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"Weiss, Luisa"
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COVID-19 induces a hyperactive phenotype in circulating platelets
Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.
Journal Article
Increasing clinical recruitment rate to a single-site observational study: a quality improvement study
ObjectiveClinical recruitment encompasses a significant challenge in multidisciplinary research, often acting as a bottleneck to timely completion due to slower-than-expected patient enrolment rates. Addressing this, enhanced communication within clinical departments is crucial. A quality improvement (QI) study was initiated in the Mater Misericordiae University Hospital (MMUH) to increase the slow recruitment rate of cancer-associated thrombosis patients to the EXPECT Study.MethodsProcess and stakeholder mapping as well as Plan Do Study Act (PDSA) cycles highlighted effective initiatives to increase recruitment rates to the study. The PDSA cycle 1 aimed at increasing clinical communication and study education through implementation of work package-1, which included engaging a clinical project sponsor to drive recruitment and increasing study awareness through educational talks/informative materials. The PDSA cycle 2 aimed to increase process efficiency and paired sample acquisition through implementation of work package-2, which included holding weekly QI meetings, building a strong multidisciplinary QI team and mapping the recruitment process. These efforts aimed to increase recruitment from one to four patients enrolled per month, with recruitment progress tracked with a run/bar chart over a 2 year period.ResultsThe communication/education work package-1 initiatives increased the recruitment rate from one to two patients per month, with target enrolment met or exceeded 33% of the QI-project duration. Recruitment numbers nearly doubled in roughly half the timeframe, from 10 patients enrolled in the first 16 months to 18 patients enrolled in the 9 months of the QI study. Furthermore, a greater than threefold statistically significant increase in paired sample acquisition from 20% to 66% was documented following the execution of the second PDSA cycle, aimed at improving process efficiency.ConclusionsThis QI study highlights the need for a highly engaged study team, specifically the clinical project sponsor driving recruitment from a medical front-line perspective as well as a highly efficient recruitment process.
Journal Article
Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in pulmonary arterial hypertension which may provide insights into the pathobiology of the disease and opportunities to explore new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle autocrine and paracrine signalling in pulmonary arterial hypertension, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, extracellular vesicles and coagulation pathways in the pathobiology of pulmonary arterial hypertension. We highlight important unanswered clinical questions and the implications of these observations for future research and pulmonary arterial hypertension-directed therapies.
Journal Article
Unique Patterns of Circulating Extracellular Vesicles in Preterm Infants During Adaptation to Extra‐Uterine Life
There is growing interest in the role of extracellular vesicles (EVs) in neonatal pathology. This study aimed to characterise circulating EVs following preterm birth. This single‐centre prospective observational study included cord and postnatal plasma from preterm (n = 101) and full‐term infants (n = 66). EVs were analysed using nanoparticle tracking analysis, flow cytometry, proteomics and procoagulant activity assay. We found changes in the concentration, size, cellular origin and proteomic content of circulating EVs in preterm infants during perinatal adaptation. To understand if these changes were related to prematurity or normal adaptation to extrauterine life, they were also investigated in term infants. There was a dramatic increase in the concentration of small and large EVs on Day 3 in the preterm group; specific subsets of platelet (CD42b+ and CD62P+), endothelial (VEGFR2) and tissue factor EVs were elevated. Differentially expressed proteins relating to haemostasis, pulmonary physiology and immunity were identified between Day 1 and 3 in preterm infants. These changes have never previously been described in a large cohort of preterm infants and differ from healthy term infants. These findings have major implications for future neonatal EV studies, particularly the timing of sample collection. Further work is required to understand the clinical implications of this unique EV profile following preterm birth.
Journal Article
Routine Hematological Parameters May Be Predictors of COVID-19 Severity
To date, coronavirus disease 2019 (COVID-19) has affected over 100 million people globally. COVID-19 can present with a variety of different symptoms leading to manifestation of disease ranging from mild cases to a life-threatening condition requiring critical care-level support. At present, a rapid prediction of disease severity and critical care requirement in COVID-19 patients, in early stages of disease, remains an unmet challenge. Therefore, we assessed whether parameters from a routine clinical hematology workup, at the time of hospital admission, can be valuable predictors of COVID-19 severity and the requirement for critical care. Hematological data from the day of hospital admission (day of positive COVID-19 test) for patients with severe COVID-19 disease (requiring critical care during illness) and patients with non-severe disease (not requiring critical care) were acquired. The data were amalgamated and cleaned and modeling was performed. Using a decision tree model, we demonstrated that routine clinical hematology parameters are important predictors of COVID-19 severity. This proof-of-concept study shows that a combination of activated partial thromboplastin time, white cell count-to-neutrophil ratio, and platelet count can predict subsequent severity of COVID-19 with high sensitivity and specificity (area under ROC 0.9956) at the time of the patient's hospital admission. These data, pending further validation, indicate that a decision tree model with hematological parameters could potentially form the basis for a rapid risk stratification tool that predicts COVID-19 severity in hospitalized patients.
Journal Article
The effect of UVA light/8-methoxypsoralen exposure used in Extracorporeal Photopheresis treatment on platelets and extracellular vesicles
Extracorporeal Photopheresis (ECP) is a leukapheresis based treatment for Cutaneous T-Cell Lymphoma, which takes advantage of the cellular lethal effects of UVA light in combination with a photoactivated drug, 8-methoxypsoralen. 25% of patients treated with ECP do not respond to treatment, however the underlying mechanisms for this lack of response remain unknown. Platelets, a rich source of extracellular vesicles (EVs) and key mediators in thromboinflammatory oncological progression, as well as leukocytes, are both processed through ECP and are subsequently transfused back into the patient, delivering potent immunomodulation. The effect of exposing platelets and their EVs directly to Ultra Violet A light (UVA)/8-methoxypsoralen is currently unknown. Platelet-rich plasma (PRP) was isolated from healthy donors and exposed to UVA light and/or 8-methoxysporalen in vitro and platelet activation and aggregation was assessed. EV size and concentration were also characterised by Nanoparticle Tracking Analysis and Flow Cytometry. We found that UVA light and 8-methoxypsoralen treatment in vitro does not induce platelet aggregation or significantly alter levels of the platelet activation markers, soluble P-selectin or platelet factor 4, with circulating levels of small and large EV size and concentration remaining constant. Therefore, utilising the combination of UVA light and 8-methoxypsoralen used in ECP in vitro does not activate platelets or alter important circulating EVs. Further studies will be needed to validate if our observations are consistent in vivo .
Journal Article
Improving the Management of Psoriatic Arthritis and Axial Spondyloarthritis: Roundtable Discussions with Healthcare Professionals and Patients
Psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) are both chronic, inflammatory conditions that result in a substantial burden of disease and reduced quality of life for patients. Patient involvement in developing optimal disease management strategies, including defining appropriate goals, therapies, and treatment options, as well as in setting policy priorities and agendas, is key. A working group of patient organization representatives and rheumatologists explored what patients consider to be unmet needs, important treatment gaps, and future priorities in PsA and AxSpA management. Reducing pain and fatigue, and improving physical and social functioning and work productivity were identified as important treatment goals for patients. Although the major treatment target for both PsA and AxSpA is remission, with low/minimal disease activity an alternative target for patients with established or long-standing disease, the meaning of remission from the patient’s perspective needs to be explored further as it may differ considerably from the physician’s perspective. Key recommendations from the working group to tackle unmet needs included reducing time to diagnosis, increasing patient and physician disease awareness, focusing on patients’ priorities for treatment goals, and improving patient–physician communication. By addressing these key action points moving forward, the hope is that outcomes will continue to improve for patients with PsA and AxSpA.
Journal Article