Phosphatidylserine is an overlooked mediator of COVID-19 thromboinflammation

Abstract

A ubiquitous component of cell membrane, phosphatidylserine (PS), is likely to play a major, but as yet unrecognized, role in the thromboinflammation of COVID-19 and other critical illnesses. PS is present in all plasma membranes but is "hidden" on the inner surface by the action of an ATP-requiring enzyme. Failure of PS to be sequestered on the inner surface of cell membranes, release of PS-containing microparticles from cells, or shedding of enveloped viruses allows it to interact with extracellular proteins, including those of the coagulation and complement systems. Detection and quantification of circulating PS is not standardized, and current methodologies have either focused on circulating cellular elements or subcellular plasma components, but not both. PS may also promote thromboinflammation without circulating if expressed on the surface of endothelial cells, a condition that might only be documented if novel imaging techniques are developed. Research into the role of PS in inflammation and coagulation, called here a "procoagulant phospholipidopathy" may provide novel insights and therapeutic approaches for patients with a variety of illnesses.

Keywords: COVD-19; Coagulation; Phosphatidylserine; Thromboinflammation; Thrombosis.

Figure 1

Phosphatidylserine exposure on the outside of cells and microparticles – Phosphatidylserine (PS) is maintained on the inner surface of the plasma membrane of all cells. Several mechanisms can lead to the “exposure” of PS on the external surface of cells. Physiologic or pathologic “activation” of cells can lead to exposure of phosphatidylserine (PS) on the external surface of cells, or microparticles released by cells. Enveloped viruses bud from host cells, resulting in PS-bearing virions released into the intra- and extra-vascular spaces, depending upon the location of the infected cell.

Figure 2

Phosphatidylserine exposure on the surface of cells exposed to plasma results in thrombin generation and complement system activation - Blood coagulation proteins have phosphatidylserine-binding domains, which allows them to cluster together on exposed PS, accelerating their interaction and the subsequent generation of thrombin. PS can lead to activation of the complement system. Together, the coagulation and complement systems contribute to the complex clinical phenotype of thromboinflammation.