Wednesday, April 2, 2025
4/2/2025
Investigating fibrinogen as a pathologic and targetable mediator of COVID-19-associated coagulopathy - Severe COVID-19 remains a top ten leading cause of death in the United States and is a major risk factor for the development of post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID). Despite tremendous strides in preventing and mitigating COVID-19 through vaccines and antivirals, strategies for managing critical illness in patients who nevertheless develop severe disease are insufficient. This is in large part due to an incomplete understanding in the mechanisms driving severe disease, of which COVID-19-associated coagulopathy is believed to be a major mediator. At the beginning of the pandemic, we reported elevated blood viscosity in critically ill COVID-19 patients related to hyperfibrinogenemia. More recently, our mechanistic studies uncovered a unique mechanism by which pathologically elevated fibrinogen causes the formation of red blood cell aggregates that mechanically injure the vascular endothelium. Fibrinogen is an essential clotting factor induced as part of the hepatic acute phase response during inflammation; yet, fibrinogen levels are not affected by currently available anticoagulant therapies. Thus, our findings help to explain the link between inflammation and clotting in COVID-19, including the increased risk of macrovascular thrombosis and the decreased microcirculatory perfusion of critical organs, even in patients receiving anticoagulation. Since therapeutic plasma exchange (TPE) is the recommended intervention for treating hyperviscosity in other conditions, we initiated a small randomized controlled trial to determine the safety and efficacy of TPE for COVID-19 patients with hyperfibrinogenemia, and banked biospecimens for future study. Here we propose a series of experiments testing the central hypothesis that fibrinogen is a pathologic and targetable mediator of COVID-19-associated coagulopathy. Specifically, in Aim 1 we propose to define the impact of TPE on blood rheology and vascular integrity by interrogating the molecular signatures of plasma samples from COVID-19 patients before and after the procedure. In addition, we have identified significant elevation in a variant fibrinogen isoform, g ¢ fibrinogen, in COVID-19 patients, which is most pronounced in those developing acute thrombosis. This usually minor fibrinogen isoform has unique biochemical properties, most notably its substantial negative charge, expected to exaggerate alterations in blood rheology. Thus, in Aim 2 we propose to define the impact of g¢ fibrinogen on biophysical properties of red blood cells and thrombosis in COVID-19. Together, these aims will not only advance our understanding of critical illness and acute coagulopathy in COVID-19, but also may have relevance for PASC and other non-COVID-related conditions involving thromboinflammation. Finally, as an extension of the K99 work, the R00 will afford a protected transition period critical to facilitating R01-readiness and to establishing an independent blood sciences research program.
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