COVID-19 Research: Complement Cascade Of Immunity System And Coagulation Dysfunction Are What Triggers COVID-19 Severity Outcomes

COVID-19 Research: According to a new study from researchers at Columbia University Irving Medical Center, the immune system’s oldest branches, called complement, may be influencing the severity of COVID-19 disease.


 
Interestingly among other findings linking complement to COVID, the researchers found that people with age-related macular degeneration; a disorder caused by overactive complement are at greater risk of developing severe complications and dying from COVID.
 
The research findings were published in the journal: Nature Medicine https://www.nature.com/articles/s41591-020-1021-2
 
The correlation with the complement system suggests that existing drugs that inhibit the complement system could help treat patients with severe disease.
 
The so called complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.
 
Typically the complement system consists of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this complement activation or complement fixation cascade is stimulation of phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and activation of the cell-killing membrane attack complex. Over 30 proteins and protein fragments make up the complement system, including serum proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of blood serum.


 
Three complex biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway.
 
The researchers also found evidence that clotting activity is linked to COVID severity and that mutations in certain complement and coagulation genes are associated with hospitalization of COVID patients.

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Dr Sagi Shapira, PhD, MPH, who led the study with Dr Nicholas Tatonetti, PhD, both Professors at Columbia University Vagelos College of Physicians and Surgeons told Thailand Medical News, “Together these results provide important insights into the pathophysiology of COVID-19 and paint a picture for the role of complement and coagulation pathways in determining clinical outcomes of patients infected with SARS-CoV-2.”
 
The researchers’ decision to investigate the role of coagulation and complement in COVID began with a sweeping survey of viral mimicry across all viruses on earth over 7,000 in all.
 
Dr Shapira said, “Viruses have proteins that can mimic certain host proteins to trick the host’s cells into aiding the virus with completing its life cycle. Beyond the fundamental biological questions that we were interested in addressing, based on our previous work and the work of others, we suspected that identifying those mimics could provide clues about how viruses cause disease.”
 
The survey found that coronaviruses are masters of mimicry, particularly with proteins involved in coagulation and proteins that make up complement, one of the oldest branches of the human immune system.
 
The complement proteins work a bit like antibodies and help eliminate pathogens by sticking to viruses and bacteria and marking them for destruction. Complement can also increase coagulation and inflammation in the body.
 
Dr Shapira warned, “Unchecked, these systems can also be quite detrimental. The new coronavirus by mimicking complement or coagulation proteins might drive both systems into a hyperactive state.”
 
The study team said that since complement and coagulation influence severity of COVID, people with pre-existing hyperactive complement or coagulation disorders should be more susceptible to the virus.
 
This led Dr Shapira and Dr Tatonetti to look at COVID patients with macular degeneration, an eye disease caused by overactive complement, as well as common coagulation disorders like thrombosis and hemorrhage.
 
Interestingly among 11,000 COVID-19 patients who came to Columbia University Irving Medical Center with suspected COVID-19, the researchers found that over 25% of those with age-related macular degeneration died, compared to the average mortality rate of 8.5%, and roughly 20% required intubation. The greater mortality and intubation rates could not be explained by differences in the age or sex of the patients.
 
Dr Shapira stressed, “Complement is also more active in obesity and diabetes and may help explain, at least in part, why people with those conditions also have a greater mortality risk from COVID.”
 
Individuals with a history of coagulation disorders also were at increased risk of dying from COVID infection.
 
The study team also examined how gene activity differed in individuals infected with the coronavirus.
 
Significantly, that analysis revealed a signature in COVID-infected patients indicating that the virus engages and induces robust activation of the body’s complement and coagulation systems.
 
Dr Tatonetti added, “We found that complement is one of the most differentially expressed pathways in SARS-CoV-2 infected patients. As part of the immune system, you would expect to see complement activated, but it seems over and above what you’d see in other infections like the flu.”
 
Mounting evidence linking severe COVID with coagulation and complement comes from a genetic analysis of thousands of COVID patients from the U.K. Biobank, which contains medical records and genetic data on half a million people.
 
The study team found that variants of several genes that influence complement or coagulation activity are associated with more severe COVID symptoms that required hospitalization.
 
Dr Shapira added, “These variants are not necessarily going to determine someone’s outcome. But this finding is another line of evidence that complement and coagulation pathways participate in the morbidity and mortality associated with COVID-19.”
 
Doctors treating COVID-19 patients have noticed coagulation issues since the beginning of the pandemic, and several clinical trials are underway to determine the best way to use existing anti-coagulation treatments.
Complement inhibitors are currently used in relatively rare diseases, but at least one clinical trial is testing the idea with COVID patients.
 
Dr Tatonetti added, “I think our findings provide a stronger foundation for the idea that coagulation and complement play a role in COVID and will hopefully inspire others to evaluate this hypothesis and see if it’s something that can be useful for fighting the ongoing pandemic.”
 
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