Binding of phosphatidylserine‐positive microparticles by PBMCs classifies disease severity in COVID‐19 patients

Abstract

Infection with SARS‐CoV‐2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID‐19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets and platelet‐derived microparticles (PMP), during the clinical course of COVID‐19. We found an unexpectedly high amount of blood cells loaded with PS + PMPs for weeks after the initial COVID‐19 diagnosis. Elevated frequencies of PS + PMP + PBMCs correlated strongly with increasing disease severity. As a marker, PS outperformed established laboratory markers for inflammation, leucocyte composition and coagulation, currently used for COVID‐19 clinical scoring. PS + PMPs preferentially bound to CD8 + T cells with gene expression signatures of proliferating effector rather than memory T cells. As PS + PMPs carried programmed death‐ligand 1 (PD‐L1), they may affect T cell expansion or function. Our data provide a novel marker for disease severity and show that PS, which can trigger the blood coagulation cascade, the complement system, and inflammation, resides on activated immune cells. Therefore, PS may serve as a beacon to attract thromboinflammatory processes towards lymphocytes and cause immune dysfunction in COVID‐19.

Persistent Lung Injury and Prothrombotic State in Long COVID

“…One study using flow cytometry of patient samples found that the frequency of PS + cells in the blood of all COVID-19 patients within a week of diagnosis was considerably higher than that of peripheral blood mononuclear cells (PBMC) from healthy or recovered donors. The number of PS + PBMC is strongly correlated with the severity of disease and can better predict the need for respiratory support ( 123 ). Corresponding autoantibodies to the PS/prothrombin complex have also been found in COVID-19 patients ( 124 ).…”

“…The levels of PS + cells and pEVs in COVID-19 patients were higher than those in healthy controls and are positively correlated with the severity of the disease. Due to the high likelihood of diffuse microthrombi and arteriovenous thrombus in critically ill patients and the procoagulant role of PS, we think that Annexin V or lactadherin could reduce the incidence of thrombosis in COVID-19 patients ( 118 , 123 ). In the presence of a large amount of PS, the inhibition of upstream FXIa, FXIIa, and FXa generation can block IIa generation and avoid the formation of thrombus.…”

The Role of Platelet-Derived Extracellular Vesicles in Immune-Mediated Thrombosis

“…The TF on PEVs could originate from the platelet or its uptake from TF-bearing EVs of other cellular origins [ 132 ]. Alternatively, PEVs can affect coagulation through the activation of other cells to induce a pro-thrombotic environment [ 53 , 57 , 58 , 103 , 105 , 120 , 121 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ] ( Figure 5 ). As an example, Terrisse et al found that PEVs will adhere to endothelial cells dependent on lactadherin, PS, and αVβ3 integrin.…”

Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy

“…Interestingly, one study found that severe COVID-19 cases and healthy individuals had reduced phosphatidylserine (PS) exposing PMVs compared to moderately infected individuals [96]. However, another study found that increasing PS, PMV, and peripheral blood mononuclear cell (PBMC) frequencies were found to be strongly correlated with increasing COVID-19 disease severity [101]. In either case, it appears that PS+ PMVs are biomarkers of at least moderate SARS-CoV-2 infection.…”