COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 beta [IL-1beta] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. Copyright © 2021, The Author(s), under exclusive licence to Springer Nature B.V.

Post-partum acquired haemophilia A in the COVID era -Building the case for Emicizumab?

Background: Both de-novo and relapse of Acquired Haemophilia A (AHA) have been reported following SARS-CoV- 2 infection and vaccination suggesting virus-induced immune dysregulation as a potential mechanism. The current standard of care in the potentially fatal AHA, requires the use of bypassing agents (BPA) or porcine FVIII to achieve haemostasis and immunosuppression to suppress autoantibody production. The bispecific antibody emicizumab now offers the possibility to achieve the former and reduced need for the latter but is only approved solely for use in congenital haemophilia A. Aim(s): We present a cluster of three AHA cases presenting between April to June 2021 at a single tertiary centre. Notably each patient received recent BNT162b2(Pfizer) vaccination. Method(s): Bypassing therapy and steroids were commenced with response in two cases. One case remained refractory to BPA, porcine FVIII, steroids and Azathioprine. Approval was sought for a subcutaneous biweekly injection of Emicizumab in order to avoid rituximab during the pandemic. Result(s): In 10 months since initiation of emicizumab, no further bleeding and no thrombotic events have been reported. Factor VIII (chromogenic) is now detectable in all patients. Conclusion(s): The close interaction between SARS-Cov- 2 and the haemostatic system has been evident in the COVID era. The unusual clustering of cases presented here suggests that antibody responses to SARS-Cov- 2 infection or vaccine may cross-react with coagulation factors resulting in the immunohematological phenomenon of AHA. Furthermore, to our knowledge this is the first use of Emicizumab in acquired haemophilia in the post-partum period. As well as providing excellent haemostatic efficacy and potential cost-effectiveness, emicizumab provides several advantages for a new mother during the COVID-19 pandemic. These include a return to home, contact with family and minimal attendance at hospital as well as avoiding immunosuppression conferring increased risk of infection and loss of protection from vaccinations. We note the recent application for use of emicizumab in AHA.

Thrombosis and major bleeding in patients with severe COVID-19 supported by extracorporeal membrane oxygenation (ECMO)-Multicentre observational study in UK

Background: Support with extracorporeal membrane oxygenation (ECMO) can be life saving for patients with coronavirus [Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)]-induced severe respiratory failure. However, bleeding and thrombosis are major complications in patients supported with ECMO and thrombosis is itself a prominent feature of severe COVID-19. Aim(s): To assess the rate of thrombosis and major bleeding (MB) and their impact on mortality in patients supported with veno-venous (VV)-ECMO. Method(s): This was a multicentre observational study of 320 consecutive patients (>=18 years) with severe COVID-19 supported by VV-ECMO in four nationally commissioned ECMO centres in UK from 1st March 2020 to 31st December 2021. Result(s): Median age (range) was 48 years (19-75) and 71.2% were male. Overall, the 180-day mortality was 36.6%% (117/320). The rate of MB was 27.5% (88/320), of which intracranial bleeding (ICH) was the most common [35.3% (31/88) [ followed by pulmonary haemorrhage [26.1% (23/88). Gastrointestinal bleeding accounted for 15.9% (14/88) of MB and the remainder (22.7%) had bleeding at other sites. There were 136 thrombotic events (42.5%) consisting of 80.1% (109/136) venous thrombosis (VTE) and 19.9% (27/136) arterial thromboses. Of the 109 patients with VTE, 73.4% (80/109) had pulmonary embolism (PE), 17.4% (19/109) had deep vein thrombosis (DVT) and 9.2% (10/109) had combined DVT and PE. Ischaemic stroke accounted for >50% of the arterial thrombosis (51.6%, 14/27). HIT occurred in 9.7% (31/320) and 80.6% (25/31) developed thrombosis. MB and ICH were associated with 3.51-fold (95% CI 2.56-8.41) and 6.71-fold (CI) 2.56-16.54] increased risk of mortality and PE with a 2.23-fold (95% CI1.29-3.89) risk of mortality. Conclusion(s): MB and thrombosis including HIT are frequent complications in patients supported with VV-ECMO which significantly increase the risk of mortality. This highlights the need for prospective studies assessing the optimal haemostasis management in patients on VV-ECMO.

Physician associate role in interventional radiology

1) To showcase the role of Physician Associate (PA) in Interventional Radiology (IR) as an innovative solution to address the increasing clinical workload. 2) IR has seen a dramatic increase in workload, with Covid highlighting the essential clinical service that the department provides. The PA role has been utilised in many other surgical and medical specialities to improve continuity of care, supplement the medical workforce and ease the consultant workload. 3) The PA role and responsibilities have increased in line with the demands of the department. The role has developed to support the MDT team, increase patients' clinical contact time, and ease the consultant workload. Examples of my responsibilities include: a. Performing my own ultrasound lists undertaking supra-pubic catheter insertion, vein mapping for fistula formation, and ascitic drain insertion. b. IR ward round and follow up post-procedure. c. The introduction of a robust 2-stage consent process. d. Collating audit data for IR M&M. e. Involvement in IR research. 4) PAs can be an effective, versatile and progressive addition to the IR team and should be a key part of the modern clinical IR service.

Subcutaneous unfractionated heparin in patients with end-stage kidney disease requiring anticoagulation

Acute inpatient management of patients with end-stage renal failure (ESRF) requiring anticoagulation is problematic. Low molecular heparins (LMWHs) and direct oral anticoagulants (DOAC) are convenient, but largely dependent on renal function for clearance . Vitamin K antagonists (VKAs) are suitable for long-term anticoagulation, but often not appropriate in hospital, where rapid adjustments may be required. Unfractionated heparin (UFH) infusion is the conventional alternative, but this requires intensive monitoring, often not available outside high dependency/ intensive care units. A weight-adjusted, unmonitored subcutaneous UFH regimen avoids these problems and has been successfully trialled but is not widely used. 1,2 This is a single-centre retrospective analysis of 48 patients treated with subcutaneous UFH at a dose of 250 UI/Kg twice daily for treatment or prevention of venous thromboembolism (VTE), between September 2020 and August 2021. All patients receiving this regimen were identified via pharmacy database. The aims of this study are to evaluate indication for use and to assess safety (bleeding) and efficacy (breakthrough thrombosis) in our cohort. All patients had renal impairment with a median creatinine clearance at time of prescription of 15 ml/min (range 4-48 ml/min, interquartile range 10.25). A third was on established renal replacement therapy. Overall, two thirds required anticoagulation for either atrial fibrillation (AF) or VTE treatment. In such patients, UFH was used for bridging to an oral agent and it was preferred over LMWH in view of reduced/deteriorating renal function. The remaining patients required anticoagulation for VTE prevention or for presurgical management, in view of known pre-existing pro-thrombotic conditions. One patient was incorrectly given subcutaneous UFH to manage subtherapeutic INR in the presence of a metallic heart valve. Collectively, 18 patients deceased during or within 6 months from admission. Twelve per cent experienced non-major/major bleeding. 3 Three deaths were directly attributed to major gastro-intestinal bleeding (only one case was confirmed radiologically). Non-major events included bleeding from surgical wounds ( N = 2) and skin cancer lesion ( N = 1). Only one breakthrough thrombosis was reported. No death was attributed to thrombosis (table 1). In conclusion, weight-adjusted UFH is an effective anticoagulant regimen. It was originally studied in VTE but appears to be effective in AF as well. The risk of bleeding is relatively high, but comparable to similarly ill patients (e.g. COVID19) receiving monitored UFH infusions. 4.

Do thrombotic and bleeding phenotypes differ in patients with severe COVID-19 compared to other viral pneumoniasin the context of extracorporeal membrane oxygenation?

Background : Respiratory failure is a major complication in patients with COVID-19. Some patients rapidly develop severe acute respiratory distress syndrome (ARDS) with profound hypoxaemia despite mechanical ventilation and rescue therapies such as nitric oxide and require veno-venous extracorporeal membrane oxygenation (VVECMO). Bleeding and thrombosis are major complications in patients treated with ECMO irrespective of the cause for underlying respiratory failure. Thrombosis, mainly pulmonary thrombosis or pulmonary embolism, is frequently seen in patients with severe COVID-19. Aims : To compare thrombosis, bleeding and mortality rates in a cohort of patients with severe COVID-19 pneumonia to a matched cohort of patients with other viral pneumonia, supported with VV-ECMO. Methods : A retrospective single-centre observational study in a tertiary ECMO referral centre. Fifty-four COVID-19 patients admitted for VV-ECMO from 17/3/20 to 26/5/20 were compared with a matched sample of 44 patients received VV-ECMO for non-COVID-19 viral pneumonia from 5/4/18 to 18/1/19. Thrombosis, bleeding and mortality rates were compared. Results : Baseline characteristics were comparable between cohorts. COVID-19 patients had higher admission platelet count and fibrinogen level. Sixty-nine thrombotic events occurred in 43/54 (80%) COVID-19 patients, compared to 34 events in 26/44 (59%) non-COVID-19 patients. Unlike the non-COVID-19 cohort, the majority of thromboses were pulmonary (57%), diagnosed early in the course of VV-ECMO. Twenty-four major bleeding (MB) events occurred in 19/54 (35%) COVID-19 patients and 11 in 9/44 (20%) non-COVID-19 patients. All 21 major haemorrhages during VV-ECMO in the COVID-19 cohort were preceded by thrombosis. Mortality rate was comparable: 9/54 (17%) versus 7/44 (16%). 5/9 COVID-19 fatalities were caused by MB;haemorrhagic transformation of ischemic stroke, versus none in the non-COVID-19 cohort. Conclusions : COVID-19 patients receiving VV-ECMO are at higher risk of thrombosis and fatal MB than patients receiving VV-ECMO for non-COVID-19 viral pneumonia. Further work is required to characterise the COVID-19/VV-ECMO coagulopathies and optimise anticoagulation strategy.

Covid-19 related concerns of people with longterm respiratory conditions: A qualitative study

Background The COVID-19 pandemic is having profound psychological impacts on populations globally, with increasing levels of stress, anxiety, and depression being reported, especially in people with pre-existing medical conditions who appear to be particularly vulnerable. There are limited data on the specific concerns people have about COVID-19 and what these are based on. Methods The aim of this study was to identify and explore the concerns of people with long-term respiratory conditions in the UK regarding the impact of the COVID-19 pandemic and how these concerns were affecting them. We conducted a thematic analysis of free text responses to the question 'What are your main concerns about getting coronavirus?', which was included in the British Lung Foundation/Asthma UK (BLF-AUK) partnership COVID-19 survey, conducted between the 1st and 8th of April. This was during the 3rd week of the UK's initial social distancing measures. Results 7,039 responses were analysed, with respondents from a wide range of ages, gender, and all UK nations. Respondents reported having asthma (85%), COPD (9%), bronchiectasis (4%), interstitial lung disease (2%), or 'other' lung diseases (e. g. lung cancer) (1%). Four main themes were identified: 1) vulnerability to COVID-19;2) anticipated experience of contracting COVID-19;3) wide-reaching uncertainty;and 4) inadequate national response. Conclusions The COVID-19 pandemic is having profound psychological impacts. The concerns we identified largely reflect objective, as well as subjective, aspects of the current situation. Hence, key approaches to reducing these concerns require changes to the reality of their situation, and are likely to include i) helping people optimise their health, limit risk of infection, and access necessities;ii) minimising the negative experience of disease where possible, iii) providing up-to-date, accurate and consistent information, iv) improving the government and healthcare response.

Respiratory patient experience of measures to reduce risk of covid-19: Findings from a descriptive cross-sectional UK wide survey

Objectives To assess the experience of people with long-term respiratory conditions regarding the impact of measures to reduce risk of COVID-19. Design Analysis of data (n=9,515) from the Asthma UK and British Lung Foundation partnership COVID-19 survey collected online between 1st and 8th of April 2020. Setting Community Participants 9,515 people with self-reported long term respiratory conditions. 81% female, age ranges from <17 years to 80 and above, from all nations of the UK. Long term respiratory conditions reported included asthma (83%), Chronic Obstructive Pulmonary Disease (COPD) (10%), bronchiectasis (4%), Interstitial Lung Disease (ILD) (2%), and 'other' (<1%) (e.g. lung cancer and pulmonary endometriosis). Outcome measures Study responses related to impacts on key elements of health care, as well as practical, psychological and social consequences related to the COVID-19 pandemic and social distancing measures. Results 45% reported disruptions to care, including cancellations of appointments, investigations, pulmonary rehabilitation, treatment, and monitoring. Other practical impacts such as difficulty accessing healthcare services for other issues, and getting basic necessities such as food, were also common. 36% did not use online prescriptions and 54% had not accessed online inhaler technique videos. Psycho-social impacts including anxiety, loneliness and concerns about personal health and family were prevalent. 81% reported engaging in physical activity. Among the 11% who were smokers, 48% reported they were planning to quit smoking because of COVID-19. Conclusions COVID-19 and related social distancing measures are having profound impacts on people with chronic respiratory conditions. Urgent adaptation and signposting of services is required to mitigate the negative health consequences of the COVID-19 response for this group.

S112 COVID-19 related concerns of people with long-term respiratory conditions: a qualitative study

BackgroundThe COVID-19 pandemic is having profound psychological impacts on populations globally, with increasing levels of stress, anxiety, and depression being reported, especially in people with pre-existing medical conditions who appear to be particularly vulnerable. There are limited data on the specific concerns people have about COVID-19 and what these are based on.MethodsThe aim of this study was to identify and explore the concerns of people with long-term respiratory conditions in the UK regarding the impact of the COVID-19 pandemic and how these concerns were affecting them. We conducted a thematic analysis of free text responses to the question ‘What are your main concerns about getting coronavirus?’, which was included in the British Lung Foundation/Asthma UK (BLF-AUK) partnership COVID-19 survey, conducted between the 1st and 8th of April. This was during the 3rd week of the UK’s initial social distancing measures.Results7,039 responses were analysed, with respondents from a wide range of ages, gender, and all UK nations. Respondents reported having asthma (85%), COPD (9%), bronchiectasis (4%), interstitial lung disease (2%), or ‘other’ lung diseases (e.g. lung cancer) (1%). Four main themes were identified: 1) vulnerability to COVID-19;2) anticipated experience of contracting COVID-19;3) wide-reaching uncertainty;and 4) inadequate national response.ConclusionsThe COVID-19 pandemic is having profound psychological impacts. The concerns we identified largely reflect objective, as well as subjective, aspects of the current situation. Hence, key approaches to reducing these concerns require changes to the reality of their situation, and are likely to include i) helping people optimise their health, limit risk of infection, and access necessities;ii) minimising the negative experience of disease where possible, iii) providing up-to-date, accurate and consistent information, iv) improving the government and healthcare response.

S111 Respiratory patient experience of measures to reduce risk of COVID-19: findings from a descriptive cross-sectional UK wide survey

ObjectivesTo assess the experience of people with long-term respiratory conditions regarding the impact of measures to reduce risk of COVID-19.DesignAnalysis of data (n=9,515) from the Asthma UK and British Lung Foundation partnership COVID-19 survey collected online between 1st and 8th of April 2020.SettingCommunityParticipants9,515 people with self-reported long term respiratory conditions. 81% female, age ranges from <17 years to 80 and above, from all nations of the UK. Long term respiratory conditions reported included asthma (83%), Chronic Obstructive Pulmonary Disease (COPD) (10%), bronchiectasis (4%), Interstitial Lung Disease (ILD) (2%), and ‘other’ (<1%) (e.g. lung cancer and pulmonary endometriosis).Outcome measuresStudy responses related to impacts on key elements of health care, as well as practical, psychological and social consequences related to the COVID-19 pandemic and social distancing measures.Results45% reported disruptions to care, including cancellations of appointments, investigations, pulmonary rehabilitation, treatment, and monitoring. Other practical impacts such as difficulty accessing healthcare services for other issues, and getting basic necessities such as food, were also common. 36% did not use online prescriptions and 54% had not accessed online inhaler technique videos. Psycho-social impacts including anxiety, loneliness and concerns about personal health and family were prevalent. 81% reported engaging in physical activity. Among the 11% who were smokers, 48% reported they were planning to quit smoking because of COVID-19.ConclusionsCOVID-19 and related social distancing measures are having profound impacts on people with chronic respiratory conditions. Urgent adaptation and signposting of services is required to mitigate the negative health consequences of the COVID-19 response for this group.