The Potential Role of Coagulation Factor Xa in the Pathophysiology of COVID-19: A Role for Anticoagulants as Multimodal Therapeutic Agents

Abstract

SARS-CoV-2 infection (COVID-19) results in local and systemic activation of inflammation and coagulation. In this review article, we will discuss the potential role of coagulation factor Xa (FXa) in the pathophysiology of COVID-19. FXa, a serine protease, has been shown to play a role in the cleavage of SARS-CoV-1 spike protein (SP), with the inhibition of FXa resulting in the inhibition of viral infectivity. FX is known to be primarily produced in the liver, but it is also expressed by multiple cells types, including alveolar epithelium, cardiac myocytes, and macrophages. Considering that patients with preexisting conditions, including cardiopulmonary disease, are at an increased risk of severe COVID-19, we discuss the potential role of increased levels of FX in these patients, resulting in a potential increased propensity to have a higher infectious rate and viral load, increased activation of coagulation and inflammation, and development of fibrosis. With these observations in mind, we postulate as to the potential therapeutic role of FXa inhibitors as a prophylactic and therapeutic treatment for high-risk patients with COVID-19.

Keywords: COVID-19; SARS-CoV-2; anticoagulants; coagulation; coronavirus; factor X; factor Xa.

Fig. 1

The potential role of factor Xa in Co-V cellular infection. Top: The coronavirus (left) binds to multiple cells that express receptors that bind to the coronavirus spike protein (a). For example, the spike protein can bind to ACE2 receptors, which are present in the alveolar and bronchiolar epithelium, cardiac myocytes, the brain/central nervous system, the kidneys (primarily the proximal tubules), and the vascular endothelium. Middle: Once the spike protein is bound to the host cell receptor, a proteolytic enzyme binds to the spike protein to cleave the protein into spike protein 1 and spike protein 2. In this example, the proteolytic enzyme is serine protease, factor Xa. (bi) Factor X and factor Xa can be expressed by the host cell directly, allowing for colocalization of the spike protein receptor and the serine protease. (bii) Factor Xa can be present, unbound in the circulation. (biii) Factor X and factor Xa can be localized to the spike protein by nearby cells expressing factor X and factor Xa, such as macrophages. Bottom: Once the spike protein is successfully cleaved by the proteolytic enzyme, spike protein 1 is released with or without the bound host cell receptor, while spike protein 2 aids in the fusion of the viral and host cell membrane. (ci) The virus and host cell membrane are fused and the viral genetic material is inserted into the host cell. (cii) The viral genetic material replicates within the host cell. (ciii) New coronavirus viral particles are released by the host cell, resulting in infection of new host cells as well as propagation of inflammation and coagulation.

Fig. 2

The potential role of factor Xa in the pathophysiology of COVID-19. This figure represents the potential sequelae of COVID-19 in the context of various organ systems that are known to express factor Xa (FXa). ( A ) demonstrates the consequences of COVID-19 in both healthy (Ai) and diseased (Aii) lungs. In the diseased lungs, the presence of preexisting inflammation and fibrosis exacerbates further inflammation and fibrosis. ( B ) demonstrates the consequences of COVID-19 in both the healthy (Bi) and diseased (Bii) heart. Similar to the pulmonary system, the presence of preexisting fibrosis further exacerbates the inflammation and fibrosis secondary to COVID-19. ( C ) represents both uninfected brain tissue (Ci) and brain tissue with COVID-19 (Cii). The infected tissue demonstrates an increase in microglial activation, inflammation, and intravascular thrombosis. Panel D represents the consequences of COVID-19 in both health (Di) and diseased (Dii) kidneys (specifically focusing on the glomerulus). The infected tissue demonstrates increased inflammation, fibrosis, and capillary thrombosis. Panel E represents blood vessels and the role of the vascular endothelium in COVID-19. The healthy, uninfected blood vessel (Ei) has an open lumen with laminar blood flow, while the infected blood vessel (Eii) has endothelial damage resulting in increased inflammation, fibrosis, vascular permeability, thrombosis formation, and turbulent flow resulting in damage to red blood cells in the form of hemolysis and schistocyte formation.

Fig. 3

Proposed therapeutic mechanism of factor Xa inhibitor on CoV cellular infection. (Top) SARS coronavirus binds to the host cell expressing a receptor (purple) that binds to the SARS coronavirus spike protein (blue club-shape). Factor Xa (FXa) then acts as a proteolytic enzyme, cleaving spike protein into spike protein 1 (pink circle) and spike protein 2 (green diamond). The spike protein 1 then parts from the virus–cell complex with or without the attached receptor, while spike protein 2 serves to aid in the fusion of the virus and cell membranes. (Bottom) The addition of a factor Xa inhibitor (FXa) blocks FXa from acting as a proteolytic enzyme, therefore leaving the spike protein intact and preventing virus and host cell membrane fusion.