Antibody-Activated Endothelial Cells Increase the Risk of Blood Clots with Covid-19

(Posted on Friday, March 4, 2022)

The activity of antiphospholipid antibodies may help explain hypercoagulation associated with late stages of Covid-19 and long-term post-acute sequelae SARS-CoV-2 infection (PASC), also known as long-haul Covid-19. A recent study found that at least forty-five individuals out of every thousand infected with Covid-19, regardless of age, gender, race, and prevalence of pre-existing conditions, experience serious cardiovascular consequences, including widespread blood clots. Forty-five out of a thousand may seem small, but given that there are an estimated 140 million Covid-19 cases nationally, over six million people could be at risk. Shi et al., writing for Arthritis & Rheumatology, analyzed blood samples from nearly 250 individuals hospitalized for Covid-19 and found that Covid-19-induced blood clots may be triggered partly by “rouge” autoantibodies.

Unlike other antibodies, natural autoantibodies can be generated outside of the immune system and bind to a variety of non-related antigens. These antibodies, by definition, attack the body’s own cells. Exposure to the SARS-CoV-2 virus seems to induce a vigorous antibody response, including an enhanced recruitment of autoantibodies that may attack uninfected cells and tissues.

Covid-19-induced thrombosis, or blood clotting, is common among people hospitalized for severe infection, with estimates suggesting that nearly 60% of those that die from the virus are affected. Emerging research reveals that SARS-CoV-2 activates endothelial cells that line blood vessels, making them vulnerable to clotting. As Dr.Hui Shi, lead author and rheumatology research fellow at Michigan Medicine, explains “When endothelial cells are activated, they cause healthy blood vessels to become ‘sticky’, attracting other cells to the vessel walls and becoming more prone to thrombosis. This can affect many of the body’s essential organs,”

How are endothelial cells activated in the first place? Shi et al. 2022 suggests there may be a connection between increased circulation of antiphospholipid autoantibodies and endothelial activation. In a previous investigation, the team intriguingly found that exposing mice to the autoantibodies from the blood of Covid-19 patients produced a “striking amount of clotting.”

Their interest in autoantibodies as potential biomarkers for Covid-19 was further supported by evidence that antiphospholipid antibodies mediate a rare autoimmune disorder called antiphospholipid syndrome (APS). In this condition, the body produces antibodies that target its own fat molecules— phospholipids— involved in forming blood clots. The present study not only shed light on how Covid-19 induces thrombosis but may also explain the underlying mechanisms of this life-threatening disease.

Shi et al. began their investigation by confirming that Covid-19 does in fact activate endothelial cells. Using blood samples from 118 individuals hospitalized with Covid-19, serum collected after blood cells were left to clot revealed increased expression of cell adhesion molecules, E-selectin, VCAM-1 and ICAM-1. These surface proteins are upregulated during immune responses to facilitate the binding and activation of white blood cells on endothelial cells. Overexpression of E-selectin, VCAm-1, and ICAM-1 surface proteins, however, can signify that endothelial cells are being overpowered and subsequently weakened by immune activity.

In fact, increased expression of these adhesion proteins was shown to correlate with worse Covid-19 outcomes. For example, after obtaining additional serum samples from 126 hospitalized Covid-19 patients, Shu et al. 2020 found that individuals requiring oxygen ventilation experienced greater upregulation of ICAM-1, compared to unventilated controls.

How much does Covid-19 contribute to these effects? Could endothelial activation simply be a symptom of any severe disease? To answer these questions, investigators compared plasma samples from 100 individuals admitted to intensive care for sepsis infections to plasma from their Covid-19 cohort. Unlike serum, plasma is extracted after anti-clotting agents are added to blood samples. Although the individuals with sepsis more often required mechanical ventilation, their ICAM-1 levels were significantly lower compared to plasma samples from individuals hospitalized for Covid-19. This suggests that increased expression of surface adhesion molecules, as well as the corresponding activation of endothelial cells, may be specific to the SAR-CoV-2.

The team then asked how antiphospholipid antibodies may mediate these effects. Interestingly, they found a strong correlation between endothelial activation and the prevalence of autoantibody subtypes, anticardiolipin and anti-phosphatidylserine/prothrombin (anti-PS/PT), in immunoglobulin tests. In particular, significantly high levels of anticardiolipin and anti-PS/PT autoantibodies were detected in IgG tests from their Covid-19 cohort with enhanced expression of ICAM-1, compared to healthy controls and sepsis patients. Depleting the IgG samples of anticardiolipin and anti-PS/PT also prevented the upregulation of E-selectin, VCAM-1 and ICAM-1 surface proteins

Although the researchers conclude that the presence of antiphospholipid antibodies in Covid-19 IgG samples can activate endothelial cells, the underlying mechanism remains unclear. Further investigations are needed to determine if the prevalence of these autoantibodies could be a useful biomarker for identifying an infected individual’s risks for severe Covid-19 compilations, such as thrombosis and respiratory failure.

How such high amounts of autoantibodies are created in the first place also remains a mystery. An emerging theory suggests that the heightened activity of autoantibodies may be linked to the immune response of circulating B cells during Covid-19. Naïve B cells generated from bone marrow stem cells circulate the body looking for foregin pathogens, without first being “educated” at the follicles of the lymph nodes. When the body is exposed to SARS-Cov-2, naïve B cells seem to take an extrafollicular route, bypassing the lympoids, to quickly transform into antibodies. As seen in the autoimmune disease lupus, antibodies created outside of lymphoid follicles do not benefit from counterselection against those that may react against the body, aka autoantibodies. As one recent study reports, extrafollicular maturation of B cells may be a hallmark of Covid-19 infection. Our understanding of this mechanism, however, is limited.

Given the very high incidence of Covid-19-induced coagulation, as well as short and long term cardiovascular disease, understanding the contribution of antiphospholipid autoantibodies is increasingly important. Several likely mechanisms seem to contribute to bystander damage to blood vessels exposed to SARS-CoV-2, including direct infection and exaggerated activation of the immune system via a “cytokine storm.” Autoantibodies may only be one piece of a much larger puzzle.

Read the full article on Forbes.