Tag: red blood cells

Red Blood Cell Morphology Is Associated with Altered Hemorheological Properties and Fatigue in Patients with Long COVID

Simple Summary:
SARS-CoV-2 alters the properties of oxygen-carrying red blood cells (RBCs) through a possible deterioration of hemorheological properties, such as aggregation and deformability. However, long-term changes in these properties and a possible association with morphological abnormalities remain unknown. Therefore, this study aims to investigate changes in the above-mentioned RBC properties in Long-COVID (LC). Venous blood was collected from n = 30 diagnosed LC and n = 30 non-Long-COVID controls (non-LC). Hematological parameters were measured, as well as the aggregation, deformability, and morphology of the RBCs and the mechanical sensitivity index (MS), which reflects the functional capacity of RBCs to deform. The results indicate that hematological parameters were not altered in LC. However, LC showed higher overall aggregation parameters. RBC deformability was higher in LC compared to non-LC; however, MS was limited in this group. LC showed a higher percentage of RBCs with abnormal shapes, which was related to MS and to fatigue, which is considered the leading symptom of LC. It is concluded that the symptoms of LC and changes in the blood flow determining the properties of RBCs are related to the morphological changes in RBCs. Future studies should investigate the underlying causes in order to develop appropriate therapies for this relatively new disease.
Abstract:

Background: SARS-CoV-2 infection adversely affects rheological parameters, particularly red blood cell (RBC) aggregation and deformability, but whether these changes persist in patients suffering from Long-COVID (LC) and whether these changes are related to RBC morphology remain unknown.
Methods: Venous blood was collected from n = 30 diagnosed LC patients and n = 30 non-LC controls and RBC deformability, RBC aggregation, and hematological parameters were measured. In addition, RBCs were examined microscopically for morphological abnormalities. The mechanical sensitivity index (MS) was assessed in n = 15 LC and n = 15 non-LC samples.
Results: Hematological parameters did not differ between the groups. However, LC showed higher aggregation-related parameters. Although RBC deformability was higher in LC, MS, reflecting the functional capacity to deform, was limited in this group. RBCs from LC showed significantly more morphological abnormalities. The extent of morphological abnormalities correlated with MS and the FACIT-Fatigue score of the LC patients.
Conclusion: RBCs from LC show a high degree of morphological abnormalities, which might limit the blood flow determining RBC properties and also be related to fatigue symptomatology in LC. Approaches are now needed to understand the underlying cause of these alterations and to ameliorate these permanent changes.
Source: Grau M, Presche A, Krüger A-L, Bloch W, Haiduk B. Red Blood Cell Morphology Is Associated with Altered Hemorheological Properties and Fatigue in Patients with Long COVID. Biology. 2024; 13(11):948. https://doi.org/10.3390/biology13110948 https://www.mdpi.com/2079-7737/13/11/948 (Full text)

Bone marrow alterations in COVID-19 infection: The root of hematological problems

Abstract:

Introduction: The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow.

Method: To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms “COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia.

Results: Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations.

Conclusion: To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.

Source: Zeylabi F, Nameh Goshay Fard N, Parsi A, Pezeshki SMS. Bone marrow alterations in COVID-19 infection: The root of hematological problems. Curr Res Transl Med. 2023 Jul 25;71(3):103407. doi: 10.1016/j.retram.2023.103407. Epub ahead of print. PMID: 37544028. https://www.sciencedirect.com/science/article/abs/pii/S2452318623000314 (Full text)

Hematological alterations associated with long COVID-19

Abstract:

Long COVID-19 is a condition characterized by persistent symptoms lasting beyond the acute phase of COVID-19. Long COVID-19 produces diverse symptomatology and can impact organs and systems, including the hematological system. Several studies have reported, in COVID-19 patients, hematological abnormalities. Most of these alterations are associated with a higher risk of severe disease and poor outcomes.

This literature review identified studies reporting hematological parameters in individuals with Long COVID-19. Findings suggest that Long COVID-19 is associated with a range of sustained hematological alterations, including alterations in red blood cells, anemia, lymphopenia, and elevated levels of inflammatory markers such as ferritin, D-dimer, and IL-6.

These alterations may contribute to a better understanding of the pathophysiology of Long COVID-19 and its associated symptoms. However, further research is needed to elucidate the underlying mechanisms and potential treatments for these hematological changes in individuals with Long COVID-19.

Source: Lechuga Guilherme C., Giovanni De-Simone Salvatore, Morel Carlos M. Hematological alterations associated with long COVID-19. Frontiers in Physiology, Vol 14, 2023. DOI: 10.3389/fphys.2023.1203472  ISSN: 1664-042X https://www.frontiersin.org/articles/10.3389/fphys.2023.1203472 https://www.frontiersin.org/articles/10.3389/fphys.2023.1203472/full (Full text)

Increased red blood cell deformation in children and adolescents after SARS-CoV-2 infection

Abstract:

Severe coronavirus disease 2019 (COVID-19) is associated with hyperinflammation, hypercoagulability and hypoxia. Red blood cells (RBCs) play a key role in microcirculation and hypoxemia and are therefore of special interest in COVID-19 pathophysiology. While this novel disease has claimed the lives of many older patients, it often goes unnoticed or with mild symptoms in children.

This study aimed to investigate morphological and mechanical characteristics of RBCs after SARS-CoV-2 infection in children and adolescents by real-time deformability-cytometry (RT-DC), to investigate the relationship between alterations of RBCs and clinical course of COVID-19. Full blood of 121 students from secondary schools in Saxony, Germany, was analyzed. SARS-CoV-2-serostatus was acquired at the same time.

Median RBC deformation was significantly increased in SARS-CoV-2-seropositive compared to seronegative children and adolescents, but no difference could be detected when the infection dated back more than 6 months. Median RBC area was the same in seropositive and seronegative adolescents. ‘

Our findings of increased median RBC deformation in SARS-CoV-2 seropositive children and adolescents until 6 months post COVID-19 could potentially serve as a progression parameter in the clinical course of the disease with an increased RBC deformation pointing towards a mild course of COVID-19.

Source: Eder J, Schumm L, Armann JP, Puhan MA, Beuschlein F, Kirschbaum C, Berner R, Toepfner N. Increased red blood cell deformation in children and adolescents after SARS-CoV-2 infection. Sci Rep. 2023 Jun 17;13(1):9823. doi: 10.1038/s41598-023-35692-6. PMID: 37330522. https://www.nature.com/articles/s41598-023-35692-6 (Full text)

Persistent capillary rarefication in long COVID syndrome

Abstract:

Background: Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection.

Methods: This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4-25 µm.

Measurements and main results: Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: – 45.16%; D6: – 35.60%; D7: – 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).

Conclusions: Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

Source: Osiaevi I, Schulze A, Evers G, Harmening K, Vink H, Kümpers P, Mohr M, Rovas A. Persistent capillary rarefication in long COVID syndrome. Angiogenesis. 2022 Aug 11:1–9. doi: 10.1007/s10456-022-09850-9. Epub ahead of print. PMID: 35951203; PMCID: PMC9366128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366128/ (Full text)

Red blood cell biomechanics in Chronic Fatigue Syndrome

INTRODUCTION:

Chronic Fatigue Syndrome (CFS) is a multi-systemic illness of unknown etiology, affecting millions worldwide [1], with the capacity to persist for several years. It is characterized by persistent or relapsing unexplained fatigue of at least 6 months’ duration that is not alleviated by rest. CFS can be debilitating, and its clinical definition includes a broad cluster of symptoms and signs that give it its distinct character, and its diagnosis is based on these characteristic symptom patterns including cognitive impairment, post-exertional malaise, unrefreshing sleep, headache, hypersensitivity to noise, light or certain food items. Although an abnormal profile of circulating proinflammatory cytokines, and the presence of chronic oxidative and nitrosative stresses have been identified and correlated with severity in CFS [2], there are no reliable molecular or cellular biomarkers of the disease.

Read the rest of this article HERE.

Source: Saha, Amit & R. Schmidt, Brendan & Kumar, Arun & Saadat, Amir & C. Suja, Vineeth & Nguyen, Vy & K. Do, Justin & Ho, Wendy & Nemat-Gorgani, Mohsen & Shaqfeh, Eric & Ramasubrmanian, Anand & Davis, Ronald. (2019). Red Blood Cell Biomechanics in Chronic Fatigue Syndrome. Summer Biomechanics, Bioengineering and Biotransport Conference. June 25 -28, Seven Springs, PA, USA

Altered Erythrocyte biophysical properties in Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide. In this work, we tested the hypothesis that erythrocyte biophysical properties are adversely affected in ME/CFS.

We tested erythrocyte deformability using a high-throughput microfluidic device which mimics microcapillaries. We perfused erythrocytes from ME/CFS patients and from age and sex matched healthy controls (n=14 pairs of donors) through a high-throughput microfluidic platform (5μmx5μm). We recorded cell movement at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by cells to completely enter the test channels), average transit velocity (velocity of cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that erythrocytes from ME/CFS patients had higher entry time, lower average transit velocity and lower elongation index as compared to healthy controls.

Taken together, this data shows that erythrocytes from ME/CFS patients have reduced deformability. To corroborate our findings, we measured the erythrocyte sedimentation rate for these donors which show that the erythrocytes from ME/CFS patients had lower sedimentation rates. To understand the basis for differences in deformability, we investigated changes in the fluidity of the membrane using pyrenedecanoic acid and observed that erythrocytes from ME/CFS patients have lower membrane fluidity. Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the erythrocyte plasma membrane. Higher levels of reactive oxygen species in erythrocytes from ME/CFS patients were also observed. Using scanning electron microscopy, we also observed changes in erythrocyte morphology between ME/CFS patients and healthy controls.

Finally, preliminary studies show that erythrocytes from “recovering” ME/CFS patients do not show such differences, suggesting a connection between erythrocyte deformability and disease severity.

Source: Amit K. Saha, Brendan R. Schmidt, Julie Wilhelmy, Vy Nguyen, Justin K. Do, Vineeth C. Suja, Mohsen Nemat-Gorgani, Anand K. Ramasubramanian, Ronald W. Davis. Altered Erythrocyte Biophysical Properties in Chronic Fatigue Syndrome. Biophys. Journal. VOLUME 116, ISSUE 3, SUPPLEMENT 1, 122A, FEBRUARY 15, 2019. https://www.cell.com/biophysj/fulltext/S0006-3495(18)31946-5

Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome

[Editor’s comment: Conspicuously absent from the reference section in this paper is the pioneering work of L. O. Simpson. In 1989 Dr. Leslie O. Simpson, a New Zealand pathologist, discovered that the blood of people with ME/CFS tends to have a higher proportion of cup-shaped red blood cells. (Simpson, L.O. “Nondiscocyte Erythrocytes in Myalgic Encephalomyelitis.” New Zealand Medical Journal 2(864):126-127,1989.) Cup-shaped cells are more difficult to squeeze through small capillaries than disc-shaped cells, making it harder for blood to oxygenate capillary-dependent tissues. In further investigations, Dr. Simpson also observed similar changes in red blood cell morphology in other diseases. He noted that red blood cell shape can change from minute to minute. A summary of Dr. Simpson’s work on red blood cell morphology in ME/CFS can be found HERE.]

Abstract:

BACKGROUND: Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood disease. Amongst others symptoms, the disease is associated with profound fatigue, cognitive dysfunction, sleep abnormalities, and other symptoms that are made worse by physical or mental exertion. While the etiology of the disease is still debated, evidence suggests oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Since red blood cells (RBCs) are well-known scavengers of oxidative stress, and are critical in microvascular perfusion and tissue oxygenation, we hypothesized that RBC deformability is adversely affected in ME/CFS.

METHODS: We used a custom microfluidic platform and high-speed microscopy to assess the difference in deformability of RBCs obtained from ME/CFS patients and age-matched healthy controls.

RESULTS AND CONCLUSION: We observed from various measures of deformability that the RBCs isolated from ME/CFS patients were significantly stiffer than those from healthy controls. Our observations suggest that RBC transport through microcapillaries may explain, at least in part, the ME/CFS phenotype, and promises to be a novel first-pass diagnostic test

Source: Saha KA, Schmidt RB, Wilhelmy J, Nguyen V, Abugherir A, Do KJ, Nemat-Gorgani M, Davis WR, Ramasubramanian KA. Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome.Clin Hemorheol Microcirc. 2018 Dec 28. doi: 10.3233/CH-180469. [Epub ahead of print]  https://content.iospress.com/articles/clinical-hemorheology-and-microcirculation/ch180469 (Full article)

Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years. ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes. The shape of erythrocytes change from biconcave discoid to an ellipsoid due shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology. Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques.

We tested the deformability of RBCs using a high-throughput microfluidic device which mimics blood flow through microcapillaries. We perfused RBCs (suspension in plasma) from ME/CFS patients and from age and sex matched healthy controls (n=9 pairs of donors) through a high-throughput microfluidic platform of 5µm width and 3-5 µm height. We recorded the movement of the cells at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by the cells to completely enter the test channels), average transit velocity (velocity of the cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that RBCs from ME/CFS patients had higher entry time (~12%, p<0.0001), lower average transit velocity (~17%, p<0.0001) and lower elongation index (~14%, p<0.0001) as compared to RBCs from healthy controls. Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.

To understand the basis for differences in deformability, we investigated the changes in the fluidity of the membrane using a lateral diffusion assay using pyrenedecanoic acid (PDA), and observed that RBCs from ME/CFS patients have lower membrane fluidity (~30%, p<0.01). Apart from the fluidity, Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the RBC plasma membrane (~18%, p<0.0001). Higher levels of reactive oxygen species (ROS) in RBCs from ME/CFS patients (~30%, p<0.008) were also observed, as compared to healthy controls. Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls (presence of different morphological subclasses like biconcave disc, leptocyte, acanthocyte and burr cells; area and aspect ratio; levels of RBC aggregation). Despite these changes in RBC physiology, the hemoglobin levels remained comparable between healthy donors and ME/CFS patients. Finally, preliminary studies show that RBCs from recovering ME/CFS patients do not show such differences in cellular physiology, suggesting a connection between RBC deformability and disease severity.

Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.

Source: Saha, A. K., Schmidt, B. R., Wilhelmy, J., Nguyen, V., Do, J., Suja, V. C., Nemat-Gorgani, M., Ramasubramanian, A. K., & Davis, R. W. (2018).Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome. Blood, 132(Suppl 1), 4874. Accessed November 28, 2018. https://doi.org/10.1182/blood-2018-99-117260.

Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study

Editor’s comment: In the 1980s, L. O. Simpson studied abnormally shaped red blood cells in patients with ME, which he published in a paper, “Nondiscocyte Erythrocytes in Myalgic Encephalomyelitis.” He later summarized his findings in a paper entitled “The Results from Red Cell Shape Analyses of Blood Samples From Members of Myalgic Encephalomyelitis Organisations in Four Countries.” You can read it HERE.

Abstract:

BACKGROUND: Veterans with Gulf War Illness (GWI) experience chronic symptoms that include fatigue, pain, and cognitive impairment. This symptom cluster may be the consequence of impaired tissue oxygen delivery due to red blood cell (RBC) dysfunction.

OBJECTIVE: The purpose of this preliminary study was to determine whether the microrheological behavior of RBCs is altered in GWI.

METHODS: We recruited 17 cases of GWI (GWI+) and 10 age matched controls (GWI-), and examined RBC deformability and aggregation via ektacytometry along with measurement of complete blood counts.

RESULTS: RBCs were more deformable in GWI+, as indicated by higher elongation indices particularly at higher shear stress values (5.33, 9.49, and 16.89) when compared to GWI-. Aggregation formation, stability and kinetics were similar between GWI+and GWI-. Complete blood counts were also similar, with the exception of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC distribution width (RDW) which was elevated in GWI+.

CONCLUSIONS: In this preliminary study, we observed increased deformability along with increased MCH, MCHC and RDW in veterans with GWI+, which may contribute to the symptomatology of GWI. Further research is required to confirm our findings and the role of RBC microrheology in GWI.

Source: Falvo MJ, Chen Y, Klein JC, Ndirangu D, Condon MR. Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study. Clin Hemorheol Microcirc. 2018;68(4):361-370. doi: 10.3233/CH-170262. https://www.ncbi.nlm.nih.gov/pubmed/29660926