Influence of personality, resilience and life conditions on depression and anxiety in 104 patients having survived acute autoimmune thrombotic thrombocytopenic purpura

Autoimmune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening, relapsing disease in which an acquired deficiency of the enzyme ADAMTS13 leads to generalised microvascular thrombosis. Survivors have a high prevalence of depression and impaired cognitive function. The aim of this study was to determine whether life circumstances and personality have an influence on the development and severity of depression and anxiety in iTTP patients and how they impact the quality of life. With validated questionnaires, we examined the prevalence of depression and anxiety symptoms in 104 iTTP patients, as well as parameters of subjective cognitive deficits, quality of life, attitude to life and resilience. iTTP patients had significantly more depressive symptoms (p p = 0.035) and a significantly worse cognitive performance (p = 0.008) compared to the controls. Sex, age, physical activity and partnership status had no significant influence on depression, whereas the number of comorbidities did. Lower scores of resilience, attitude to life and quality of life were reported by patients compared to controls. iTTP patients had a high prevalence of depression and anxiety, as well as a more negative attitude to life and low resilience. Resilience correlated negatively with the severity of the depression. Furthermore, quality of life and cognitive performance were significantly reduced

BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT0097415

Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19

Background Coronavirus disease 19 (COVID-19)–associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome—microvascular thrombosis, stroke, and venous and pulmonary clots—are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven. Objectives To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients. Methods Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome–coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19. Results We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA. Conclusions COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19–associated coagulopathy

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Influence of Personality, Resilience and Life Conditions on Depression and Anxiety in 104 Patients Having Survived Acute Autoimmune Thrombotic Thrombocytopenic Purpura

Autoimmune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening, relapsing disease in which an acquired deficiency of the enzyme ADAMTS13 leads to generalised microvascular thrombosis. Survivors have a high prevalence of depression and impaired cognitive function. The aim of this study was to determine whether life circumstances and personality have an influence on the development and severity of depression and anxiety in iTTP patients and how they impact the quality of life. With validated questionnaires, we examined the prevalence of depression and anxiety symptoms in 104 iTTP patients, as well as parameters of subjective cognitive deficits, quality of life, attitude to life and resilience. iTTP patients had significantly more depressive symptoms (p < 0.001), a tendency to have anxiety disorders (p = 0.035) and a significantly worse cognitive performance (p = 0.008) compared to the controls. Sex, age, physical activity and partnership status had no significant influence on depression, whereas the number of comorbidities did. Lower scores of resilience, attitude to life and quality of life were reported by patients compared to controls. iTTP patients had a high prevalence of depression and anxiety, as well as a more negative attitude to life and low resilience. Resilience correlated negatively with the severity of the depression. Furthermore, quality of life and cognitive performance were significantly reduced

No Evidence for Classic Thrombotic Microangiopathy in COVID-19

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Results: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient

Untersuchungen über ADAMTS13 in Gerinnungsfaktorpräparaten

Zusammenfassung rnIn der vorliegenden Arbeit wurden sechs VWF/FVIII Gerinnungsfaktorkonzentrate unterschiedlicher Chargen auf ihre ADAMTS13 Aktivität, Antigen und VWF Multimere untersucht. Grund dafür ist die Annahme, dass bei der Aufkonzentrierung des VWFs möglicherweise auch erhöhte Mengen an ADAMTS13 vorhanden sind. Wäre dies nachweisbar, könnten die entsprechenden Konzentrate auch Anwendung bei TTP Patienten finden. Neben den Gerinnungsfaktorkonzentraten wurden ebenfalls die zur Plasmapherese verwendeten Therapeutika FFP und s/d Plasma analysiert. Es soll getestet werden, ob Unterschiede hinsichtlich der Qualität zwischen den Präparaten bestehen und inwiefern die Blutgruppen eine Auswirkung auf die ADAMTS13 Aktivität/Antigen haben. Überdies wurde die Bedeutung von ADAMTS13 als wichtiges diagnostisches Merkmal im Rahmen der Gegenüberstellung von Patienten mit thrombotischen Mikroangiopathien erörtert. Alle angewandten Methoden wurden zudem kritisch miteinander verglichen und auf ihre Eignung für die klinische Diagnostik getestet. Zur Untersuchung der ADAMTS13 Aktivität kamen drei unterschiedliche Methoden zur Anwendung, die BCS-Methode nach Böhm und zwei FRET Kits ( Technozym®ADAMTS13/ActifluorTMADAMTS13). Für die Bestimmung des ADAMTS13 Antigen wurde das Technozym®ADAMTS13 Kit verwendete als auch der Imubind®ELISA angewendet. Mittels der SDS-Gelelektrophorese konnten die VWF Multimere dargestellt werden. Die Untersuchungen konnten zeigen, dass nur in Haemate®P, deutlich höhere ADAMTS13 Aktivitäten (12,3% bzw. 470ng/ml) sowie ein physiologische Antigenwerte vorlagen. Die anderen Faktorkonzentrate wiesen entweder nur sehr geringe bzw. keine Aktivitäten auf. Das Antigen lag bei allen Konzentraten im nachweisbaren Bereich. Folglich ist ein Einsatz von Haemate®P bei der Therapie der TTP, insbesondere bei hereditären Formen sowie bei Kindern, die durch eine Plasmapherese stark belastet werden, und bei Schwangeren, könnten, in Erwägung zu ziehen und innerhalb der Klinik zu testen. Die Plasmapräparate FFP und Octaplas® wiesen in allen Untersuchungen ADAMTS13 Aktivitäten und Antigen im mittleren bis hohen physiologischen Bereich auf. Insbesondere bei Blutgruppe 0 ließ sich beiden Präparaten eine höhere ADAMTS13 Aktivität und Antigen gegenüber den drei anderen Blutgruppen darstellen. Insgesamt waren die interindividuellen Schwankungen bei FFP deutlich höher als bei Octaplas®, was sich in der unterschiedlichen Herstellung der Präparate begründen lässt. Octaplas® ist also genauso geeignet zur Plasmapherese bei der TTP wie FFP, kann jedoch aufgrund seiner intensiveren Virusinaktivierung eine größere Sicherheit aufweisen und stellt sich auch in der Klinik als nebenwirkungsärmer dar. Bei der Gegenüberstellung der thrombotischen Mikroangiopathien konnte gezeigt werden, dass eine verminderte ADAMTS13 Aktivität ein wichtiges Unterscheidungsmerkmal ist und auch während der Remission schon diagnostizierbar werden kann. Auf der Grundlage der labordiagnostischen Werte und dem klinischen Erscheinungsbild im akuten Schub und in der Remission konnte ein diagnostischer Algorithmus für den klinischen Alltag erstellt werden. In der Methodenvalidierung erwies sich der ActifluorTMADAMTS13 Kit als der beste Kit, da er innerhalb kürzester Zeit zuverlässige Werte in Standardeinheiten liefert. Nach neuesten Erkenntnissen, bei der eine Unterscheidung von ADAMTS13 Aktivitäten über und unter 5 % von großer prognostischer Bedeutung sind, ist die BCS-Methode nach Böhm mit einer unteren Nachweisgrenze von 6,2% zu ungenau und auch hinsichtlich ihres Zeitaufwandes eher ungünstig.rnSummary rnIn 1996 Furlan et al. and Tsai discovered both coincidentally the protease ADAMTS13 during their studies on the disease of TTP. A low activity or the total absence of this protein is the cause of TTP. Whereas slightly low activity of ADAMTS13 is discussed to be the reason of juvenile strokes and cardiovascular incidences. We investigated ADAMTS13 acitivity, antigen and VWF multimere in six VWF/FVIII blood clotting factors concentrates. The underlying hypothesis states that the manufacturing process of VWF concentrates also increases ADAMTS13. We also investigated FFP and s/d plasma. Additionally this testing can show differences in quality of the compounds as well as the impact of different blood types on ADAMTS13 activity and antigen. ADAMTS13 was tested as a diagnostic sign for patients with thrombotic microangiopathies. Due to this an algorithm was found for patients who suffer HUS; TTP-like syndromes and TTP with and without antibodies. All methods for measurements are proved on critically as well as the comparison to each other and the suitability for diagnostics in everyday life. For ADAMTS13 activity measurement BCS-Method according to Boehm two fluorescence resonance energy transfer methods (Technozym®ADAMTS13 / ActiflourTMADAMTS13) were used. ADAMTS13 antigen was detected with Technozym®ADAMT13 and Imubind®ELISA. By using SDS gel electrophoresis VWF multimers were detected. The research proved that only Haemate®P has a higher activity of ADAMST13 (12,3% / 470ng/ml) and it also has an physiologic antigen. In the other factor concentrates only the antigen could be detected. Using the gel electrophoresis one could find the typical triplet structure of VWF and UL VWF multimers. There was no prove of ADAMTS13 antibodies. Haemate®P is the only concentrate which can probably be tested in the diagnostics and therapy of TTP. Haemate®P could be used for children, who suffer under the procedure of plasmapheresis or during pregnancy. FFP and Octaplas® showed in all examinations ADAMTS13 activity in an average to high amount. Octaplas® was slightly higher. FFP was able to be measured three very low mean values out of four blood types. Also a difference within blood types concerning the activity of ADAMS13 and its antigen could be found. Especially type 0 shows a higher activity and more antigens than the other blood types. The fluctuations between individuals by using FFB were higher than with Octaplas®. The reason can be explain in the manufacturing process of making the preparations. UL VWF multimers could be found in every sample and in different concentrations. Octaplas® is as suitable for the treatment of TTP as FFP. It stands out by less side effects and lower risks of viruses transmitted diseases. ADAMTS13 is an important distinguishing feature for the diagnosis of thrombotic microangopathies. Based on the diagnostic parameters and clinical features an algorithm could be established in which ADAMTS13 activity and UL VWF multimers are the key issue. Little time consumption and standard units waited Actifluor®ADAMTS13 as the best assay for laboratory work. According to recent findings the BCS-Method becomes too imprecise when the ADAMTS13 activity differs more than 5 %. The detection limit is 6.2 %, which is very poor and it takes too much time.rnr

Thrombotische Mikroangiopathien, speziell die thrombotisch thrombozytopenische Purpura und die Metalloprotease ADAMTS13

Im Rahmen dieser Habilitationsschrift wurde der Krankheitsverlauf der iTTP am damals größten in Deutschland existierenden Patientenkollektiv in retrospektiven und prospektiven Studien untersucht. Kernergebnisse unserer Studien sind: Die iTTP ist keine rein akute Erkrankung, sondern eine chronische Erkrankung mit potentiell schweren Langzeitfolgen. Patienten sind nachhaltig in ihrem Leben belastet und eingeschränkt. Folglich bedürfen sie neben der Akutbehandlung einer längerfristigen Nachsorge. Vor allem leiden die Patienten unter zum Teil schweren Depressionen und Angstzuständen. Darüber hinaus weisen iTTP-Patienten eine verminderte kognitive Leistungsfähigkeit gegenüber Gesunden auf, deren Ausmaß signifikant mit der Schwere der Depression korreliert. Interessanterweise ist kein Zusammenhang zwischen der Entwicklung von Depressionen und der Schwere sowie der Anzahl der akuten Schübe nachweisbar. Des Weiteren ist die Resilienz der iTTP-Patienten geringer ausgeprägt als die von Gesunden und die Lebensqualität, sowie die Lebenseinstellung, nachhaltig schlechter. Retrospektiv wie prospektiv wurde die Pathophysiologie der iTTP verfolgt. Die Studiendaten beweisen, dass ein akuter iTTP Schub zwingend mit einem massiven Abfall bzw. einer deutlich verminderten ADAMTS13-Aktivität (<10%) einhergeht. Allerdings ist auch ersichtlich, dass Patienten mit konstant niedrigem ADAMTS13 nicht zwingend einen Schub erleiden. Das Substrat der ADAMTS13, der VWF, welcher in diesem Zusammenhang relativ wenig untersucht ist, muss mehr im Blickpunkt stehen. Im Rahmen der Originalarbeit VI konnte eine neue VWF Multimer Ratio etabliert werden. Das Verhältnis zwischen hochmolekularen zu niedermolekularen VWF Multimeren spiegelt das in vivo bestehende Zusammenspiel zwischen ADAMTS13 und dem VWF wider. Vor akuten Schüben verschiebt sich der Anteil der VWF Multimeren zu den hochmolekularen, folglich steigt der Quotient an. Zu Beginn des Schubes fällt er deutlich ab, was auf den Verbrauch in den Mikrothromben zurückzuführen ist. Überraschend ist, dass einige Tage bis Wochen vor einem akuten iTTP-Rezidiv eine signifikant höhere VWF MM Ratio nachzuweisen war, als bei den Patienten, die sich in Remission über den ganzen Studienzeitraum befanden, und das unabhängig davon, ob die ADAMTS13-Aktivität 10% lag. Darüber hinaus war die ADAMTS13-Aktivität Tage bis Wochen vor dem akuten Schub nicht zwingend <10%. Die Hypothese, dass Entzündungen einen akuten Schub triggern, da sie die Spaltung des VWF durch ADAMTS13 vermindern, kann in diesem Fall nicht bestätigt werden. Patienten die im Beobachtungszeitraum keine akuten iTTP-Schübe hatten, haben hingegen konstante VWF MM Ratio Werte. An unserem retrospektiven Patientenkollektiv kann nicht belegt werden, dass sich die Gabe von Rituximab signifikant positiv auf die Schubschwere oder auf die Rückfallrate auswirkt. Allerdings ist ein Trend zu kürzerer Schubdauer und zu weniger Frührezidiven, binnen des ersten Jahres, nach einem akuten Schub, erkennbar. Die klinische Einteilung der Schübe nach ihrer Schwere ist an retrospektiven Patientenkollektiven etabliert worden und bestätigt die These, dass Initialschübe die schwerwiegendsten Verläufe aufweisen. Insgesamt sind Männer deutlich seltener von der iTTP betroffen, dafür legen die Daten nahe, dass sie deutlich schwerer an der Erkrankung leiden mit einer signifikant höheren Rückfallrate als Frauen. Mikrothrombosen, insbesondere im Lungenkreislauf, bei Patienten mit COVID-19, führten zur Hypothese, dass es sich hierbei um eine thrombotische Mikroangiopathie handeln könnte. Wir haben in einem Mainzer Kollektiv keinen Anhaltspunkt dafür gefunden, dass COVID-19 eine klassische thrombotische Mikroangiopathie ist.133 Seiten, Illustrationen, Diagramm