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ASH 2020 | TMA-associated variants linked to severe COVID-19

Eleni Gavriilaki, MD, PhD, National and Kapodistrian University of Athens, Athens, Greece, shares the findings of an investigation into genetic susceptibility in patients with severe COVID-19, and its association with disease severity. Evidence indicates the presence of excessive complement activation in severe COVID-19 and common characteristics with complement-mediated thrombotic microangiopathy (TMA). Therefore, the prospective study obtained patient DNA and created amplicons to TMA-associated gene exons. The findings of pathogenic variants in complement-regulatory genes suggest genetic susceptibility to COVID-19. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

Transcript (edited for clarity)

So when the COVID-19 pandemic started, we were looking to the scientific field to see if our expertise can be in use to fight this new deadly virus.

We have been working with complement over the last years, and we have expertise in functional and genetic complement assays in our laboratory at George Papanicolaou Hospital in Thessaloniki, Greece. Therefore, we based our project on the initial results showing complement activation in patients with severe COVID-19...

So when the COVID-19 pandemic started, we were looking to the scientific field to see if our expertise can be in use to fight this new deadly virus.

We have been working with complement over the last years, and we have expertise in functional and genetic complement assays in our laboratory at George Papanicolaou Hospital in Thessaloniki, Greece. Therefore, we based our project on the initial results showing complement activation in patients with severe COVID-19.

These results we’re prompted by previous studies in previous coronaviruses, but also were confirmed in the SARS-CoV-2 virus. What we know from complement-mediated diseases and complement-mediated thrombotic microangiopathy is that there is an existing genetic susceptibility. That means that many patients have genetic variance with germline mutations. They have this variance when they are born, but when they have a certain trigger, they may develop the thrombotic microangiopathy manifestations.

In COVID-19, this had not been studied yet. So we aimed firstly, to see if there is a genetic susceptibility and then to try to find certain variants that could help build an everyday clinical testing to see which patient might have severe COVID-19 and might need intensive care unit hospitalization.

In our study, we were able to identify a combination of variants between three major genes, ADAMTS-13, complement C3 and complement factor 8. The combination of these variants was independently associated with the severity of the disease. And also with other severity markers, like the lymphocyte count and the ratio of lymphocytes to neutrophils. These findings are very encouraging, and we now try first to validate them in other cohorts, and second, and more important, to identify an algorithm that will help us select one or two variants, and along with a laboratory and clinical parameters of the patient could get 100% of prediction of severe disease.

We believe that this is very important to help intensify the treatment of COVID-19, because we know that intensified treatment needs to be given as early as possible. Also, we think that these findings will help develop furthermore, the complement inhibitors in this field. We know that several complement inhibitors have shown encouraging results during the early phase of this pandemic, and now there are ongoing clinical trials to help establish their role.

In Greece, we’re very lucky to participate in a clinical trial of AMY-101. That is expected to have a very good results in our patients.

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