The endothelium is vital for maintaining vascular homeostasis, acting as a barrier, and regulating immune responses to repair damage and combat pathogens. Its protective mechanisms can, however, exacerbate disease progression when excessively activated. Altered endothelial function contributes to organ dysfunction in acute COVID-19 and possibly to post-COVID syndrome.
At rest, the endothelium produces substances that inhibit clot formation and promote vasodilation, such as heparan sulfate proteoglycans, nitric oxide, and prostacyclin.
During injury or infection, the endothelium rapidly shifts to a procoagulant state, releasing von Willebrand factor, a key mediator of clot formation. Pro-inflammatory cytokines further amplify endothelial activation by stimulating leukocyte adhesion and infiltration into the vessel walls.
A review by Harvard Medical School demonstrated how SARS-CoV-2 disrupts endothelial function, promoting thrombosis and inflammation that lead to long-term complications, including post-COVID syndrome.
SARS-CoV-2 and Endothelial Dysfunction
The infection induces the release of pro-inflammatory cytokines such as interleukin-1 (IL-1), interferons, and interleukin-6 (IL-6), which contribute to thrombosis:
- IL-1 promotes excessive IL-6 production. IL-6 increases fibrinogen synthesis in the liver and endothelial secretion of PAI-1, a protein that inhibits clot breakdown.
- IL-1 also affects the hypothalamic thermoregulatory center, triggering fever—a clinical marker of cytokine storm. This storm activates the endothelial “combat mode,” fostering thrombosis and organ inflammation.
- Inflamed endothelium releases molecules that enhance leukocyte adhesion and infiltration into lung tissue, disrupting oxygen exchange. This inflammatory process may also lead to vasoconstriction.
- Activated leukocytes generate superoxide anions, which react with nitric oxide to form peroxynitrite, inducing oxidative stress and tissue damage.
- During inflammation, the endothelium produces endothelin, a peptide that narrows blood vessels and exacerbates inflammation.
Figure 1. Endothelial function in health and disease
Image source: https://www.science.org/doi/10.1126/science.add2962
Thrombosis in COVID-19
Early in COVID-19, elevated D-dimer levels indicate systemic clotting activation. Higher D-dimer levels correlate with worse outcomes. Thrombosis in COVID-19 stems from endothelial changes and blood composition alterations. Additionally, neutrophil extracellular traps (NETs)—formed during neutrophil-mediated cell death—can promote thrombosis by capturing platelets and fibrin.
Some patients with COVID-19 develop ischemic strokes caused by blocked arteries supplying the brain. Microthrombosis in the heart, kidneys, and lungs has also been observed, contributing to multi-organ failure. Myocardial damage may result from both thrombosis and direct viral infection of cardiac cells. Venous thrombosis occurs in up to 20% of patients and can lead to pulmonary embolism.
Long-Term Consequences of COVID-19
Resolution of acute inflammation and tissue healing may lead to fibrosis in the lungs, kidneys, and heart. Over 40% of recovered COVID-19 patients experience impaired myocardial function for more than four months. Some patients with post-COVID syndrome exhibit autonomic cardiovascular dysfunction resembling postural orthostatic tachycardia syndrome (POTS), characterized by an inappropriately high heart rate upon standing.
Therapeutic Approaches
While anticoagulants and antiplatelet drugs showed promise, they have not significantly improved outcomes due to increased bleeding risks. Current clinical guidelines recommend prophylactic or low-dose anticoagulant therapy with heparin only for hospitalized patients.
Glucocorticoids, such as dexamethasone, have proven effective in reducing inflammation in severe COVID-19. Agents targeting IL-6 or baricitinib—a Janus kinase 1 and 2 inhibitor—are reserved for severe cases due to the potential weakening of the immune response.
Conclusions
The endothelium plays a central role in COVID-19 progression. Its dysfunction leads to thrombosis, multi-organ failure, and long-term complications. Despite the risk of thrombosis, anticoagulants should be used judiciously, considering bleeding risks, and anti-inflammatory therapies should be reserved for severe cases only.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Endothelial inflammation in COVID-19
