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

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


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 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 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.


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-Barr virus, which could cause PASC pathophysiology.


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.

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