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Review 1: "Physical phenotype of blood cells is altered in COVID-19"

Published onApr 14, 2022
Review 1: "Physical phenotype of blood cells is altered in COVID-19"
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key-enterThis Pub is a Review of
Physical phenotype of blood cells is altered in COVID-19

Clinical syndrome coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by rapid spreading and high mortality worldwide. While the pathology is not yet fully understood, hyper-inflammatory response and coagulation disorders leading to congestions of microvessels are considered to be key drivers of the still increasing death toll. Until now, physical changes of blood cells have not been considered to play a role in COVID-19 related vascular occlusion and organ damage. Here we report an evaluation of multiple physical parameters including the mechanical features of five frequent blood cell types, namely erythrocytes, lymphocytes, monocytes, neutrophils, and eosinophils. More than 4 million blood cells of 17 COVID-19 patients at different levels of severity, 24 volunteers free from infectious or inflammatory diseases, and 14 recovered COVID-19 patients were analyzed. We found significant changes in erythrocyte deformability, lymphocyte stiffness, monocyte size, and neutrophil size and deformability. While some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This interesting article deals with the deformability of red blood cells and white blood cells, comparing hospitalized patients from Covid-19, recovering patients, and healthy subjects.

Strength of Evidence Scale: Reliable. The article is very interesting and should be published after minor revision. The methodology and findings are correct. The results regarding the deformability of red blood cells and white blood cells help us to understand the physiopathology of Covid-19.

Some considerations are discussed below:

In the abstract, the authors wrote “Until now, physical changes of blood cells have not been considered to play a role in COVID-19 related vascular occlusion and organ damage”. A paper describing a link between erythrocyte deformability and Covid-19 comorbidities has been published and a possible role of erythrocyte deformability and aggregation in impaired microcirculation of Covid-19 patients has been discussed in this paper 1 .

Some parts of the introduction refer to materials and methods and results and are usually not included in the introduction. The paper should be edited accordingly to IMRAD.

There is a lack of important information: the shear stress of the system. Red blood cells deform according to shear stress, the higher shear stress is found in the large arteries and the smallest in the capillaries in the microcirculation. Although the results show significant changes between the groups analyzed, it would be important to know the shear stress.

The author wrote: “ However, we observed that erythrocyte deformability in recovered patients had not returned to healthy donor levels.”. Probably the erythrocyte deformability in hospitalized patients was impaired even before they had Covid-19, as many comorbidities such as obesity, diabetes, cardiovascular disease, low vitamin D, and low estrogen are linked to the severity of Covid-19 also are linked to low erythrocyte deformability 1 . (the authors discussed only age) Erythrocyte deformability is essential to blood rheology and its implication in the blood flow in macrocirculation and microcirculation should be discussed more deeply 2–4. Also, relationships between white blood cells and red blood cells deformability have been described before and should be discussed 5,6 .

As for white blood cells, the results of this experiment reveal an increase in the deformability of the neutrophils that contrasts with the previous experiments that found that the activated neutrophils impaired the microcirculation 7 although neutrophils deformability has been found to increase in patients with sepsis 8. The main limitation of this study is that the majority of patients with Covid-19 used drugs such as anticoagulants and hydroxychloroquine that may have interfered with the results.


1. Farber, P. L. Can erythrocytes behavior in microcirculation help the understanding the physiopathology and improve prevention and treatment for covid-19? Clin. Hemorheol. Microcirc. 1–7 (2021) doi:10.3233/ch-201082.

2. Litvinov, R. I. & Weisel, J. W. Role of red blood cells in haemostasis and thrombosis. ISBT Sci. Ser. 12, 176–183 (2017).

3. Baskurt, O. K., Ph, D., Meiselman, H. J. & Sc, D. Blood Rheology and Hemodynamics. 1, 435–450 (2003).

4. Connes, P. & Favret, F. Blood Rheology, Blood Flow and Human Health. 283–293 (2013) doi:10.1016/B978-0-12-396454-0.00028-X.

5. Silva-Herdade, A. S., Andolina, G., Faggio, C., Calado, Â. & Saldanha, C. Erythrocyte deformability - A partner of the inflammatory response. Microvasc. Res. 107, 34–38 (2016).

6. Korbut, R. & Gryglewski, R. J. Nitric oxide from polymorphonuclear leukocytes modulates red blood cell deformability in vitro. Eur. J. Pharmacol. 234, 17–22 (1993).

7. Eppihimer, M. J. & Lipowsky, H. H. Effects of leukocyte-capillary plugging on the resistance to flow in the microvasculature of cremaster muscle for normal and activated leukocytes. Microvasc. Res. 51, 187–201 (1996).

8. Morikawa, M., Inoue, Y., Sumi, Y., Kuroda, Y. & Tanaka, H. Leukocyte deformability is a novel biomarker to reflect sepsis-induced disseminated intravascular coagulation. Acute Med. Surg. 2, 13–20 (2015).

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