The coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-Coronavirus-2 (SARS-CoV-2), represents an unprecedented world health crisis. In addition to causing pneumonia and lung injury, COVID-19 is linked to increased risk of cardiovascular events including thrombosis, pulmonary embolism, and stroke, especially in critically-ill patients. Approximately 10% of patients with severe COVID-19 develop a serious thrombotic event. However, almost all patients show some abnormal coagulation. Thus, SARS-CoV-2 infection drastically changes the hosts' coagulation cascade, and in many cases, leads to onset of serious thrombotic events. Monocytes are white blood cells that protect us from pathogens, including viruses. We have reported that the patrolling action of a subset of monocytes, nonclassical monocytes, is required to maintain vascular homeostasis. Reduction in activity or number of nonclassical monocytes causes endothelial activation and dysregulation, thus exacerbating coagulation events. Early reports by our group indicate decreased numbers of nonclassical monocytes in COVID-19 patients, and this loss associates with disease severity. Some monocytes can also release Tissue Factor, which causes clotting. Monocytes from severe COVID patients express SARS-CoV-2 RNA. The monocyte subsets that express SARS-CoV-2 RNA are not known, and whether this is due to scavenging of viral particles or direct infection of monocytes is unclear. How this infection impacts their release of Tissue Factor is not known. In the current study, we will assess monocyte changes in mild to severe COVID-19 patients that clinically present with and without thrombotic events. We will compare these patients to healthy controls. We will test the hypothesis that monocyte phenotype and function is changed in COVID-19 patients to drive thrombotic changes in circulation, contributing to thrombotic events. We will utilize high dimensional profiling via CyTOF mass cytometry and RNA-seq to study monocyte changes in PBMC from mild and severe COVID-19 patients, including those with clinically diagnosed thrombotic events. Matching plasma from each patient will tested for coagulation factors. All monocyte data will be linked with clinical coagulation and immune cell data from each patient. Understanding mechanisms for how thrombosis occurs by SARS-CoV-2 is critical for effective treatment of all COVID-19 patients, especially those with life-threatening thrombotic events.
Coronavirus Disease 2019 (COVID-19) has caused a world-wide pandemic with high mortality that has changed all of our lives. Almost all patients with COVID-19 experience some type of blood-clotting abnormality. In many cases, this abnormality resolves and does not cause serious damage to the person. However, in many cases, particularly in those patients who have underlying health problems such as heart disease or diabetes, the clotting changes become very serious, resulting in blood clots that cause lung and heart complications, and even stroke. This proposal aims to understand why these clotting abnormalities occur. We hypothesize that specific white blood cells in circulation, whose normal role is to protect the blood vessels from viruses and cell damage, become overwhelmed by SARS-CoV-2, the virus that causes COVID-19. We will study these specific white blood cells, called monocytes, in blood of healthy people, and in patients with COVID-19, particularly those that develop serious life-threatening clots to understand how these monocytes are changed by the virus. Our work will help us understand how to prevent this serious clotting complication of COVID-19.
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