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Message: Various refs on COVID as a vascular /vascular endothelial disease

 

Becker R. C. (2020, July). COVID-19-associated vasculitis and vasculopathy. Journal of thrombosis and thrombolysis, 50(3), 499–511. https://doi.org/10.1007/s11239-020-02230-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373848/

 

COVID-19 is a SARS–CoV-2 syndrome that can involve all organs, including the circulatory system. Endothelial cell inflammation occurs within arteries, arterioles, capillaries, venules and veins and contributes to pathological events; including tissue hypoperfusion, injury, thrombosis and vascular dysfunction in the acute, subacute and possibly chronic stages of disease. Beyond re-writing the textbooks that hence will include SARS–CoV-2 as a causal pathogen for multi-bed vasculitis, the data will show that it is a new category of systemic vasculitis forever captured in the annals of medicine. As clinicians and scientists, we have but to understand, prevent, treat, document and inform at every step along the way.

 

Smith, Dana (2020, May 28) Covid-19 May Be a Blood Vessel Disease, Which Explains Everything, Elemental, https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

 

40% of deaths from Covid-19 are related to cardiovascular complications, and the disease starts to look like a vascular infection instead of a purely respiratory one.

 

there is now a growing body of evidence to support the theory that the novel coronavirus can infect blood vessels, which could explain not only the high prevalence of blood clots, strokes, and heart attacks, but also provide an answer for the diverse set of head-to-toe symptoms that have emerged

 

In a paper published in April in the scientific journal The Lancet, Mehra and a team of scientists discovered that the SARS-CoV-2 virus can infect the endothelial cells that line the inside of blood vessels.

 

Etc.

 

Bhanu Kanth Manne, Frederik Denorme, Elizabeth A. Middleton, Irina Portier, Jesse W. Rowley, Chris Stubben, Aaron C. Petrey, Neal D. Tolley, Li Guo, Mark Cody, Andrew S. Weyrich, Christian C. Yost, Matthew T. Rondina, Robert A. Campbell; (2020) Platelet gene expression and function in patients with COVID-19. Blood; 136 (11): 1317–1329. https://doi.org/10.1182/blood.2020007214

 

findings demonstrate that COVID-19 is associated with substantial alterations in the platelet transcriptome and proteome, and platelet hyperreactivity.

 

Dasgupta, A (2020, November 3) The Specter of Endothelial Injury in COVID-19; The Scientist; https://www.the-scientist.com/news-opinion/the-specter-of-endothelial-injury-in-covid-19-68121

 

Fraser, Douglas D. MD, PhD Patterson, Eric K. PhD; Slessarev, Marat MD, MSc; Gill, Sean E. PhD; Martin, Claudio MD, MSc; Daley, Mark PhD; Miller, Michael R. PhD; Patel, Maitray A. BS; dos Santos, Claudia C. MD, MSc; Bosma, Karen J. MD1,,5; O’Gorman, David B. PhD1,,10; Cepinskas, Gediminas DVM, PhD1,,11; on behalf of the Lawson COVID19 Study Team; (2020, September) Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation, Critical Care Explorations. Volume 2 - Issue 9 - p e0194 http://doi.org/10.1097/CCE.0000000000000194  

 

atients that were either coronavirus disease 2019 positive or coronavirus disease 2019 negative were enrolled. Cohorts were well balanced with the exception that coronavirus disease 2019 positive patients were more likely than coronavirus disease 2019 negative patients to suffer bilateral pneumonia. Mortality rate for coronavirus disease 2019 positive ICU patients was 40%. Compared with healthy control subjects, coronavirus disease 2019 positive patients had higher plasma von Willebrand factor (p < 0.001) and glycocalyx-degradation products (chondroitin sulfate and syndecan-1; p < 0.01). When compared with coronavirus disease 2019 negative patients, coronavirus disease 2019 positive patients had persistently higher soluble P-selectin, hyaluronic acid, and syndecan-1 (p < 0.05), particularly on ICU day 3 and thereafter. Thrombosis profiling on ICU days 1–3 predicted coronavirus disease 2019 status with 85% accuracy and patient mortality with 86% accuracy. Surface hyaluronic acid removal from human pulmonary microvascular endothelial cells with hyaluronidase treatment resulted in depressed nitric oxide, an instigating mechanism for platelet adhesion to the microvascular endothelium.

 

Thrombosis profiling identified endothelial activation and glycocalyx degradation in coronavirus disease 2019 positive patients. Our data suggest that medications to protect and/or restore the endothelial glycocalyx, as well as platelet inhibitors, should be considered for further study.

 

George Goshua, MD;    Alexander B Pine, MD;  Matthew L Meizlish, MPhil;  C-Hong Chang, PhD; Hanming Zhang, PhD;   Parveen Bahel, MS;  Audrey Baluha, RN;  Noffar Bar, MD; Robert D Bona, MD;    Adrienne J Burns, PA-C; Charles S Dela Cruz, MD;  Anne Dumont, RN; Stephanie Halene, MD; Prof John Hwa, MD;  Jonathan Koff, MD; Hope Menninger, PA-C;  Natalia Neparidze, MD;  Christina Price, MD;     Jonathan M Siner, MD;  Christopher Tormey, MD; Prof Henry M Rinder, MD; Hyung J Chun, MD; Alfred I Lee, MD;

 

(2020, Aug 1, e-pub 2020 June 30) Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study; The Lancet. 7(8) E575-E582; https://doi.org/10.1016/S2352-3026(20)30216-7

 

An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.

 

68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan–Meier analysis (hazard ratio 5·9, 95% CI 1·9–18·4; p=0·0087)

 

Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.

 

Eugenio D. Hottz, Isaclaudia G. Azevedo-Quintanilha, Lohanna Palhinha, Lívia Teixeira, Ester A. Barreto, Camila R. R. Pão, Cassia Righy, Sérgio Franco, Thiago M. L. Souza, Pedro Kurtz, Fernando A. Bozza, Patrícia T. Bozza; (2020) Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood;  136 (11): 1330–1341. doi: https://doi.org/10.1182/blood.2020007252

 

Although the mechanisms underlying platelet activation in COVID-19 remain unknown, our data show that inflammatory and/or procoagulant mediators in COVID-19 patients may contribute to platelet activation. These data are consistent with the notion that intense cytokine production may trigger hyperinflammation and hypercoagulability.43  Proinflammatory cytokines and procoagulant factors such as thrombin may also contribute to TF expression in monocytes,60  even though TF expression was strongly associated with platelet-monocyte interaction in our cohort of severe COVID-19. Platelets are also known to modulate monocyte secretion of cytokines and chemokines.19,20,63  We have previously shown that platelet monocyte interactions change the monocyte cytokine profile during dengue infection toward a proinflammatory pattern.20  Similar results have been reported for platelet-monocyte interactions in peripheral artery disease and aging,63,64  although different mechanisms are involved in platelet-monocyte interactions during sterile or infection-driven inflammation.20,63,64  New studies are still necessary to determine how systemic inflammation contribute to platelet activation in COVID-19 and whether activated platelets amplify inflammation and hypercoagulability in these patients.

 

In summary, we describe novel mechanisms of activation-dependent platelet-induced TF expression in monocytes during COVID-19 that were associated with severity and mortality in a cohort of ICU-admitted severe COVID-19 patients. Considering the growing body of evidence showing hypercoagulability as a pathologic feature in COVID-19 ARDS, each of these molecular events and cellular interactions potentially contributes to COVID-19 pathogenesis. New studies are still necessary to address the potential implications of platelet-monocyte interactions and TF activity as therapeutic targets in critically ill COVID-19 patients.

 

Bernard S. Kadosh, , Michael S. Garshick, , Juan Gaztanaga, , Kathryn J. Moore, , Jonathan D. Newman, Michael Pillinger, , Ravichandran Ramasamy, , Harmony R. Reynolds, , Binita Shah, , Judith Hochman, Glenn I. Fishman, , Stuart D. Katz (2020, July 20) COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients with Cardiovascular Disease, Arteriosclerosis, Thrombosis, and Vascular Biology.  40(9): 2045-2053 https://doi.org/10.1161/ATVBAHA.120.314513 

 

Patients with diabetes mellitus, obesity, and heart disease are at a greater risk for severe complications of coronavirus disease 2019 (COVID-19).

  • Vascular inflammation and trained immunity associated with cardiometabolic diseases may increase risk of hyperinflammatory response to COVID-19 infection.
  • Drugs with anti-inflammatory properties developed for the treatment of cardiometabolic disease are being evaluated in clinical trials of COVID-19 patients.

 

Peter Libby, Thomas Lüscher, (2020, August 21) COVID-19 is, in the end, an endothelial disease, European Heart Journal, Volume 41, Issue 32, Pages 3038–3044, https://doi.org/10.1093/eurheartj/ehaa623

 

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

 

Lowenstein CJ & Soloman, SD (2020) Severe COVID-19 is a Microvascular Disease; Circulation. 142: 1609-1611 https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.050354   http://www.doi.org/10.1161/CIRCULATIONAHA.120.050354

 

... accumulating  clinical,  laboratory,  and  autopsy  evidence  suggests  that  endothelial  exocyto-sis  plays  a  central  role  in  the  pathogenesis  of  severe  COVID-19.  Endothelial  release  of  P-selectin  and  VWF  activate 2 parallel pathways, leukocyte adherence and platelet  aggregation,  that  lead  to  the  cytokine  storm  and massive thrombosis that are characteristic of severe COVID-19.  Clinical  trials  are  needed  that  test  the  ef-ficacy of drugs that target the pathway of endothelial exocytosis in patients with COVID-19

 

 

 

NIH Feature (2020, Oct 20), Arterial Wall Cells Offer Insight into Coronavirus’ Rampage from Head to Toe, US Department of Health and Human Services, National Institutes of Health, National Heart Lung, and Blood Institute, Research Feature

 

https://www.nhlbi.nih.gov/news/2020/arterial-wall-cells-offer-insight-coronavirus-rampage-head-toe

 

Perico, L., Benigni, A., Casiraghi, F., Ng LFP, Renia, L & Remuzzi, G  (2020, October 19) Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nature Reviews Nephrology. https://doi.org/10.1038/s41581-020-00357-4

 

Available evidence demonstrates that SARS-CoV-2 infection induces immune dysfunction, widespread endothelial injury, complement-associated coagulopathy and systemic microangiopathy. The clinical outcome of COVID-19 seems to be profoundly dependent on the individual response of the host. Although the contribution of differences in viral loads to clinical outcome cannot be excluded271, it is possible that predisposing genetic or biological factors may modulate the degree of disease severity. Additionally, socioeconomic conditions and structural racism may contribute to poor disease outcomes in some regions, as demonstrated by disproportionately poor outcomes among minority ethnic groups, including Black, Asian and Pakistani populations272. Improved insights into the mechanisms underlying predisposition to adverse disease outcomes might aid the identification of new strategies and targets for therapy, as well as identify ways to improve outcomes for susceptible individuals and those from minority ethnic backgrounds. However, the development of new drugs is a long process and may not be useful for dealing with the immediate challenge posed by the current COVID-19 pandemic.

 

Currently, no vaccines or effective antiviral drugs are available for COVID-19, although many are in development and some may become available soon. The paucity of available specific therapies has stimulated the search for existing drugs that can be repurposed for COVID-19. So far, these drugs have included steroids, several anti-interleukin drugs, complement inhibitors and agents that target coagulation and endothelial dysfunction. However, some of these next-generation targeted therapies are not devoid of adverse effects, which can be serious and sometimes life-threatening. The identification of inexpensive and effective drugs — including low-dose steroids and LWMH — is of utmost importance to prevent exacerbation of inflammatory and thrombotic processes and halt disease progression. Given the spectrum of pathogenic mechanisms involved in the development of severe COVID-19, ranging from immune hyperactivation to thromboembolic complications, it is unlikely that a single individual treatment will be effective. Although corticosteroids may be able to target most of these pathogenic pathways, the multifactorial pathogenic nature of the disease indicates that multiple avenues of treatment might be required and major effort should therefore be invested to determine the optimal timing and combinations in which these drugs should be administered to maximize their efficacy in severely ill patients with COVID-19.

 

 Siddiqi, H. K., Libby, P., & Ridker, P. M. (2020). COVID-19 – A vascular disease. Trends in Cardiovascular Medicine, Advance online publication. https://doi.org/10.1016/j.tcm.2020.10.005

 

 Alexander P J Vlaar, PhD; Sanne de Bruin, MD; Matthias Busch, MD; Sjoerd A M E G Timmermans, MD;

 

Ingeborg E van Zeggeren, MD; Rutger Koning, MD; Liora ter Horst, MD; Esther B Bulle, MD; Frank E H P; van Baarle, MD; Marcel C G van de Poll, PhD; E Marleen Kemper, PhD; Iwan C C van der Horst, PhD; Marcus J Schultz, PhD; Janneke Horn, PhD; Frederique Paulus, PhD; Lieuwe D Bos, PhD; W Joost ; Wiersinga, PhD; Martin Witzenrath, PhD; Simon Rueckinger, PhD; Korinna Pilz, MD; Matthijs C Brouwer, PhD; Ren-Feng Guo, MD; Leo Heunks, PhD; Pieter van Paassen, PhD; Niels C Riedemann, PhD; Diederik van de Beek, PhD; (2020, September 28) Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial; The Lancet Rheumatology;  https://doi.org/10.1016/S2665-9913(20)30341-6  https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30341-6/fulltext

 

Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19.

 

In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint.

 

 

 

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