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

Severe COVID-19 infection is associated with thrombosis in the lung, heart, kidneys and other organs, and is likely to contribute substantially to the high levels of mortality and morbidity in these patients. Whether abnormal platelet function accompanies disease progression is unknown. We will use deep-phenotyping approaches combined with established multi-parameter analysis to determine whether platelet function is altered in patients upon hospital admission, if this changes through disease progression, and whether levels of change correlate with disease severity. This will be incorporated an interventional study (MATIS) designed to test the benefits of repurposing drugs that target signalling proteins expected to diminish the inflammatory response to virus, which is proposed to lie behind severe disease pathology. These targets, the kinases Syk and Jak, also regulate platelet function. We will therefore also assess the impact of drug administration on platelet function, in comparison with standard of care, and establish whether potential benefits are associated with diminished platelet function. Preliminary data indicate that abnormally glycosylated antibodies produced early in COVID-19 infection enhance platelet function through stimulation of the platelet IgG receptor. We will therefore also determine whether immune-driven activation of platelets (thrombo-inflammation) is inhibited by the licenced Syk and Jak inhibitors.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.