Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19


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My old stomping ground Damaged blood cells".
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Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.

COVID-19 patients exhibit pathological changes of RBC shapes in capillary flow

We investigate the microfluidic flow behavior of RBCs in autologous as well as in allogeneic plasma. Therefore, patient RBCs are suspended in blood group-matching control plasma and control RBCs in patient plasma. Hence, we obtain four sample groups; (i) control RBCs in control plasma (CinC), (ii) patient RBCs in patient plasma (PinP), (iii) control RBCs in patient plasma (CinP), and (iv) patient RBCs in control plasma (PinC) (Figure 1A). RBCs of the four sample groups are imaged in stasis for the assessment of shapes and cluster formation at rest. While healthy controls (CinC) form biconcave RBCs that organize into rouleaux, sphero-echinocytes for COVID-19 patients in autologous plasma (PinP) are found in stasis and highlight impaired RBC clustering (Figure 1B, Figure 1—figure supplement 2). However, upon plasma exchange (PinC), COVID-19 RBC shapes in stasis revert to biconcave disks and are able to aggregate into rouleaux. The opposite trend is observed for control cells suspended in patient plasma (CinP). The ratio of RBCs in clusters over the total number of RBCs quantifies the differences between CinC and PinP and shows the recovery of patient RBCs for PinC (Figure 1—figure supplement 2, left panel). The number of RBCs per cluster in CinC is about twice the number of PinP. Notably, patient cell shape and rouleaux formation recovery in control plasma (PinC) results in no significant differences with control RBCs (CinC) (Figure 1—figure supplement 2, right panel).
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