Review explores the involvement of the endothelium as an important underpinning of long COVID’s pathophysiology

Review explores the involvement of the

endothelium as an important
underpinning of long COVID’s
pathophysiology
By Dr. Chinta Sidharthan Sep 6 2022
Reviewed by Danielle Ellis, B.Sc.

In a review paper published in The Journal of Clinical Investigation, researchers

discussed possible mechanisms and potential treatment methods for
endotheliopathy observed in patients with post-acute sequelae of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC).

Study: Long COVID endotheliopathy: hypothesized mechanisms and potential

therapeutic approaches. Image Credit: AvDe/Shutterstock

Background
While the acute coronavirus disease 2019 (COVID-19) pandemic caused SARS-
CoV-2 and resulted in unprecedented mortality worldwide, a widely reported
phenomenon in individuals who recovered from acute COVID-19 was a form of
multi-organ dysfunction medically referred to as PASC. Commonly referred to

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Review explores the involvement of the endothelium as an important underpinning of long COVID’s pathophysiology

as long COVID, it was first observed in hospitalized COVID-19 patients who

could not carry out normal activities even 60 days after discharge.

The World Health Organization (WHO) defined PASC as a condition seen in

individuals who have had confirmed or probable SARS-CoV-2 infection, with
symptoms that usually manifest three months from COVID-19 onset and last
for two months or more and has no alternative diagnosis. The symptoms of
PASC might persist after the initial COVID-19 infection or may appear after the
recovery from COVID-19.

Many of the studied PASC cases resulted from infections with the first SARS-
CoV-2 strain or its early variants. Still, the possibility of PASC after infections
with the recent variants cannot be ruled out. Despite being a widely reported
post-COVID-19 occurrence, the pathophysiology and standard treatment
options are still unknown, highlighting the need to understand the possible
mechanisms of PASC better and explore potential therapeutic avenues.

About the study

Although the pathophysiology is still unclear, studies hypothesized various
mechanisms involving autoantibodies, proinflammatory cytokine signaling,
latent pathogen activation, and SARS-CoV-2 RNA and protein fragments. The
review explored studies that reported PASC features with qualifiable measures
and formulated the hypotheses for PASC pathogenesis based on comparisons
between acute COVID-19 and PASC along parameters such as clinical and
immunological manifestations, hematologic and immunologic markers, and
demographic parameters.

The researchers also considered studies on endothelial cell injury and

cardiopulmonary data in PASC patients. The clinical and immunological
indicators explored in the review include the activation of platelets and
coagulation cascades, an increase in proinflammatory cytokines and
chemokines, the formation of neutrophil extracellular traps, and gastrointestinal
dysfunction. The occurrence of venous and arterial microthrombosis was also
compared between COVID-19 and other acute respiratory distress syndromes,
and therapies using antithrombotics, anticoagulants, and suppressors of
inflammatory signals were considered.

Studies investigating hematologic and immunologic markers such as absolute

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Review explores the involvement of the endothelium as an important underpinning of long COVID’s pathophysiology

neutrophil count, levels of C-reactive protein, ferritin, interleukin (IL) receptors

2 and 6, lactate dehydrogenase levels, and liver function tests were also
reviewed. The impact of comorbidities and demographic parameters such as
hypertension, obesity, sex, age, diabetes mellitus, and cancer were compared
between acute COVID-19 and PASC.

Manifestations of hypoxic brain injury and neuronal degeneration were also

compared between COVID-19 and PASC patients in many of the studies. The
review also included studies investigating cutaneous lesions in COVID-19 and
PASC patients to find a link between PASC and microthrombosis associated with
livedo rash or thrombotic retiform purpura.

Results
This review reported a pattern of small-vessel thrombosis of arteries and veins
in the lungs of COVID-19 mortality cases and the skin of severe COVID-19
patients. Therapies using anticoagulants and antithrombotics to reduce
microthrombosis in SARS-CoV-2 infections have been unsuccessful. The review
found no data on the efficacy of inflammatory signal suppressors in preventing
or treating PASC.

Many studies showed no correlation between the development of PASC and

demographic factors or comorbidities such as age, type of diabetes mellitus,
hypertension, and body mass index. Sexual phenotype, however, did correlate
with the occurrence of PASC, with females showing a greater reduction in the
progression of COVID-19 but a higher tendency to develop PASC.

Endothelial cell injury markers such as von Willebrand factor antigen and
soluble thrombomodulin were higher in PASC patients, as were cytokines
indicating vascular injury. Studies exploring cardiopulmonary PASC symptoms in
patients 11 months after a mild COVID-19 found a decrease in exercise capacity
despite normal hemoglobin levels, resting echocardiograph, and chest CT scan.

The authors believe that this reflects mitochondrial injury by SARS-CoV-2 and
progressive microthrombosis. Headaches and nonspecific cognitive complaints
reported by PASC patients were likely caused by intracerebral microthrombosis.
The presence of SARS-CoV-2 RNA fragments in 25% of PASC patients indicated
that SARS-CoV-2 reservoirs could play a major role in PASC-related
endotheliopathy, as well as possible activation of latent viruses such as Epstein-

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Review explores the involvement of the endothelium as an important underpinning of long COVID’s pathophysiology

Barr virus, which could cause PASC pathophysiology.

Conclusion
Overall, the review links endotheliopathy and microthrombosis to many of the
clinical conditions of PASC and presents alternate mechanisms, such as SARS-
CoV-2 reservoirs, that may play a role in developing PASC. Possible therapeutic
avenues for PASC include steroids, intravenous immunoglobulins,
anticoagulants, antivirals, and COVID-19 vaccination.

However, the findings also show increased risk of PASC with multiple SARS-
CoV-2 infections, regardless of vaccination status, indicating the compelling
need to find effective therapies against PASC.

Journal reference:
Ahamed, J. and Laurence, J. (2022) "Long COVID endotheliopathy:
hypothesized mechanisms and potential therapeutic approaches", Journal
of Clinical Investigation, 132(15). doi: 10.1172/jci161167. https://ww
w.jci.org/articles/view/161167

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is
in evolutionary biology and genetics, and she has extensive experience in scientific
research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in
evolutionary biology from the Indian Institute of Science and is passionate about
science education, writing, animals, wildlife, and conservation. For her doctoral
research, she explored the origins and diversification of blindsnakes in India, as a
part of which she did extensive fieldwork in the jungles of southern India. She has
received the Canadian Governor General’s bronze medal and Bangalore University
gold medal for academic excellence and published her research in high-impact
journals.

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