Endothelial Damage Associated With COVID-19

The endothelium is a thin membrane that lines the entire vascular system, and it plays an important role in vascular tone, immune function, fluid filtration, vascular permeability, and hemostasis. The phenotypical heterogeneity of the endothelium’s role is due to varied membrane-bound molecular receptors¹ so that the endothelium will function differently in say, the glomeruli of the kidneys versus the arterioles of the lower extremities. The endothelium is also a source of growth factors and other vasoactive substances that play a role in angiogenesis and cell proliferation,¹ making it a key organ in response to injury and the healing cascade. The interaction between inflammation, immune cellular response, and the endothelium was first observed over 160 years ago; even without morphological damage, an inflamed endothelium can induce platelet adhesion and leukocyte rolling along its surface that leads to the extravasation of white blood cells and thrombotic vascular occlusion.¹ Viral infection is one of the known stimuli for inflammation of the endothelium.¹

Scientists have postulated that the endothelium, not the lung, is the target organ of SARS-CoV-2.² The COVID-19 virus is associated with respiratory symptoms, including cough, nasal congestion, and shortness of breath, but is also known to cause vomiting, diarrhea, confusion, headache, arthralgia, myalgia, palmus, and chest pain.^3,4 This is consistent with known damage to multiple systems that can occur outside of the lungs, such as the brain, heart, vasculature, and kidneys.⁵ Viral infections occur by a virus binding to host surface receptor on a cell, similar to a key unlocking the cell to allow for entry of the viral nucleic acids for replication. In SARS-CoV-2, the primary cellular entry receptor in target human cells is angiotensin-converting enzyme 2 (ACE2) receptor.^6,7 This leads to internalization of the receptor, which alters the availability of ACE2 to convert the vasoconstrictive/pro-inflammatory hormone angiotensin II into its vasodilatory/anti-inflammatory-form angiotensin.^1-7 Different body tissues exhibit different expression of ACE2, including the brain, heart, vascular system, kidneys, and lungs.^4,8 A dysregulated renin-angiotensin system also occurs in hypertension. Hypertension is a common comorbidity in COVID-19 infection and known to produce chronic low-grade vascular inflammation. COVID-19 can result in systemic inflammation and high levels of inflammatory cytokines, which is more pronounced in patients who have hypertensive.⁴  Hypertension is also associated with increased transmissibility and severity of COVID-19, including increased mortality, acute respiratory distress syndrome, intensive care unit admission, and disease progression.⁴ Knowing that SARS-CoV-2 uses specific receptors in the endothelium for cellular entry, and the expression of these receptors vary in body tissues begins to explain the myriad of symptoms experienced by the infected.

Negative outcomes associated with COVID-19 also include arterial and venous thrombosis, which can lead to thrombo-embolism and their negative sequelae as well as cardiac events and stroke.⁵ Respiratory infections are a known risk factor for myocardial infarction.⁹ With patients who are hospitalized for COVID-19, over 60% have been shown to have myocardial injury, which was also associated with increased mortality.¹⁰ In the field of wound management, alterations in immune function, inflammation, and circulation can lead to negative outcomes including wound healing stagnation, wound deterioration, reduced ankle-brachial index, osteomyelitis, and amputation. Endothelial dysfunction may worsen peripheral arterial disease due to impaired formation of collateral vessels, impaired remodeling, and promotion of plaque rupture by pro-inflammatory and pro-thrombotic factors.¹ The endothelium normally contributes to vasodilation, but in a disease state the endothelium can produce the potent vasoconstrictor endothelin-1 leading to ischemia.⁵ Derangements in the immune system then result in reduced clearance of enothelin-1.⁴ A condition known as COVID toes presents as red-to-purple macules and papules to the lower extremity digits. They are associated with less severe viral infection, and typically present in younger patients who are otherwise asymptomatic.¹¹ Patients with more serious COVID-19 infections have been found to have ischemic lesions on the feet that may appear as patchy purple to red, livedo, or purpuric, and are a physical sign of inflammatory viral micro-angiopathy localized due to endothelial vascular phenotypical heterogeneity, and indicative of tissue ischemia.⁵

The cerebral-vascular system is not exempt from COVID-19-associated endothelial damage. One study found postmortem high-resolution magnetic resonance imaging brain scans of most patients with COVID-19 were noted to have microvascular changes, including punctate hyper-intensities indicating microvascular injury and fibrinogen leakage and punctate hypo-intensities corresponding to congested blood vessels with surrounding fibrinogen leakage and largely intact vasculature confirming vascular damage is not only thrombotic in nature.¹²

What does this mean for the field of wound management? Anticoagulant and antiplatelet therapies are under evaluation for treatment of COVID-19; however, this must be balanced with an elevated bleeding risk.⁵ Many patients are discharged on extended courses of traditional anti-coagulant and anti-platelet therapies for complications they experienced while an inpatient. Endothelial dysfunction in COVID-19 can be both reversible and irreversible.¹³ Clinicians should have a high index of suspicion for macrovascular and microvascular complications in patients with wounds and COVID-19, especially given the proclivity of chronic wound patients to have comorbidities that also impact the endothelium (eg, diabetes, arterial disease, venous insufficiency, lymphedema, and hypertension).

References

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