Pulmonary Hypertension in Systemic Sclerosis.

Systemic sclerosis is a multisystem connective tissue disease that is associated with substantial morbidity and mortality. Visceral organ involvement is common in patients with systemic sclerosis and occurs independently of skin manifestations. Pulmonary hypertension (PH) is an important and prevalent complication of systemic sclerosis. The clinical classification of PH cohorts conditions with similar pathophysiological mechanisms into one of five groups. While patients with systemic sclerosis can manifest with a spectrum of pulmonary vascular disease, notable clinical groups include group 1 pulmonary arterial hypertension (PAH) associated with connective tissues disease, PAH with features of capillary/venous involvement, group 2 PH associated with left heart disease, and group 3 PH associated with interstitial lung disease. Considerable efforts have been made to advance screening methods for PH in systemic sclerosis including the DETECT and ASIG (Australian Scleroderma Interest Group) composite algorithms. Current guidelines recommend annual assessment of the risk of PAH as early recognition may result in attenuated hemodynamic impairment and improved survival. The treatment of PAH associated with systemic sclerosis requires a multidisciplinary team including a PH specialist and a rheumatologist to optimize immunomodulatory and PAH-specific therapies. Several potential biomarkers have been identified and there are several promising PAH therapies on the horizon such as the novel fusion protein sotatercept. This chapter provides an overview of PH in systemic sclerosis, with a specific focus on group 1 PAH.

ERS International Congress 2023: highlights from the Pulmonary Vascular Diseases Assembly.

Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation.

Safety, feasibility and effectiveness of the remotely delivered Pulmonary Hypertension and Home-Based (PHAHB) physical activity intervention.

Background: Pulmonary hypertension (PH) is a heterogeneous condition, associated with a high symptom burden and a substantial loss of exercise capacity. Despite prior safety concerns regarding physical exertion, exercise training as a supportive therapy is now recommended for PH patients. Currently, most programmes are hospital-based, which limits accessibility. There is a need to provide alternative approaches for physical activity engagement for PH patients. The aim of this research was to develop, implement and evaluate the safety, feasibility and effectiveness of home-based physical activity intervention for PH. Methods: An entirely remotely delivered home-based physical activity intervention underpinned by behaviour change theory and informed by end-users, was assessed using a single-arm feasibility study design. Participants (n=19; 80% female) with a mean±sd age of 49.9±15.9 years with a diagnosis of PH undertook a 10-week, home-based physical activity intervention with induction training, support materials, telecommunication support, health coaching, exercise training and assessments, all remotely delivered. Training involved respiratory training along with a combination of aerobic and resistance exercises. Results: The intervention was deemed safe as no adverse events were reported. A high level of feasibility was demonstrated as the protocol was implemented as intended, sustained a high level of engagement and adherence and was well accepted by participants in terms of enjoyment and utility. There was a significant improvement in functional capacity, physical activity, exercise self-efficacy and quality of life, between baseline and post-training. Conclusion: The study demonstrates that an entirely remotely delivered home-based physical activity programme is safe, feasible and effective in improving functional capacity, physical activity and quality of life in PH patients.

An optimized protocol to isolate quiescent washed platelets from human whole blood and generate platelet releasate under clinical conditions.

The contents of the platelet releasate (PR) play significant roles in hemostasis, inflammation, and pathologic sequelae. Careful platelet isolation to ensure quiescence and subsequent activation is key to the successful generation of PR. Here, we describe steps to isolate and aggregate quiescent washed platelets from whole blood of a clinical patient cohort. We then detail the generation of PR from isolated human washed platelets under clinical conditions. This protocol allows the investigation of platelet cargoes released through various activation pathways.

New trends in pulmonary hypertension.

Pulmonary hypertension (PH) is a prevalent disease of the pulmonary vasculature that is characterised by considerable morbidity and mortality. Substantial efforts have been made in recent years to improve disease recognition, diagnosis and management, and this is reflected in current guidelines. The haemodynamic definition of PH has been revised and a definition for exercise PH has been provided. Risk stratification has been refined and the importance of comorbidities and phenotyping have been highlighted. These changes provide an opportunity to potentially identify pulmonary vascular disease at an earlier stage and to enhance patient-centred, goal-orientated treatment decisions. A promising fourth treatment pathway for pulmonary arterial hypertension and potential targeted therapies for group 3 PH are on the horizon, concepts which seemed inconceivable only a few years ago. Beyond medication, there is a greater appreciation for the importance of supervised training in stable PH and the possible role of interventional therapies in select cases. The landscape of PH is changing and it is characterised by progress, innovation and opportunities. In this article, we highlight some of the new trends in PH, with a specific focus on the revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and management of PH.

Exploration of physical activity knowledge, preferences and support needs among pulmonary hypertension patients.

OBJECTIVE: Physical activity (PA) is an established adjunct therapy for pulmonary hypertension (PH) patients to mitigate PH symptoms and improve quality of life. However, PA engagement within this population remains low. This study investigated PH patients' knowledge of PA, recalled advice, exercise preferences and PA support needs. METHODS: Semi-structured interviews were conducted with 19 adults (mean age 50 years; SD ±12 years) diagnosed with PH, living in Ireland. Interview scripts were digitally recorded and transcribed verbatim. Thematic analysis was used to analyse the data. RESULTS: Four key themes were identified: Lack of PA knowledge; exercise setting preference; accountability and monitoring; and clinician delivered PA information and guidance. CONCLUSION: This study found that PH clinicians provide suboptimal PA advice, yet patients desired clinician-delivered PA guidance. Home-based exercise was preferred with monitoring and external accountability deemed as important to facilitate sustained engagement. PRACTICE IMPLICATIONS: PH clinicians are well positioned to play a critical role in assisting and empowering PH patients to engage in PA. Providing training and education to PH clinicians regarding exercise prescription may be beneficial. Further research is needed to evaluate the feasibility and efficacy of home-based exercise interventions to improve quality of life and physical activity in PH.

Being (past and present) President of the ERS: interview about the role, perspectives on career development, and vision for the Society.

This article presents the views of the past and current Presidents of the ERS regarding their role, perspectives on career development and vision for the Society, along with important messages to inspire ECMs to build their own successful career. https://bit.ly/3kAvxIM.

Incidence and outcomes of pulmonary hypertension in the Ireland.

INTRODUCTION: Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature, which is characterised by premature morbidity and mortality. The aim of this study is to define the characteristics of PH in the national PH unit (NPHU) in Ireland between 2010 and 2020. METHODS: Cases of PH which were referred to the NPHU between 2010 and 2020 were included. PH was defined as a mean pulmonary artery pressure ≥25 mm Hg at right heart catheterisation. RESULTS: Four hundred and fifteen cases of PH were identified during the study period. Group 1 pulmonary arterial hypertension (PAH) accounted for 39% (n=163) of cases, with a calculated annual incidence of 3.11 per million population (95% CI 1.53 to 4.70). The leading PAH subgroup was connective tissue disease-associated PAH (CTD-PAH), which was responsible for 49% of PAH referrals. This was followed by idiopathic PAH, with an estimated annual incidence of 0.63 cases per million population. The mean age at PAH diagnosis was 56±15 years and 86% (n=111) received double-combination or triple-combination therapy within the first 12 months of diagnosis. The 1-year, 3-year and 5-year transplant-free survival for PAH was 89%, 75% and 65%. This was significantly lower for individuals with CTD-PAH relative to other PAH subgroups (p<0.05). DISCUSSION: This study describes the incidence and outcomes of PH in Ireland. While the outcomes are comparable to other centres, the incidence of PAH and specific subgroups appears low, suggesting that improved disease awareness and case recognition are required. Furthermore, the survival of individuals with CTD-PAH is poor and requires additional exploration.

Progressive dyspnoea in a patient with idiopathic non-cirrhotic portal hypertension.

This case of progressive dyspnoea in a 43-year-old with idiopathic non-cirrhotic portal hypertension highlights important pulmonary vascular complications of chronic liver disease https://bit.ly/3rwEkhP.

Non-severe COVID-19 is associated with endothelial damage and hypercoagulability despite pharmacological thromboprophylaxis.

BACKGROUND: Hypercoagulability and endothelial dysfunction are hallmarks of coronavirus disease 2019 (COVID-19) and appear to predict disease severity. A high incidence of thrombosis despite thromboprophylaxis is reported in patients with moderate to severe COVID-19. Recent randomized clinical trials suggest that therapeutic-intensity heparin confers a survival benefit in moderate-severity COVID-19 compared to standard-intensity heparin, potentially by harnessing heparin-mediated endothelial-stabilizing and anti-inflammatory effects. OBJECTIVE: We hypothesized that patients with moderate-severity COVID-19 exhibit enhanced hypercoagulability despite standard-intensity thromboprophylaxis with low molecular weight heparin (LMWH) compared to non-COVID-19 hospitalized patients. METHODS: Patients with moderate COVID-19 and a control group (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-negative hospitalized patients) receiving LMWH thromboprophylaxis were recruited. Markers of endothelial damage and plasma thrombin generation parameters were assessed. RESULTS: Tissue plasminogen activator levels were significantly increased in the COVID-19 group (8.3 ± 4.4 vs. 4.9 ± 2.4 ng/ml; P = .02) compared to non-COVID-19-hospitalized patients. Despite thromboprophylaxis, mean endogenous thrombin potential was significantly increased among COVID-19 patients (1929 ± 448 vs. 1528 ± 460.8 nM*min; P = .04) but lag time to thrombin generation was significantly prolonged (8.1 ± 1.8 vs. 6.2 ± 1.8 mins; P = .02). While tissue factor pathway inhibitor (TFPI) levels were similar in both groups, in the presence of an inhibitory anti-TFPI antibody, the difference in lag time between the groups was abrogated. CONCLUSIONS: Collectively, these data demonstrate that COVID-19 of moderate severity is associated with increased plasma thrombin generation and endothelial damage, and that hypercoagulability persists despite standard LMWH thromboprophylaxis. These findings may be of clinical interest given recent clinical trial data which suggest escalated heparin dosing in non-severe COVID-19 may be associated with improved clinical outcomes.

The role of the calibrated automated thrombogram in neonates: describing mechanisms of neonatal haemostasis and evaluating haemostatic drugs.

Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known: • The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways. • CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New: • This review summarises the physiological differences in haemostasis between neonates and adults described using CAT. • The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.

Diagnosis and management of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that is characterised by elevated pressures within the pulmonary vascular tree. Recent decades have witnessed a dramatic expansion in our understanding of the pathobiology and the epidemiology of PAH, and improvements in treatment options and outcomes. The prevalence of PAH is estimated to be between 48 and 55 cases per million adults. The definition was recently amended and a diagnosis of PAH now requires evidence of a mean pulmonary artery pressure >20 mmHg, a pulmonary vascular resistance >2 Wood units and a pulmonary artery wedge pressure ≤15 mmHg at right heart catheterisation. Detailed clinical assessment and a number of additional diagnostic tests are required to assign a clinical group. Biochemistry, echocardiography, lung imaging and pulmonary function tests provide valuable information to assist in the assignment of a clinical group. Risk assessment tools have been refined, and these greatly facilitate risk stratification and enhance treatment decisions and prognostication. Current therapies target three therapeutic pathways: the nitric oxide, prostacyclin and endothelin pathways. While lung transplantation remains the only curative intervention for PAH, there are a number of promising therapies under investigation which may further reduce morbidity and improve outcomes. This review describes the epidemiology, pathology and pathobiology of PAH and introduces important concepts regarding the diagnosis and risk stratification of PAH. The management of PAH is also discussed, with a special focus on PAH specific therapy and key supportive measures.

"It is the fear of exercise that stops me" - attitudes and dimensions influencing physical activity in pulmonary hypertension patients.

Pulmonary hypertension is a progressive cardiorespiratory disease that is characterized by considerable morbidity and mortality. While physical activity can improve symptoms and quality of life, engagement in this population is suboptimal. The aim of this study was to explore attitudes towards exercise and the dimensions that influence physical activity participation in individuals with pulmonary hypertension. Virtual, semi-structured interviews were conducted with individuals, with a formal diagnosis of pulmonary hypertension. Participants were recruited through the Pulmonary Hypertension Association of Ireland. Interviews were transcribed and analysed using thematic analysis. Nineteen patients were interviewed (n = 19). There was a female preponderance (n = 13) and the mean age was 50 ± 12 years. Three themes were identified and included fear, perceived value of exercise and environmental factors. Fear was the primary theme and included three sub-themes of fear of (i) over-exertion, (ii) physical damage and (iii) breathlessness. The perceived value of exercise encompassed two distinct sub-themes of perceived (i) exercise importance and (ii) benefits of exercise. Environmental factors included the terrain, weather conditions and location. Fear of overexertion, harm and dyspnoea strongly influenced attitudes to and engagement in physical activity. This study revealed heterogenous patient perspectives regarding the importance of physical activity and exercise. Future interventions that mitigate fear and promote the value of physical activity for individuals with pulmonary hypertension may have considerable benefits in promoting physical activity engagement. Such interventions require multidisciplinary involvement, including specialised pulmonary hypertension clinicians and exercise and behaviour change specialists.

Characteristics of chronic thromboembolic pulmonary hypertension in Ireland.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and under-recognised complication of acute pulmonary embolism. Information regarding the characteristics of CTEPH in Ireland is limited, and the aim of this retrospective cohort study was to address this knowledge gap. Seventy-two cases of CTEPH were diagnosed in the National Pulmonary Hypertension Unit (NPHU) in Ireland between 2010 and 2020. This accounted for 6% of all referrals to the unit and translates to an estimated annual incidence of 1.39 per million population (95% confidence interval, 0.33-2.46). The prevalence of diagnosed CTEPH in Ireland in 2020 was estimated at 12.05 per million population (95% CI 9.00-15.10). The average duration of symptoms prior to CTEPH diagnosis was 23 (±22) months. Patients with CTEPH were more likely to be male (n = 40, 56%), older (60 ± 17 years) and have identifiable risk factors for CTEPH (n = 61, 85%) at diagnosis. Regarding treatment, pulmonary hypertension (PH) vasodilator therapy was prescribed in 75% (n = 54) within 12 months of diagnosis, inferior vena cava filters were placed in 24% (n = 17) and 97% (n = 70) of cases were anticoagulated. Pulmonary endarterectomy was performed in 35% (n = 25), balloon pulmonary angioplasty in 6% (n = 4). One-, three- and five-year survival was 93%, 80% and 65% from the time of diagnosis, and this was significantly better in patients who underwent pulmonary endarterectomy (p = 0.01). This is the first study describing the characteristics of CTEPH in Ireland and highlights suboptimal disease recognition and referral for the assessment for pulmonary endarterectomy.

Haematological parameters and coagulation in umbilical cord blood following COVID-19 infection in pregnancy.

OBJECTIVE: The aim of this study was to evaluate infants, born to women with SARS-CoV-2 detected during pregnancy, for evidence of haematological abnormalities or hypercoagulability in umbilical cord blood. STUDY DESIGN: This was a prospective observational case-control study of infants born to women who had SARS-CoV-2 RNA detected by PCR at any time during their pregnancy (n = 15). The study was carried out in a Tertiary University Maternity Hospital (8,500 deliveries/year) in Ireland. This study was approved by the Hospital Research Ethics Committee and written consent was obtained. Umbilical cord blood samples were collected at delivery, full blood count and Calibrated Automated Thrombography were performed. Demographics and clinical outcomes were recorded. Healthy term infants, previously recruited as controls to a larger study prior to the outbreak of COVID-19, were the historical control population (n = 10). RESULTS: Infants born to women with SARS-CoV-2 had similar growth parameters (birth weight 3600 g v 3680 g, p = 0.83) and clinical outcomes to healthy controls, such as need for resuscitation at birth (2 (13.3%) v 1 (10%), p = 1.0) and NICU admission (1 (6.7%) v 2 (20%), p = 0.54). Haematological parameters (Haemoglobin, platelet, white cell and lymphocyte counts) in the COVID-19 group were all within normal neonatal reference ranges. Calibrated Automated Thrombography revealed no differences in any thrombin generation parameters (lag time (p = 0.92), endogenous thrombin potential (p = 0.24), peak thrombin (p = 0.44), time to peak thrombin (p = 0.94)) between the two groups. CONCLUSION: In this prospective study including eligible cases in a very large population of approximately 1500 women, there was no evidence of derangement of the haematological parameters or hypercoagulability in umbilical cord blood due to COVID-19. Further research is required to investigate the pathological placental changes, particularly COVID-19 placentitis and the impact of different strains of SARS-CoV-2 (particularly the B.1.1.7 and the emerging Delta variant) and the severity and timing of infection on the developing fetus.

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.

An interesting case of progressive dyspnoea and diffuse mediastinal adenopathy in a 25-year-old man.

Mediastinal adenopathy, septal line thickening, centrilobular ground glass opacities on CT and a markedly reduced T LCO in a young patient with pulmonary hypertension, should alert the clinician to this potential diagnosis https://bit.ly/3cfe9pX.

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.

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.

Real-world experience of selexipag titration in pulmonary arterial hypertension.

Selexipag is an oral selective prostacyclin-receptor agonist that was approved for use in patients with World Health Organisation (WHO) functional class II-III pulmonary arterial hypertension (PAH). Treatment with individualised doses of selexipag resulted in significant reductions in the composite end point of death or a complication related to PAH in the phase III GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) study. In order to better understand the real-world approach to selexipag titration and to establish the individualised maintenance regimens used in our centre, we performed this retrospective study of the first 20 patients prescribed selexipag. Baseline characteristics differed from the GRIPHON study, with more combination therapy and comorbidities at drug initiation. Maintenance doses were stratified as low-dose in 10% (n=2), medium-dose in 70% (n=14) and high-dose in 20% (n=4). This study highlights that selexipag can be safely initiated, titrated and transitioned in an outpatient setting to achieve an individualised dosing regimen.