Mechanisms of Thrombosis in SARS CoV-2 Infection

Mechanisms of Thrombosis in SARS-CoV-2 Infection Abstract Since the onset of the pandemic in 2019, more than one billion people worldwide have become infected with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). Early in the pandemic, it became clear that COVID-19 is associated with an increased risk of life- threatening thrombotic events, which affect up to 2-3% of hospitalized patients. In addition, up to 30% of patients experience prolonged symptoms following recovery from the acute infection, termed “long COVID”, which are thought to involve microthrombosis. Thus, long COVID is a major health problem in the United States and will likely continue to be for the foreseeable future. Though the mechanisms leading to thrombosis, in either the acute or long-term phase, are not clear, our studies, and the work of others, suggests contributions of coagulation proteins, platelets, fibrinolytic components, and immune cells to the pathology. We hypothesize that prolonged inflammation results in a hypercoagulable state, characterized by elevated tissue factor and reduced anticoagulant protein S, platelet hyper-reactivity, and impaired fibrinolysis, and leads to the observed increased rate of thrombosis. Our preliminary data support this hypothesis, as we have detected elevated procoagulant tissue factor and von Willebrand Factor, reduced anticoagulant protein S, elevated markers of neutrophil activation (myeloperoxidase, histone H3), increased inflammatory monocytes/macrophages, reduced fibrinolytic activity, and platelet structural abnormalities in blood samples from hospitalized SARS-CoV-2+ patients. Though the frequency is reduced, these same alterations are also apparent in some SARS-CoV-2+ outpatients with mild symptoms, and persist at least 3-6 months post- infection. In the present study, we will extend these findings by following patients longitudinally from first diagnosis through their recovery. We will perform detailed analyses of their coagulation, platelet, fibrinolytic, and inflammatory systems, and will compare the results to clinical and laboratory markers of thrombosis and of long COVID symptoms. Finally, we will utilize in vitro assays to test the hypothesis that inflammatory mediators released or expressed by leukocytes mediate the coagulation, fibrinolytic, and platelet alterations observed in patients. These studies will provide critical insights into the mechanisms of thrombosis in acute and long COVID and will help guide future therapeutic strategies.