Endothelial cell activation, Weibel-Palade body secretion, and enhanced angiogenesis in severe COVID-19.

Background: Severe COVID-19 is associated with marked endothelial cell (EC) activation that plays a key role in immunothrombosis and pulmonary microvascular occlusion. However, the biological mechanisms through which SARS-CoV-2 causes EC activation and damage remain poorly defined. Objectives: We investigated EC activation in patients with acute COVID-19, and specifically focused on how proteins stored within Weibel-Palade bodies may impact key aspects of disease pathogenesis. Methods: Thirty-nine patients with confirmed COVID-19 were recruited. Weibel-Palade body biomarkers (von Willebrand factor [VWF], angiopoietin-2 [Angpt-2], and osteoprotegerin) and soluble thrombomodulin (sTM) levels were determined. In addition, EC activation and angiogenesis were assessed in the presence or absence of COVID-19 plasma incubation. Results: Markedly elevated plasma VWF antigen, Angpt-2, osteoprotegerin, and sTM levels were observed in patients with acute COVID-19. The increased levels of both sTM and Weibel-Palade body components (VWF, osteoprotegerin, and Angpt-2) correlated with COVID-19 severity. Incubation of COVID-19 plasma with ECs triggered enhanced VWF secretion and increased Angpt-2 expression, as well as significantly enhanced in vitro EC tube formation and angiogenesis. Conclusion: We propose that acute SARS-CoV-2 infection leads to a complex and multifactorial EC activation, progressive loss of thrombomodulin, and increased Angpt-2 expression, which collectively serve to promote a local proangiogenic state.

Core curriculum in pathology for future Irish medical students.

Pathology is important in training to become a medical doctor but as curricula become more integrated, there is a risk that key aspects of pathology may be excluded. Following a survey of the current delivery of teaching in Ireland under the auspices of the Faculty of Pathology at the Royal College of Physicians of Ireland, suggested components of a core curriculum in pathology have been developed to be delivered at some stage during the medical course. These have been based on key principles and themes required by the Medical Council in Ireland. Professionalism is one of the core principles emphasised by the Medical Council. It includes the role of the pathologist in patient care and other professional values such as patient-centred care, clinical competencies and skills, e.g. explaining results, and knowledge under the various sub-disciplines, i.e. histopathology (including neuropathology), clinical microbiology, haematology, chemical pathology and immunology. In each of these, we suggest key aspects and activities that the medical graduate should be comfortable in carrying out. The methods of delivery of teaching and assessment across pathology disciplines have evolved and adapted to recent circumstances. Lessons have been learned and insights gained during the COVID-19 pandemic as educators have risen to the challenge of continuing to educate medical students. Integrated and multi-disciplinary teaching is recommended to reflect best the professional environment of the medical graduate who works as an integral part of a multi-disciplinary team, with the minimum dependence on the traditional lecture, where at all possible. Finally, options on assessment are discussed, e.g. multiple-choice questions, including their respective advantages and disadvantages.

Online Search Trends Influencing Anticoagulation in Patients With COVID-19: Observational Study.

BACKGROUND: Early evidence of COVID-19-associated coagulopathy disseminated rapidly online during the first months of 2020, followed by clinical debate about how best to manage thrombotic risks in these patients. The rapid online spread of case reports was followed by online interim guidelines, discussions, and worldwide online searches for further information. The impact of global online search trends and online discussion on local approaches to coagulopathy in patients with COVID-19 has not been studied. OBJECTIVE: The goal of this study was to investigate the relationship between online search trends using Google Trends and the rate of appropriate venous thromboembolism (VTE) prophylaxis and anticoagulation therapy in a cohort of patients with COVID-19 admitted to a tertiary hospital in Ireland. METHODS: A retrospective audit of anticoagulation therapy and VTE prophylaxis among patients with COVID-19 who were admitted to a tertiary hospital was conducted between February 29 and May 31, 2020. Worldwide Google search trends of the term "COVID-19" and anticoagulation synonyms during this time period were determined and correlated against one another using a Spearman correlation. A P value of <.05 was considered significant, and analysis was completed using Prism, version 8 (GraphPad). RESULTS: A statistically significant Spearman correlation (P<.001, r=0.71) was found between the two data sets, showing an increase in VTE prophylaxis in patients with COVID-19 with increasing online searches worldwide. This represents a proxy for online searches and discussion, dissemination of information, and Google search trends relating to COVID-19 and clotting risk, in particular, which correlated with an increasing trend of providing thromboprophylaxis and anticoagulation therapy to patients with COVID-19 in our tertiary center. CONCLUSIONS: We described a correlation of local change in clinical practice with worldwide online dialogue and digital search trends that influenced individual clinicians, prior to the publication of formal guidelines or a local quality-improvement intervention.

ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.

BACKGROUND: Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis. OBJECTIVES: This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis. PATIENTS AND METHODS: Patients with COVID-19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS-13 activity, and known inhibitors thereof were assessed. RESULTS: We observed markedly increased VWF collagen-binding activity in patients with severe COVID-19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID-19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS-13 and other proteases. We observed that both N- and O-linked sialylation were altered in severe COVID-19. Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6, thrombospondin-1, and platelet factor 4 were significantly elevated. CONCLUSIONS: These findings support the hypothesis that SARS-CoV-2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down-regulation in ADAMTS-13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS-13-VWF multimer dysfunction may be useful in COVID-microvascular thrombosis and angiopathy.

Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation.

Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID-19). Consistent with EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID-19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID-19. Markedly increased plasma VWF:Ag [median (interquatile range, IQR) 608·8 (531-830)iu/dl] and pro-coagulant factor VIII (FVIII) levels [median (IQR) 261·9 (170-315) iu/dl] were seen in patients with severe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Sequential testing showed that these elevated VWF-FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated [median (IQR) 324·6 (267-524) iu/dl]. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID-19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis-Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID-19, and further suggest that VWFpp may have a role as a biomarker in this setting.