Unraveling Cytotoxic and Thrombotic Signals in COVID-19

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

Individuals with severe coronavirus disease (COVID-19) develop hyperinflammation and are at high risk for thrombosis in multiple vascular beds. Interruption of organ perfusion by fibrin-rich clots leads to tissue malperfusion and organ failure that is responsible for the mortality and morbidity associated with COVID-19. At the onset of the pandemic, the underlying mechanisms of hyperinflammation and thrombosis in COVID-19 were unknown. In pursuit of novel and improve therapeutic approaches to combat the pandemic, we undertook mechanistic, translational studies using patient samples, in vitro studies, and animal modeling that identified several mechanisms of thrombosis and potential therapeutic targets. These studies have resulted in three new paradigms of thromboinflammation in COVID-19, and these discoveries have been rapidly translated to the clinic in the form of multiple clinical trials: Project (1): Neutrophil Extracellular Traps in COVID-19. Early reports of inflammation in COVID focused on the role of lymphocytes and monocytes. We discovered a neutrophil-based signature of hyperinflammation in the blood of patients with severe COVID-19, marked by a particularly inflammatory form of neutrophil death by which DNA is extruded as sticky, neutrophil extracellular traps (NETs). We were the first to identify exuberant NET formation as a hallmark of severe COVID-19 and its association with respiratory failure, thrombosis, and death. This work opened a new line of investigation in the field for neutrophil hyperinflammation in COVID-19, and has been validated by several teams across the world. Work from our group and others has shown that NETs potentiate inflammation and thrombosis, laying the foundation for multiple clinical trials to mitigate thromboinflammation. We have provided additional expert input and guidance for many of these clinical trials, and contribute directly to the NHLBI efforts to prioritize new drugs and therapeutic approaches that target immunomodulation and thrombosis for NIH-sponsored clinical trials. Project (2): Biomarkers To Predict Severe COVID-19. In the context of strained hospital resources at the height of the pandemic, we sought biomarkers to prospectively identify patients at the highest risk of respiratory failure in order help clinicians direct resources appropriately. We discovered that a neutrophil cytoplasmic calgranulin called calprotectin, also known as MRP8-14 or S100A8/9 measured in serum at the time of hospitalization was able to identify patients who later developed respiratory failure. Serum calprotectin was not available to clinicians for use. We assisted in the development of a serum calprotectin measurement assay that is now in clinical use in Europe for patients with critical illness and other diseases. Project (3): Pathologic Autoantibodies in COVID-19. The coagulopathy of COVID-19 has many similarities with the catastrophic variant of Antiphospholipid Syndrome (APS), an autoimmune thrombophilia marked by circulating autoantibodies to phospholipids and phospholipid-binding proteins. Our studies were the first to reveal that half of patients hospitalized with COVID-19 test positive for at least one type of antiphospholipid antibody (aPL) which was associated with worse clinical outcomes. We identified that COVID-19 serum, and in particular, the IgG fraction from patients testing positive for aPL created a hyperinflammatory phenotype in healthy human neutrophils, exuberant pro-inflammatory NET formations, and exaggerated clotting in an animal model of venous thrombosis. These were the first description of the body producing prothrombotic autoantibodies in COVID-19, and led to a new line of investigation on the pathologic crosstalk between adaptive and immune responses that drives coagulation. We found that in addition to heightened NET formation, autoantibodies also shield NETs from normal degradation and potentiate thromboinflammatory signaling. We identified that the autoantibodies in patients with COVID and similarly in patients with non-COVID sepsis, disrupt the normal homeostatic endothelial surface, and tip the blood:vessel interface toward inflammation and thrombosis during critical illness. These published and further ongoing studies have been pivotal in advancing the HHS/NIH mission to respond to the pandemic and improve public health.