Studies by researchers at Columbia University Irving Medical Center suggest that one of the immune system’s oldest branches, the complement system, and coagulation dysfunction, may be influencing the severity of COVID-19. The team found evidence that clotting activity is linked to COVID-19 severity and that mutations in certain complement and coagulation genes are associated with hospitalization of COVID-19 patients. Among the results linking complement to COVID-19 severity, was the finding that individuals with age-related macular degeneration—a disorder caused by overactive complement—are at greater risk of developing severe complications and dying from SARS-CoV-2 infection.

The link between disease severity and complement indicates that existing drugs that inhibit the complement system could feasibly help to treat patients with severe COVID-19. “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,” said Sagi Shapira, PhD, MPH, who led the reported study with Nicholas Tatonetti, PhD, who are both professors at Columbia University Vagelos College of Physicians and Surgeons.

The scientists’ results are published in Nature Medicine, in a paper titled, “Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection.”

Understanding the pathophysiology of SARS-CoV-2 infection will be “critical” for developing therapeutic and public health strategies, the authors wrote. Their idea to investigate the role of coagulation and complement in COVID began following a sweeping survey of viral mimicry across more than 7,000 viruses. “Viruses have proteins that can mimic certain host proteins to trick the host’s cells into aiding the virus with completing its life cycle,” Shapira said. “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. “Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses,” the team noted “… we mapped over 140 cellular proteins that are structurally mimicked by coronaviruses (CoVs) and identified complement and coagulation pathways as targets of this strategy across all CoV strains.”

Complement proteins work a bit like antibodies and help to eliminate pathogens by sticking to viruses and bacteria and marking them for destruction. Complement can also increase coagulation and inflammation in the body. “Unchecked, these systems can also be quite detrimental,” noted Shapira. “The new coronavirus—by mimicking complement or coagulation proteins—might drive both systems into a hyperactive state.”

So, if complement and coagulation influence severity of COVID-19, then people with pre-existing hyperactive complement or coagulation disorders should be more susceptible to the virus. That led Shapira and Tatonetti to look at COVID-19 patients who also had macular degeneration—an eye disease caused by overactive complement—as well as common coagulation disorders like thrombosis and hemorrhage. They reviewed data on 11,000 patients who came to Columbia University Irving Medical Center with suspected COVID-19, and found that more than 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.

The study also found that individuals with a history of coagulation disorders also were at increased risk of dying from COVID-19 infection. “To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis, and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex, or history of smoking.”

The findings might also help to explain why people with other health conditions are more likely to develop severe COVID-19. “Complement is also more active in obesity and diabetes,” Shapira stated, “and may help explain, at least in part, why people with those conditions also have a greater mortality risk from COVID-19.”

The researchers also examined how gene activity differed in people infected with the coronavirus. That analysis revealed a signature in COVID-infected patients indicating that the virus triggered activation of the body’s complement and coagulation systems. “Transcriptional profiling of nasopharyngeal swabs (NPs) from 650 control and SARS-CoV-2-infected patients demonstrated that infection results in robust engagement and activation of complement and coagulation pathways,” they wrote. “We found that complement is one of the most differentially expressed pathways in SARS-CoV-2 infected patients,” Tatonetti noted. “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.”

More evidence linking severe COVID-19 with coagulation and complement was garnered from a genetic analysis of thousands of COVID-19 patients from the U.K. Biobank, which contains medical records and genetic data on half a million people. The authors found that variants of several genes that influence complement or coagulation activity are associated with more severe COVID-19 symptoms that required hospitalization. “ … our candidate-driven analysis of genetic variation and severe SARS-CoV-2 disease yielded putative loci including missense, eQTL, and sQTL variants of critical regulators of the complement and coagulation cascades,” the team noted. “In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility.”

The authors acknowledged that their findings don’t pin causality on complement or coagulation factors. “So, claims on causality cannot be made, nor can we definitively rule out other clinical factors as possible drivers of disease,” they wrote. “These variants are not necessarily going to determine someone’s outcome,” Shapira further noted. “But this finding is another line of evidence that complement and coagulation pathways participate in the morbidity and mortality associated with COVID-19.”

In fact, physicians 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-19 patients. “I think our findings provide a stronger foundation for the idea that coagulation and complement play a role in COVID,” Tatonetti stated, “and will hopefully inspire others to evaluate this hypothesis and see if it’s something that can be useful for fighting the ongoing pandemic.”

As the authors concluded, “ … the observations advance our understanding of how SARS-CoV-2 infection leads to disease and can help explain variability in clinical outcomes. Among the implications, the data warrant heightened public health awareness for the most vulnerable individuals and further investigation into an existing menu of complement and coagulation targeting therapies that were recently shown to be beneficial in a small cohort of patients with SARS-CoV-2 infection.”

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