Adenosine triphosphate (ATP) is a major player as a signaling molecule in blood microcirculation (McMahon et al.). It is released by erythrocytes when subjected to solid shear stresses (McMahon et al.), large enough to induce a sufficient shape deformation (Mcmahon, 2019). RBCs produce ATP from the anaerobic conversion of D-glucose to lactate. Alternatively, RBCs can make 2,3-biphosphoglycerate (2,3-BPG, or 2,3-DPG) that reduces the hemoglobin affinity to oxygen (McMahon et al.). Most ATP is used to maintain the ion balance, cell volume, and RBC deformability (Mcmahon, 2019). And although there are conflicting data (Barshtein et al.) on the relationship between intracellular ATP content and RBC deformability, the effectiveness of restoring the ATP level in packed RBCs for reducing cells stiffness has been demonstrated previously (Barshtein et al., 2018a).

PS in normal RBCs is restricted to the inner leaflet of the membrane bilayer, but it is externalized in a high but variable proportion of pathological or aged cells (Kuypers and De Jong, 2004). PS externalization can be stimulated during cell aging (Barshtein et al.), external influence, or as a consequence of pathology (Lu D. et al.). In this issue, Lu D. et al. conclude that PS exposure in RBCs from sickle anemia patients increases under hypoxic, acidic, and hypertonic conditions but is markedly reduced by high urea concentrations thus, showing the role of the renal medulla in RBC sickling. The externalization of PS on the surface of the cell membrane, on the one hand, affects RBC functionality, and on the other hand, is a marker for cell aging (Kuypers and De Jong, 2004). Moreover, the relationship between PS extracellular level and RBC adhesion to the endothelium has previously been demonstrated for some RBC pathologies (sickle anemia, thalassemia, malaria, etc.) (Wautier and Wautier, 2013, 2020; Fraser et al., 2021) and cold storage (Barshtein et al.)

RBC biophysical properties contribute to blood flow features. Impairment of these flow-affecting properties of RBCs was associated with RBCs pathology, a characteristic of numerous diseases, such as sickle cell anemia (Lu M. et al.; Lu D. et al.), thalassemia (Lu D. et al.), cerebral malaria (Wautier and Wautier, 2013), sepsis (Mcmahon, 2019), and diabetes (Sun et al.), in which, microcirculation disorders are an integral feature of their pathophysiology (Yedgar et al., 2002). The development of microfluidic devices that can concurrently measure RBC deformability and adhesiveness (Lu M. et al.) or enable motion study of RBC (Atwell et al.) are proposed to discriminate pathological RBC. These devices should fulfill the need for biomedical markers to identify abnormal RBCs.

Unfortunately, the ability to improve the flow-affecting properties of RBCs with the help of medicaments is limited; however, the targeted application of the dietary approach and nutritional supplements can significantly improve the situation (Stupin et al., 2019). Information on the effect of physical activity on the flow-affecting properties of erythrocytes is controversial. The outcome is primarily determined by the exercise protocol and the physiological state of the subjects (Connes et al., 2011; Mury et al., 2017; Nader et al., 2019). So, Hsu et al. showed that supervised cycling training improves functional aerobic capacity, enhances erythrocyte membrane stability as well as osmotic deformability, and consequently promotes peripheral arterial disease patients.

The effect of storage on RBCs deformability has a long history and began in the mid-1980s. At present, with the advent of new approaches (microfluidics) which enable to determine the distribution of deformability in the cell population (Relevy et al., 2008; Guruprasad et al., 2019; Barshtein et al., 2020b; Islamzada et al., 2020; Man et al., 2020), the scientific interest in this field has increased. Most researchers observed a significant fall in cell deformability after 14–21 days of storage (Barshtein et al.). At the same time (for several units), the stability of deformability was observed throughout storage (Barshtein et al.). There was also significant variability in the deformability of the RBCs, both between different donors and between RBC units. In addition, it was found that the preparation of the RBC unit causes an alteration in the deformability of cells (Barshtein et al., 2020a).

We hope that this Research Topic (which is a continuation of the previous collection on the same issue), which focuses on the flow-affecting properties of RBCs, will contribute to the knowledge about RBCs. We thank all the participants in the collection who presented their exciting publications. We also hope that the topic we have raised will attract many new researchers in future.

HG and GB wrote the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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