Red Blood Cell Abnormalities as the Mirror of SARS-CoV-2 Disease Severity: A Pilot Study

Abstract

Graphical AbstractSARS-CoV-2 infection has significant effects on red blood cells that seems to be associated with disease severity in these patients. (A) Non-Intensive care unit hospitalized patients due to severe COVID-19 disease were included in this study (n = 36). (B) The control group included healthy subjects without renal or hepatic impairment, no diagnosis of anemia or myeloid malignancy, and no blood transfusion over the past 3 months (n = 18). (C) Demographic data, clinical, laboratory and chest Computed Tomography (CT) findings at time of admission were recorded. Hematological tests, standard biochemical analysis of serum components were performed both in the patient and in the control group and coagulation analysis were evaluated in the patient group. A peripheral blood smear examination was also performed in all patients and control samples. (D) Plasma free hemoglobin and red blood cell (RBC) osmotic fragility and free hemoglobin (Free-Hb) after mechanical stress (MECH) by mechanical hemolysis were assesed in both patients and controls. Intracellular (i) calcium (iCa2 +) levels, RBCs phosphatidylserine exposure (PS), RBC membrane-bound immunoglobulins G (IgGs), and activate RBC caspase-3 levels as cell clearance and apoptotic markers were measured by flow cytometry. A spectrophotometric assay was used to quantify the activity of G6PD enzyme. Intracellular RBC reactive oxidative species (iROS) were assesed in both patients and controls. (E) Elevated hemolysis markers (Free-Hb) and Lactate Dehydrogenase (LDH) were observed in patients compared to the control group. Patients’ RBCs were more vulnerable to mechanical stress, and exhibited significantly elevated apoptotic markers (iCa2 + and RBC-PS+). Erythrocyte iROS levels were significantly lower in the patients’ group compared to healthy controls. This finding possibly correlates with the increased G6PDH activity levels in this group, suggesting a compensatory mechanism against the virus. (F) Patients’ D-Dimers correlated with RBC-PS +, implying a possible contribution of the erythrocytes in the thrombotic diathesis associated with the SARS-CoV-2 disease. (G) Free-Hb levels correlated with the extend of pulmonary infiltrates on chest CT in COVID-19 patients. RBC-IgGs+ correlated with the severity of pulmonary CT imaging features as well as the abnormality of lung function, expressed by the PO2/FiO 2 ratio. This finding suggests that hypoxia may lead to RBC senescence.

Morphological abnormalities of peripheral blood cells among patients with COVID-19 disease

“…As a consequence, these cells may undergo lysis and lose their ability to carry oxygen, resulting in dysregulation of erythrocyte metabolism and decreased levels of RBCs. Furthermore, SARS-CoV-2 has been shown to impair heme metabolism and cause hemoglobin cleavage, ultimately thinning the membrane of erythrocytes [ [35] , [36] , [37] ], leading to abnormal changes in their morphology. ROS-induced damage to hemoglobin functionality is also known to cause anemia and a multi-faceted syndrome in COVID-19 [ 38 ].…”

Exploring unconventional attributes of red blood cells and their potential applications in biomedicine

“…In accordance, shape abnormalities were found in RBCs from ASD subjects, without evidence of a specific genetic defect in the progenitor cells ( Ciccoli et al, 2013 ). Moreover, RBCs change during viral infections; for example, their elasticity is reversibly affected when exposed to COVID-19 patient plasma ( Recktenwald et al, 2022 ), whereas senescence markers correlate with disease severity ( Bouchla et al, 2021 ). It does not appear to be a coincidence that activation of antiviral interferon responses in COVID-19 patients is accompanied by metabolic markers such as kynurenine ( Recktenwald et al, 2022 ), fragmentation, and oxidation of structural membrane proteins ( Thomas et al, 2020 ), which in turn have been recently associated to increased osmotic fragility, acute phase response protein deposition on RBC membranes and ultimately increased extravascular hemolysis in healthy, older male blood donors with higher body mass indices ( Nemkov et al, 2023 ).…”

Nutrients, herbal bioactive derivatives and commensal microbiota as tools to lower the risk of SARS-CoV-2 infection

“…In patients with pneumonia, the deterioration of the B-cell compartment could be one of the reasons for immunological failure in controlling SARS-CoV2 ( 52 ). During SARS-CoV-2 infection, there is a decrease in the number of red blood cells, leading to anemia ( 69 ). Anemia can cause fatigue, shortness of breath, and other symptoms.…”

“…Anemia can cause fatigue, shortness of breath, and other symptoms. The decrease in red blood cell count is also associated with the severity of the disease ( 69 ). Overall, structural and functional alterations of the blood cell compartment have an important role in the pathogenesis of SARS-CoV-2 infection; recent data highlight the predictive role of these alterations in prognosis and in the long COVID clinical setting ( 70–72 ).…”