. Traditional treatments for TTP also were administered., Results: There were numerous schistocytes (more than 5%) in peripheral blood smears for each patient. ADAMTS13 antigen activity level was below 10%, and ADAMTS13 antibody was elevated for each patient. COVID-19 PCR was positive for all patients, and CT-Scans were indicative of the involvement of COVID-19., Conclusion: In this case series, we reported four COVID-19 patients who presented with signs and symptoms of anemia and thrombocytopenia, resulting in thrombotic thrombocytopenic purpura., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare but severe disease with a mortality rate of almost 100 % in the absence of adequate treatment. iTTP is caused by a severe deficiency in ADAMTS13 activity due to the production of inhibitory antibodies. Age has been shown to be a major prognostic factor. iTTP patients in the elderly (60yo and over) have more frequent organ involvement, especially heart and kidney failures compared with younger patients. They also have non-specific neurologic symptoms leading to a delayed diagnosis. Factors influencing this impaired survival among older patients remain unknown so far. Alteration of the functional capacity of involved organs could be part of the explanation as could be the consequences of vascular aging. In fact, severe ADAMTS13 deficiency is necessary but likely not sufficient for iTTP physiopathology. A second hit leading to endothelial activation is thought to play a central role in iTTP. Interestingly, the mechanisms involved in endothelial activation may share common features with those involved in vascular aging, potentially leading to endothelial dysfunction. It could thus be interesting to better investigate the causes of mid- and long-term mortality among older iTTP patients to confirm whether inflammation and endothelial activation really impact vascular aging and long-term mortality in those patients, in addition to their presumed role at iTTP acute phase. If so, further insights into the mechanisms involved could lead to new therapeutic targets., (Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a devastating disease characterized by disseminated microvascular thrombosis. Despite pro-thrombotic predisposing conditions, the prevalence of macrovascular venous thrombosis event (VTE) in immune-mediated TTP (iTTP) has rarely been assessed., Methods: We reviewed data of all iTTP patients of the French reference Center for thrombotic microangiopathies registry prospectively enrolled through a 10-year period, between 2008 and 2018. Venous thrombosis included either thrombosis of central venous catheter, symptomatic deep venous thrombosis of the limbs or pulmonary embolism., Results: Forty-eight (12.7%) VTE were diagnosed. VTE was diagnosed after a median time of 7 [IQR, 3-16] days following the first therapeutic plasma exchange (TPE) and consisted mainly in catheter-related thrombosis (73%), and to a lesser extend symptomatic deep venous thrombosis (16%), proximal pulmonary embolism (8%) and splanchnic vein thrombosis (2%). Cases with VTE (VTE+ cases), required more TPE to achieve remission (P < 0.01), and the total volume of plasma required to achieve remission was larger (P < 0.01) than for VTE- cases. There was also a trend for more rituximab use in the VTE+ cases as compared to the VTE- cases (47% vs 33%; respectively; P = 0.07). Curative anticoagulation was started in 38 cases (79%), while 6 VTE cases did not receive any antithrombotic agents, and catheter was systematically removed when catheter-related thrombosis was diagnosed. VTE+ cases had a higher number of inserted central venous catheters than VTE- cases (P < 0.05)., Conclusion: VTE is a frequent condition occurring during iTTP management and is observed when patients require a prolonged treatment with daily TPE and multiple catheter insertions. Therapeutic strategies aimed at reducing the duration of TPE treatment in iTTP should substantially reduce this complication., (Copyright © 2020. Published by Elsevier Masson SAS.)

Introduction: Literature on epidemiology of thrombotic thrombocytopenic purpura (TTP) in the Middle East is scarce., Materials and Methods: We prospectively examined the association between infection and clinical outcomes in 44 patients with idiopathic TTP, with severely deficient ADAMTS13. We also investigated seasonality of the disease, hoping to better understand the epidemiology of idiopathic TTP., Results: Summer demonstrated significantly lower incidence for idiopathic TTP, compared with other seasons P = 0.0003. Fourteen patients had 15 episodes with a suspected concomitant infection. Five initial episodes were triggered by an infection (33.3 %), all presenting in winter, six episodes were associated with an exacerbation (40 %) and infection triggered a relapse in the other four episodes (26.7 %), with 2 episodes presenting in winter. TTP associated infections included: central line infection, urinary tract infection and post-operative infection. One patient had respiratory tract infection, on both his initial and relapsing episodes. Refractoriness to treatment was demonstrated in 4 patients (28.6 %) and it was associated with dental abscess (one patient), septic shock (one patient) and Mycoplasma pneumonia (2 patients). All 4 patients had markedly elevated CRP values with a median of 335 mg/L., Conclusion: Most of the infection associated episodes developed in winter (77.8 %). In patients with idiopathic TTP refractory to conventional treatment, infection should be seriously considered as an additional contributing factor for their initial and /or recurrent episodes, particularly when CRP is markedly elevated., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Arterial thromboembolic events are relatively common and well-described in patients with thrombotic thrombocytopenic purpura (TTP). However, the literature describing venous thromboembolism (VTE) in TTP is scarce., Methods: Single-institution retrospective chart review was conducted in TTP patients over a 10-year period to describe the point prevalence of VTE. Data were analyzed using descriptive statistics., Results: We identified 77 consecutive patients with 123 episodes of TTP. Of these patients, 14 (18%) experienced 16 VTEs (6 pulmonary embolisms, 6 deep vein thromboses, 4 superficial vein thromboses [SVT]). Excluding SVT, the point prevalence of VTE was 14%. All were acute and associated with admission for acute TTP. All patients were treated with plasma exchange (PLEX); 6/8 patients on concurrent PLEX at VTE diagnosis were exchanged with solvent-detergent plasma (SDP). Platelet and lactate dehydrogenase levels at time of VTE diagnosis had largely normalized from presentation values (median 175 × 10 9  U/L [interquartile range 130.75, 250] and 232 U/L [interquartile range 178.75, 263.5], respectively). Most VTEs (9/16) occurred while patients were not on pharmacologic thromboprophylaxis. All but one VTE was treated with anticoagulation. No VTEs were fatal or massive., Conclusions: Our data provide additional evidence that TTP patients may be at risk for VTE. It is possible that SDP exerted a prothrombotic effect. TTP-associated VTEs may be pathophysiologically distinct from arterial thromboses because they occur following hematological recovery. VTE thromboprophylaxis was not commonly used. Our findings suggest the need to implement VTE thromboprophylaxis earlier in hospitalized patients with TTP., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by inactivation of ADAMTS13. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia. Previous studies have produced conflicting data regarding seasonal association of TTP diagnoses. This study evaluated the seasonal distribution of acute TTP in southern Louisiana. Additionally, this study timeline overlapped with the initiation of a new screening protocol for ADAMTS13 testing., Study Design and Methods: A retrospective analysis of patients receiving ADAMTS13 testing at Ochsner Medical Center from January 2010 to December 2017 was performed. TTP patient episodes were defined by ADAMTS13 activity <10%. Episodes were plotted according to season of presentation and a chi-square analysis was performed. Data of identified TTP patients was analyzed to evaluate for confounding variables. ADAMTS13 order volumes and results before and after screening protocol implementation were compared., Results: Two hundred and fifty-two ADAMTS13 tests were ordered on 245 unique patients. Twenty-five patients had ADAMTS13 activity <10%. No significant differences in seasonal TTP case distribution were identified. Patients with confirmed TTP were younger and more likely to be Black or African American. A screening protocol did not decrease the number of annual ADAMTS13 test orders in our time frame, but was associated with a nonsignificant increase in the percentage of positive results., Conclusion: No significant seasonal distribution of TTP was identified in our population. This analysis provides previously unexamined regional information regarding this diagnosis. The number of tests ordered after the implementation of the screening protocol increased, corresponding with our facility's expanding reach., (© 2020 Wiley Periodicals, Inc.)

Thrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. The disease is caused by a severe deficiency of the enzyme ADAMTS13 ( a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 ), which can either be acquired, mainly by autoantibodies targeting ADAMTS13, or congenital due to mutations in the ADAMTS13 gene. Thanks to the establishment of national registries worldwide, fundamental and translational research, major advances have been made on the diagnosis, treatment, and fundamental understanding of TTP, since the description of the first TTP case almost 100 years ago. The introduction of therapeutic plasma exchange in the 1970s has significantly improved patient survival, but novel diagnostic assays, targeted treatments (rituximab, caplacizumab, recombinant ADAMTS13), and the unraveling of both ADAMTS13 function and TTP pathophysiology should help to further improve the patients' quality of life. However, differential diagnosis of TTP remains challenging and still a lot of questions remain unanswered to completely understand this rare and devastating disease., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Despite proven efficacy and increased availability of therapeutic plasma exchange, thrombotic thrombocytopenic purpura (TTP) is associated with significant morbidity and mortality., Study Design and Methods: This study utilized the Kids' Inpatient Database and National Inpatient Sample (2003 to 2016) to study predictors of in-hospital mortality in hospitalized TTP patients. Adjusted odds ratios of death with various putative risk factors were calculated using multiple regression analysis., Results: Among 1568 hospitalizations with TTP as primary admission diagnosis who underwent therapeutic plasma exchange, 69 deaths were identified (all-cause mortality, 0.04%; median time-to-death, 6 wk). Overall, hospitalizations rates were fairly similar across the study period. The overall incidence of TTP related hospitalizations is 1.51 per 100,000 hospitalizations. A total of 69 deaths were reported with an all-cause in-hospital mortality rate of 0.04% (69/1568). The median time-to-death was 6 weeks. The majority of deaths occurred in age 16 to 20 years (58%), females (56.5%), and African American (42.9%) as shown in Table 2. Mean age for nonsurvivors was 14 years and the mean age of 15 years for survivors (P=0.01). Younger age, male sex, African-American ethnicity, malignancy, sepsis, acute kidney injury, platelet transfusion was significantly associated with mortality in patients with TTP., Conclusions: Early and targeted therapy for high risk individuals should be used to guide management of TTP patients for improved survival outcomes.

Neurological symptoms related to microthrombosis are the hallmark of acute manifestations of acquired thrombotic thrombocytopenic purpura (TTP). Despite the achievement of hematological remission, patients may report persisting neurological impairment that affects their quality of life. To assess the long-term neuropsychological consequences of acute TTP, we recruited 35 acquired TTP patients (77% females, median age at onset 41 years, interquartile range: 35-48) regularly followed at our out-patient clinic of thrombotic microangiopathies in Milan (Italy) from December 2015 to October 2016. Patients underwent a psychological evaluation of memory and attentional functions, emotional wellbeing and health-related quality of life at least three months after their last acute TTP event (median 36 months, interquartile range: 17-54). During the psychological consultation, 17 patients (49%) referred persisting subjective neurological impairment in the frame of a remission phase, with at least one symptom as disorientation, loss of concentration, dizziness, lack of balance, headache and diplopia. Neuropsychological assessment revealed lower scores than the Italian general population pertaining to direct, indirect and deferred memory. A higher degree of impairment of memory domains was found in patients with neurological involvement at the time of presentation of the first acute TTP episode. Anxiety and depression were detected in seven (20%) and 15 (43%) patients, respectively. Health-related quality of life was lower than the Italian general population, with mental domains more impacted than physical domains (mean difference 58.43, 95% confidence interval: 71.49-45.37). Our study demonstrates compromised memory and attention functions, persisting anxiety/depression symptoms and a generally reduced quality of life in patients recovering from acute acquired TTP. New clinical strategies should be considered to improve these symptoms., (Copyright© 2020 Ferrata Storti Foundation.)

Background: The prevalence of older patients with acquired thrombotic thrombocytopenic purpura (TTP) is increasing. There is scarce information on the prevalence of multimorbidity, polypharmacy and age-related diseases in aging TTP patients. This study aimed to evaluate the prevalence of multimorbidity and polypharmacy in a population of acquired TTP patients aged 65 years or more compared with a group of age-matched controls., Methods: Acquired TTP patients enrolled in the Milan TTP registry from December 1st 1999 to March 31th 2018 and aged 65 years or more at the date of last follow-up were evaluated. Controls were Italian healthy individuals recruited from 2006 to March 31th 2018 among friends and non-consanguineous relatives of patients tested for thrombophilia screening at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan., Results: 36 TTP patients and 127 age-matched controls were included. Compared with controls, TTP patients had a higher prevalence of multimorbidity and polypharmacy. They also showed a higher prevalence of autoimmune diseases, osteoporosis and arterial hypertension and were more chronically treated with corticosteroids and antiplatelets for primary cardiovascular prevention. All these results were confirmed after adjusting for sex. Compared with the general elderly population, TTP patients showed a higher prevalence of ischemic heart disease and stroke., Conclusions: Our findings suggest that a careful comprehensive geriatric assessment of acquired TTP patients is necessary. It is important to look for other autoimmune diseases and such age-related comorbidities as osteoporosis, arterial hypertension, ischemic heart disease and cerebrovascular disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ilaria Mancini has received honoraria for participating as a speaker at an educational meeting organized by Instrumentation Laboratory and for participating to a Sanofi advisory board meeting. Barbara Ferrari has received honoraria for participating to a Sanofi advisory board meeting. Flora Peyvandi has received honoraria for participating to advisory board meetings organized by Takeda, Sobi, Grifols, Spark, Sanofi, Roche and Bioverativ. The other authors do not have any conflict of interest to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare life-threatening thrombotic microangiopathy (TMA) affecting more frequently women of 30-50 years of age. There is scarce information on the clinical features of aTTP occurring in the elderly. Our goal was to evaluate the impact of an elderly-onset disease on the expression, severity and management of aTTP., Materials and Methods: We performed a cross-sectional study of patients enrolled in the Milan TTP Registry (www.ttpdatabase.org) after a first acute episode of aTTP from January 2002 to March 2018. The aTTP diagnosis was suspected on the basis of the presence of thrombocytopenia and microangiopathic hemolytic anemia with no alternative causes, and was confirmed centrally by a severe plasma deficiency of ADAMTS13 activity (<10%). Triggers, clinical manifestations, laboratory parameters, management and outcome of the first acute events of elderly-onset aTTP patients (≥65 years) were compared with those of younger patients., Results: Among 143 eligible patients, 16 (11%) were elderly at onset. In comparison with younger cases they showed a lower rate of bleeding symptoms and severe anemia (30% and 18%), with a trend towards a higher rate of neurological and renal signs and symptoms. These patients were less frequently treated with plasma exchange and corticosteroids and more often with plasma infusion. No difference for gender, triggers and episode outcomes was observed., Conclusions: Older patients with aTTP differed from younger patients mainly for being treated less frequently with plasma exchange and corticosteroids, perhaps for the perceived risks associated with these treatments in the elderly., Competing Interests: Declaration of competing interest Ilaria Mancini and Barbara Ferrari have participated to a Sanofi advisory board meeting. Flora Peyvandi has received honoraria for participating as a speaker at satellite symposia and educational meetings organized by Ablynx, Grifols, Novo Nordisk, Roche, Shire and Sobi, and she is a member of the scientific advisory board of Ablynx. The other authors do not have any conflict of interest to disclose., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Acquired thrombotic thrombocytopenic Purpura (aTTP) is a life-threatening ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million in Europe and mainly affecting otherwise young and healthy adults aged 40 years on average. The goal of this study was to assess the incidence of aTTP in Germany., Methods: A systematic review was performed to determine the published evidence on the aTTP epidemiology in Germany. To obtain additional evidence on the proportion of aTTP cases within the national Thrombotic Microangiopathy (TMA) population a hospital-level study was performed, using a retrospective data collection approach. Diagnosis of aTTP was confirmed if ADAMTS13 level were < 10% and/or the medical records explicitly mentioned aTTP diagnosis. The aggregated hospital data were then projected to the national level using logistic regression techniques., Results: The systematic literature search did not provide incidence estimates of aTTP in Germany. Eight centers (≈27% of the top 30 TMA hospitals) delivered data according to a predefined data collection form. On average (year 2014-2016) a total number of 172 aTTP episodes per year was projected (95% confidence interval [95%CI]: 132-212). The majority were newly diagnosed aTTP cases (n = 121; 95%CI: 105-129), and 51 were recurrent aTTP cases (95%CI: 27-84). The average annual projected incidence (year 2014-2016) of aTTP episodes was 2.10 per million inhabitants in Germany (95%CI: 1.60-2.58)., Conclusions: The determined annual incidence of newly diagnosed aTTP cases and the overall annual incidence of aTTP episodes in Germany confirm the ultra-orphan character of aTTP. An external validation against international registries (France, UK and USA) shows that our findings are quite comparable with those international incidence rates.

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by the immune-mediated severe deficiency of ADAMTS13. We hereby report the demographic and disease-related data of acquired TTP patients recorded in the Milan TTP Registry (www.ttpdatabase.org). We performed a cross-sectional study of 302 individuals enrolled in our registry for an acute episode of acquired TTP occurred between 2002 and 2015 (female 77%; median age at onset 40 years, interquartile range: 30-50). Twenty per cent of patients had concomitant autoimmune disorders. Among potential triggers of acute episodes, infections were the most prevalent (27%), followed by estroprogestinics use and pregnancy (5 and 4% of women, respectively). At presentation, systemic (72%), bleeding (68%) and neurological (43%) symptoms were the most frequent, whereas a lower prevalence of renal (18%) and cardiovascular (10%) signs and symptoms was observed. Almost all acute events were treated by plasma exchange and steroids, and 15% by rituximab. Exacerbation of acute TTP occurred in 15% of events. The TTP-related mortality was 5%. In survivors, the median number of plasma exchange procedures to remission was 9 (interquartile range: 6-14), longer for first events than relapses (median difference 3, 95% confidence interval: 2-4). Of 251 survivors of the first TTP episode with at least a 6-month follow-up, 55% had a relapse. In conclusion, acquired TTP is a severe disease with highly variable clinical presentation, usually requiring a long hospitalization. The Milan TTP Registry represents a powerful tool to improve our knowledge and management of acquired TTP., Competing Interests: I. Mancini and B. Ferrari have participated to a Sanofi advisory board meeting. R. Palla has received travel support from Grifols and Pfizer. F. Peyvandi has received honoraria for participating as a speaker at satellite symposia and educational meetings organized by Ablynx, Grifols, Novo Nordisk, Roche, Shire and Sobi. She has received consulting fees from Kedrion. She is member of the scientific advisory board of Ablynx. V. Agostini has received honoraria for participating as a speaker at educational meetings organized by CSL Behring and is a member of the Ablynx and Werfen-IL scientific advisory board. U. Roncarati is a member of the Ablynx scientific advisory board. The other authors do not have any conflict of interests to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

Acquired autoimmune thrombotic thrombocytopenic purpura (TTP)-the most common form of TTP-is a life-threatening hematologic disease characterized by hemolytic anemia and thrombocytopenia. Acquired autoimmune TTP can cause signs and symptoms of neurologic and other organ involvement, with mortality approaching 90% if the disease is not promptly recognized and treated. Since the introduction of plasma exchange in 1991, the acquired autoimmune TTP survival rate has increased to 78%.

Background: The recently published PLASMIC score was shown to be an excellent diagnostic model to identify patients with severe ADAMTS-13 deficiency. However, it is unclear if this score is suitable for Chinese patients with suspected thrombotic thrombocytopenic purpura (TTP)., Methods: We retrospectively studied a Chinese cohort of 134 consecutively hospitalized patients with thrombotic microangiopathy, ADAMTS-13 test results, and clinical information between January 2015 and June 2018, the PLASMIC score's distinguishing ability in this cohort was evaluated. We also combined the lactate dehydrogenase (LDH)-to-aspartate aminotransferase (AST) ratio with the PLASMIC score to determine its predictive value for TTP in pregnancy., Results: In this Chinese cohort, 39 patients were diagnosed with TTP using ADAMTS13 testing. When stratified at high (score, 6-7) vs. low-intermediate (score, 0-5) risk, the PLASMIC test predicted TTP with a positive predictive value of 51%, negative predictive value of 92%, sensitivity of 85%, and specificity of 58%. In pregnant patients, a combination of the PLASMIC score of 6-7 and LDH-to-AST ratio of ≥5.5 showed a higher positive predictive value for TTP compared with the PLASMIC score alone (71% vs. 35%, P < 0.001). Removing the component MCV < 90 fL from the PLASMIC score did not reduce its distinguishing power, as measured using the C statistic (0.837, 95%CI 0.767-0.907 vs. 0.797, 95%CI 0.718-0.877; P = 0.771)., Conclusions: Combination with a higher LDH-to-AST ratio improves the positive predictive value of the PLASMIC score in pregnant patients. A simpler score without MCV < 90 fL can be used to identify TTP in Chinese patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.

Background:  Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw-Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 ( ADAMTS13 ) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer-CUB interaction is abrogated when ADAMTS13 is conformationally activated., Objective:  This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS., Patients and Methods:  All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS., Results:  Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations ( n  = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations ( n  = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation., Conclusion:  In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation., Competing Interests: B.S.J. received the MaRIH award from Alexion. P.C. is a member of the Advisory boards for Ablynx, Alexion, Octapharma and Cerus. A.V. and K.V. are members of the Advisory board for Ablynx. All other authors declare no competing financial interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Thrombotic microangiopathies (TMAs) are associated with microangiopathic hemolytic anemia and thrombocytopenia, resulting in microvascular thrombosis and end-organ damage. In pregnancy, this may be the result of pregnancy-related TMAs such as preeclampsia; hemolysis, elevated liver enzymes, and low platelets; or pregnancy-associated TMAs, specifically thrombotic thrombocytopenic purpura (TTP) or complement-mediated hemolytic uremic syndrome (CM HUS). TTP and CM HUS are rare disorders, and their diagnosis may be missed, no less because features at presentation may be misdiagnosed as a pregnancy-related TMA, such as hypertension, proteinuria, fetal growth restriction, or in utero fetal death. The mainstay of treatment for pregnancy-associated TMAs is plasma exchange. Presentation is likely in the third trimester for TTP and postpartum for CM HUS. However, both conditions can present in any trimester, unlike pregnancy-related TMAs which rarely present before the second trimester, commonly in the third trimester. Delivery is the mainstay of treatment for pregnancy-related TMAs. More recently, it has become clear that pregnancy may be a trigger for late-onset congenital TTP, as well as immune-mediated TTP, diagnosed by ADAMTS13 analysis. Complement inhibitor therapy is the treatment of choice for CM HUS cases. However, their diagnosis is by exclusion, but complement inhibitor therapy reduces the risk of end-stage renal failure. Subsequent pregnancies can be supported for TTP and CM HUS., (Copyright © 2018. Published by Elsevier Inc.)

This open-label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30-minute intravenous infusion on Days 1, 8 and 15 in a 28-day cycle starting at 20 mg/m 2 on Day 1/Cycle 1 and 70 mg/m 2 thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1-9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4-8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose-limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6-97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m 2 was well-tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy-related events and efficacy., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)