Immune responses to SARS-CoV2 cause activation of platelets, resulting in thrombosis, which can be ameliorated by re-purposed drugs

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Severe COVID-19 infection is associated with the formation of blood clots in the lungs and other organs which dangerously compromise their functions and contribute to mortality of this disease. Platelets are blood cells that trigger blood clotting following an injury, and while abnormal platelet function is associated with thrombosis, the role of these cells in triggering COVID-19-associated clotting is uncertain. In this study we will determine whether changes in platelet function accompanies disease progression and recovery. The serious symptoms suffered by COVID-19 patients are associated with an exaggerated inflammatory response. We hypothesise that this leads to activation of clotting within the blood vessels of the lungs. Importantly the control of clotting and inflammation involves similar processes and proteins within platelets and immune cells involving molecules that may be controlled using drugs that have been designed to control immune responses. Our preliminary experiments have revealed a mechanism which may explain why some patients appear to be particularly predisposed to serious effects of COVID-19 infection while others are relatively unaffected. Antibodies again the virus formed in seriously ill patients appear to be abnormal (pathological antibodies). These stimulate enhanced immune cell function, which may initiate inflammation of blood vessels. Importantly, we have found that these antibodies also stimulate enhanced platelet clotting. This study will be incorporated with an ongoing clinical trial to test the benefits of repurposing drugs that are designed to target the over-active inflammatory response to virus seen in severe infection through inhibiting enzyme proteins that are also important for the regulation of platelet function. Importantly, we have shown that one drug in our trial, fostamatinib, targets the effects of pathological antibodies on platelets, and prevents them from enhancing platelet clotting. We will therefore assess whether drugs that target the effects of these antibodies reduce platelet function in patients, in comparison with patients receiving standard treatments, and examine whether potential benefits of these new treatments are associated with diminished platelet function. The outcomes from this study will establish whether abnormal platelet function lies behind life-threatening COVID pathology, and whether use of drugs that target both the platelet and immune responses to the virus offer promising therapeutic options. If successful, drug repurposing would offer the potential for rapid impact on patient outcomes.