Phosphatidylserine inside out: a possible underlying mechanism in the inflammation and coagulation abnormalities of COVID-19

Abstract

The rapid ability of SARS-CoV-2 to spread among humans, along with the clinical complications of coronavirus disease 2019—COVID-19, have represented a significant challenge to the health management systems worldwide. The acute inflammation and coagulation abnormalities appear as the main causes for thousands of deaths worldwide. The intense inflammatory response could be involved with the formation of thrombi. For instance, the presence of uncleaved large multimers of von Willebrand (vWF), due to low ADAMTS13 activity in plasma could be explained by the inhibitory action of pro-inflammatory molecules such as IL-1β and C reactive protein. In addition, the damage to endothelial cells after viral infection and/or activation of endothelium by pro-inflammatory cytokines, such as IL-1β, IL-6, IFN-γ, IL-8, and TNF-α induces platelets and monocyte aggregation in the vascular wall and expression of tissue factor (TF). The TF expression may culminate in the formation of thrombi, and activation of cascade by the extrinsic pathway by association with factor VII. In this scenario, the phosphatidylserine—PtdSer exposure on the outer leaflet of the cell membrane as consequence of viral infection emerges as another possible underlying mechanism to acute immune inflammatory response and activation of coagulation cascade. The PtdSer exposure may be an important mechanism related to ADAM17—mediated ACE2, TNF-α, EGFR and IL-6R shedding, and the activation of TF on the surface of infected endothelial cells. In this review, we address the underlying mechanisms involved in the pathophysiology of inflammation and coagulation abnormalities. Moreover, we introduce key biochemical and pathophysiological concepts that support the possible participation of PtdSer exposure on the outer side of the SARS-CoV-2 infected cells membrane, in the pathophysiology of COVID-19.

Skin imprints to provide noninvasive metabolic profiling of COVID-19 patients

“…Four previous studies reported reduced levels of PS in COVID-19 cases 5,11 , even when mild 10 , moderate and severe 13 cases were compared to controls, on both blood-derived samples 5,10,13 and naso-oropharyngeal swabs 11 , corroborating our findings. PS is a negatively-charged membrane phospholipid that may translocate from inner to outer cell membrane layer in early stages of viral infection 24,25 . It functions as a signal for macrophages cell phagocytoses and may also occur during platelet activation to contribute to the inflammatory and coagulopathy patterns observed in COVID-19 24,25 .…”

“…PS is a negatively-charged membrane phospholipid that may translocate from inner to outer cell membrane layer in early stages of viral infection 24,25 . It functions as a signal for macrophages cell phagocytoses and may also occur during platelet activation to contribute to the inflammatory and coagulopathy patterns observed in COVID-19 24,25 . Zaid et al (2020) noticed a significant increase in platelet extracellular vesicles in patients with COVID-19 compared to healthy subjects, and a decrease in severe cases against mild manifestations.…”

The role of phosphatidylserine on the membrane in immunity and blood coagulation

“…TAM is a single transmembrane receptor (the orange part in the figure). From N-terminal to C-terminal (from top to bottom in the figure), there are three parts:1, the extracellular domain, including two IG domains (IG1, IG2) and two FNIII domains; 2, one single TM; 3, the intracellular domain, including one conserved PTK domain, one autophosphorylation site, and one ITIM domain [ 23 – 27 ]. The intracellular PTK domain of TAM is the functional domain.…”

“…Once the functions of PtdSer are abnormal, they will cause many diseases, including Scott syndrome [ 3 ], Systemic lupus erythematosus (SLE) [ 4 ], Essential hypertension (EH) [ 5 ], Hemophilia A [ 6 ], Alzheimer’s disease (AD) [ 7 ], Human Immunodeficiency Virus (HIV) [ 8 ], Ebola virus (EBOV) [ 9 – 12 ], Dengue virus (DENV) [ 13 – 15 ] and Respiratory Syncytial Virus (RSV) [ 16 – 18 ], and certain tumors or cancers [ 19 – 22 ]. It was also speculated that PtdSer might be a potential mechanism or participant of inflammation and coagulation abnormalities in COVID-19 [ 23 , 24 ]. Therefore, studies in Ptdser, its interacted molecules and their structure features, are of significance, not only an aspect to further understand these diseases but also a potential therapeutic target.…”

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

“…Sars-CoV-2 infection also alters the lipidome, resulting in higher concentrations of lyso-PE and lyso-PS, with no changes in lyso-PC, which is a hallmark of hGIIA activity [ 97 ]. Other research suggests COVID-19 may also increase levels of PS on the surface of the cell membrane, exposing cells to catalytic activity of hGIIA [ 97 , 98 ]. The authors suggest that hGIIA may mediate severe COVID-19 disease and as its expression is closely linked to disease outcome, that hGIIA is an attractive therapeutic target.…”