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Blood clots in severely ill COVID-19 patients caused by abnormal antibody response

Since the pandemic has unfolded, we have learned more about different symptoms affecting COVID-19 patients, such as a cough and shortness of breath to loss of smell or taste. Symptoms vary depending on the severity of the disease; such as reports of inflammation and fatal blood clotting in critically ill COVID-19 patients. However, it is now believed that these latter symptoms of inflammation and blood clotting may be the result of an excessive immune response rather than the direct actions of the virus itself.

A new paper published in the journal Blood includes work by researchers at the University of Reading which focused on thrombi formation (blood clots) in severely ill COVID-19 patients and importantly, they provide evidence of how to treat this condition, [1].

Study Overview

Researchers successfully isolated monoclonal antibodies from samples of severely ill COVID-19 patients, [2]. They cloned and analysed these antibodies and found that they had low levels of fucosylation and elevated galactosylation (Low Fuc High Gal) in the Fc domain; thus illustrating qualitative and quantitative differences compared to those with mild illness.

Gibbins et al., Fig. 1 Ci: Volume of thrombi formed on vWF with immune complexes containing spike and either WT IgG or IgG with modified glycosylation; and Fig. 1 Cii: representative images of thrombi stained with DiOC6.

The study then further examined how this affected platelet-mediated thrombus formation. The study revealed that potent activation of platelets by immune complexes containing SARS-CoV-2 spike and anti-spike IgG only occurs when the IgG expressed both Low Fuc and High Gal in the Fc domain and an additional prothrombotic signal, vWF, is also present.

Gibbins et al., Fig. 5: Aberrant glycosylation of anti-spike IgG in immune complexes act in concert with vWF to enhance platelet thrombus formation.

Enhanced thrombus formation was measured in vitro using Cellix’s Vena8 Fluoro+ biochips. Researchers also found that thrombus formation was sensitive to Fc-gamma-RIIA inhibition and small molecule inhibitors of Syk, Btk and P2Y12, providing a potential treatment strategy to reduce blood clots in critically ill COVID-19 patients.

Professor Jon Gibbins, Director of the Institute for Cardiovascular and Metabolic Research at the University of Reading said, [3]: