Pathophysiological Changes in Erythrocytes Contributing to Complications of Inflammation and Coagulation in COVID-19

Abstract

Higher thrombotic burden in the acute phase of COVID-19 relies on a complex interplay between pro-inflammatory cytokine/chemokine release, increased endothelial dysfunction/damage, and potential sepsis-induced coagulopathy development in severe cases, all promoting coagulation activation. Plasma levels of cytokines and chemokines are known to be increased in COVID-19 however, are much higher in severe infections. Increased levels of IL-1β, IL-6, and IL-8 are known to play an important role in both acute and chronic inflammation, resulting in pathological clotting. However, little has been published on the effects of these interleukins on red blood cells (RBCs). Evidence shows that cytokines have a negative effect on the RBCs ultrastructure and introduce signs of eryptosis. Eryptosis can be described as a form of suicidal death of RBCs characterized by distinct findings of cell shrinkage, membrane blebbing, activation of proteases, and phosphatidylserine exposure at the outer membrane leaflet. Red blood cells from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Emerging research suggests that RBCs may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis as research indicates that complement activation products and viral antigens are present on RBCs in patients with COVID-19.

The oxygen dissociation curve of blood in COVID-19–An update

“…Significant alterations in RBC glycolysis in COVID-19 (67) must also be considered in relation to the ODC shift discussed above. Significantly altered RBC metabolism of lipids, in particular short-and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids, has been observed (73). A further indicator for RBC membrane alterations are changes in the polyunsaturated fatty acid composition of the RBC membrane which correlate with inflammatory marker expression in COVID-19 patients (74).…”

Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review

“…COVID-19 is an endothelial disease, triggering the “cytokine storm” and inflammation, oxidative stress, and coagulopathy [ 93 ]. SARS-CoV-2 S protein–ACE-2 interaction activates the endothelium, which will lead to stimulation of immune responses and EC damage, activation of coagulation, reduction of fibrinolysis, and platelet adhesion and aggregation [ 94 ].…”

“…This interaction is followed by alterations in CO 2 uptake and oxygen release from hemoglobin, inducing thrombosis by tissue hypoxia [ 43 ]. Increased plasma levels of IL-1β, IL-6, and IL-8 in patients with COVID-19 also has a negative effect on the RBCs’ ultrastructure and induces signs of eryptosis, a form of suicidal death of RBCs, that exhibits an increased tendency of adhering to ECs as well as platelets, contributing to thrombosis [ 93 ]. Moreover, COVID-19 patients’ D-dimers are correlated with RBC surface phosphatidylserine (RBC-PS), another potential contribution of RBCs in the thrombotic diathesis [ 143 ].…”

“…Moreover, COVID-19 patients’ D-dimers are correlated with RBC surface phosphatidylserine (RBC-PS), another potential contribution of RBCs in the thrombotic diathesis [ 143 ]. Induced EC dysfunction, and the presence of surface binding proteins for IL-8 and Duffy antigen receptor for chemokines on their surface [ 93 ], also link the RBCs with the immuno-stimulatory pathways and the crossroads of inflammation and thrombosis.…”

Progress in Biosensors for the Point-of-Care Diagnosis of COVID-19

“…The disease has typical indicators of shortness of breath (dyspnea), fever, fatigue and cough, but other manifestations can occur depending on the variant of COVID-19 and individual dispositions, and some post-COVID-19 syndromes can remain even after the infection resolves [ 18 , 19 , 20 , 21 , 22 , 23 ]. An increase in inflammatory cytokines and the appearance of symptoms after inflammation is also typical for COVID-19 [ 24 , 25 , 26 , 27 , 28 ]. The exact diagnosis can be based on various techniques and instruments, including the techniques locating damaged tissues such as tomography and sonography [ 29 , 30 , 31 ] and molecular biology methods such as polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) in their reverse transcriptase [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”