Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

Abstract

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

The Impact of COVID-19 on Cellular Factors Influencing Red Blood Cell Aggregation Examined in Dextran: Possible Causes and Consequences

“…Emerging evidence shows that RBC aggregation can cause damage to the endothelial cell glycocalyx [72]. This finding is quite unexpected and has not been previously reported.…”

“…Interestingly, in in vitro experiments with the blood from COVID-19 patients, aggregation occurred in the microfluidic channel. This contrasted with virtually no aggregation of erythrocytes from the blood of healthy individuals [72]. It has also been observed that with increased aggregation, more force is required to separate the aggregates into individual red blood cells as blood flows into the capillaries from larger vessels.…”

Severe pediatric COVID-19: a review from the clinical and immunopathophysiological perspectives

“…Identification and close monitoring of children at risk of severe COVID-19 represent a concrete first step in clinical assessment. The risk factors with the highest relative risks for severe COVID-19 in children are chronic lung diseases, obesity, diabetes, cardiovascular disease, neurological comorbidities including seizure disorders, and prematurity (among children below 2 years of age) [ 1 , 17 , 18 ], many of which are linked to endothelial impairment and a pro-inflammatory state [ 19 ], and odds of critical care admission and mortality increase in a step-wise manner with increased number of comorbidities [ 20 ].…”

Marginated aberrant red blood cells induce pathologic vascular stress fluctuations in a computational model of hematologic disorders

“…In addition, the recent global pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 infection, can lead to substantial alterations of RBCs ( 2 ). Emerging evidence suggests that organ dysfunction associated with severe COVID-19 may result from endothelial damage and microvascular thrombosis ( 3 ). Sepsis, a life-threatening condition arising from severe systemic infection, disrupts the morphology and function of RBCs, precipitating organ failure, hypotension, and increased mortality rates ( 4 ).…”

“…When exposed to COVID-19, morphologically normal RBCs exhibited a conformational change to sphero-echinocytes with reduced size and deformability ( 2 ). Relatedly, plasma from adult patients with COVID-19 causes substantial RBC aggregation under flow, and fibrinogen-mediated aggregation directly damages the endothelial glycocalyx ( 3 ). In hereditary spherocytosis (HS), genetic mutations affect RBC membrane proteins, breaking the linkage between the membrane skeleton and the lipid bilayer, causing membrane loss ( 6 ).…”