Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome, 2021, Fogarty et al

[Andy]

Abstract

Background
Persistent symptoms including breathlessness, fatigue and decreased exercise tolerance have been reported in patients after acute SARS-CoV-2 infection. The biological mechanisms underlying this ‘Long COVID’ syndrome remain unknown. However, autopsy studies have highlighted the key roles played by pulmonary endotheliopathy and microvascular immunothrombosis in acute COVID-19. We hypothesized that endothelial cell activation may be sustained in convalescent COVID-19 patients and contribute to Long COVID pathogenesis.

Patients and Methods
Fifty patients were reviewed at a median of 68 days following SARS-CoV-2 infection. In addition to clinical workup, acute phase markers, EC activation and NETosis parameters and thrombin generation were assessed.

Results
Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI -2.57– -1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID-19 patients. These pro-thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID-19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID-19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6-minute walk tests.

Conclusions
Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID-19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.

Open access, https://onlinelibrary.wiley.com/doi/10.1111/jth.15490

 

[Hutan]

Summary:

• patients with moderate to severe Covid-19 were found to show signs of endothelial damage and thrombosis type issues for at least a couple of months after the acute phase of their illness
• this study doesn't tell us much about Long Covid
• this is another example of researchers not having much idea about how to identify and quantify Long Covid symptoms. Perhaps they could ask people who know something about ME/CFS research.

50 patients were included in the review, consecutive patients from a post-Covid-19 review clinic. They were assessed only a median of 68 days after hospital discharge or end of acute Covid-10 symptoms, with a minimum time of 6 weeks. 74% of the patients had been hospitalised and 16% had been in ICU.

The paper presents a range of measures related to thrombin - I don't know the significance of the various measures. Some do look quite different between the patients and the healthy controls (for example B. Lag time), while others had a lot of overlap (for example C. endogenous thrombin potential).



They suggest that persistent increases in plasma Factor VIII levels contribute to ongoing increased thrombin potential in a significant proportion of convalescent Covid-19 patients. They noted that markers of acute phase markers (e.g. CRP, IL6) had normalised in most patients. They didn't find evidence of NETosis in blood (the neutrophil extracellular traps, thought to be used to deal with pathogens).

They did find raised levels of Von Willebrand Factor (like Factor VIII - much VWF is produced by endothelial cells) compared to controls - but there was a big range of results. 30% of patients had VWF:Ag levels above the normal range. They suggest that their findings suggest that endotheliopathy is a common finding in convalescent Covid-19 patients.

They looked at levels of thrombomodulin, because it has been suggested that 'shedding' of thrombomodulin is related to endothelial activation. It, like other markers of endothelial activation, were increased in the Covid-19 convalescents.

Severity of illness, age, co-morbidities all tended to increase VWF, Factor VIII and thrombomodulin.


So, does this have anything to do with Long Covid? They looked to see if Long Covid symptoms correlated with various markers, and didn't find that they did. It's not very clear what they did to measure Long Covid symptoms, other than a 6 minute walk test, maximal exertion (modified Borg scale) and the Chalder Fatigue Scale . So, I don't think that analysis was very strong. They note that the 6 minute walk test result may have been confounded by old age and co-morbidities. (I wish people wouldn't use the 6 minute walk test thinking it is an objective test or that it says much about Long Covid or ME/CFS. As the for the Chalder Fatigue Questionnaire...). And they acknowledge other shortcomings.

The result is that the study does not tell us much about Long Covid, I think, aside from it seems it is fairly normal to have signs of endotheliopathy and immunothrombosis in convalescent Covid-19 patients for two months at least, especially in those whose disease is sufficiently severe to have them being followed up at a post-Covid 19 review clinic.