Impact of COVID-19 on Red Blood Cell Dynamics: Understanding the Link Between Infection and Anemia


The coronavirus infection (COVID-19), caused by the SARS-CoV-2 virus, presents a complex challenge to global health, manifesting through symptoms like shortness of breath, persistent cough, and fever. Beyond these immediate symptoms, COVID-19’s impact extends to various physiological processes, notably affecting the properties of red blood cells (RBCs), which play a crucial role in oxygen transport and gas exchange. This article delves into the multifaceted effects of COVID-19 on RBCs, highlighting the alterations in their structural and functional aspects, the implications for patients’ health, and the broader consequences on clinical outcomes.

Alterations in Red Blood Cell Properties in COVID-19 Patients

Research has consistently shown that COVID-19 induces significant changes in the structure and function of RBCs. These alterations are closely associated with the disease’s severity and are often accompanied by elevated levels of inflammatory markers, such as interleukin-6. Notably, the cleavage of the N-terminus cytosolic domain of band 3 (SLC4A1), a change attributable to oxidant stress or proteolytic activity, and variations in the band 3 interactome involving key structural proteins like ankyrin (ANK1) and spectrin (SPTA1 and SPTB), are prominent among these modifications. Such structural changes are not merely incidental but correlate with functional impairments, including a predisposition to hemolysis, as indicated by morphological changes and proteome alterations in RBCs from COVID-19 patients.

Furthermore, studies have established a significant correlation between altered red cell distribution widths (RDWs) and the severity of COVID-19, proposing RDW as a potential marker for predicting clinical outcomes. The incidence of anemia in COVID-19-positive patients, documented at 61%, significantly exceeds that in patients with similar symptoms but negative test results, underscoring the infection’s role in compromising RBC integrity.

TABLE 1 – Changes in red blood cells (RBCs) in COVID-19 patients

The observed changes in red blood cells (RBCs) in COVID-19 patients stem from a complex interplay of various physiological, biochemical, and pathological processes. Let’s break down the reasons, including the chemical, physical, and biological factors, along with their consequences:

  • Viral Pathogenesis: The SARS-CoV-2 virus primarily targets the respiratory system but can also affect other organs due to its affinity for angiotensin-converting enzyme 2 (ACE2) receptors present on various cell types, including RBCs.
  • Inflammatory Response: COVID-19 triggers an exaggerated immune response in some individuals, leading to a cytokine storm characterized by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6). This systemic inflammation can directly affect RBCs.
  • Oxidative Stress: The infection-induced inflammatory cascade often leads to oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms. Oxidative stress can damage RBC membranes and proteins, including band 3 (SLC4A1).
  • Band 3 Cleavage: Band 3 protein, a critical component of the RBC membrane involved in gas exchange and cell integrity, undergoes cleavage at its N-terminus cytosolic domain. This cleavage is attributed to both oxidative stress and proteolytic activity associated with the inflammatory response.
  • Disruption of Band 3 Interactome: Alterations in the interaction between band 3 and other structural proteins like ankyrin and spectrin destabilize the RBC membrane cytoskeleton. Ankyrin and spectrin are crucial for maintaining the shape and flexibility of RBCs.
  • Functional Impairments: The structural changes in RBCs, including band 3 cleavage and disrupted interactome, impair their function. This may lead to decreased deformability, compromised gas exchange, and reduced lifespan of RBCs.
  • Predisposition to Hemolysis: Morphological changes in RBCs, such as membrane blebbing and proteome alterations, suggest a predisposition to hemolysis. The weakened RBC membrane and altered protein composition make the cells more susceptible to rupture under stress conditions.
  • Clinical Consequences: The observed changes in RBC structure and function correlate with the severity of COVID-19 symptoms. Patients with more pronounced alterations in RBCs are likely to experience complications such as anemia, thrombosis, and multi-organ dysfunction.

The structural and functional changes in RBCs induced by COVID-19 result from a combination of viral pathogenesis, inflammatory response, oxidative stress, and disruptions in membrane protein interactions. These alterations contribute to the pathophysiology of the disease, affecting oxygen transport, hemostasis, and overall clinical outcomes for affected individuals.

Theoretical Insights into COVID-19-Induced Anemia

The hypothesis that SARS-CoV-2 RNA might directly contribute to anemia through adverse effects on RBC structure is gaining traction, especially in light of the virus’s inability to replicate within RBCs. This theory draws parallels with the behavior of other pathogens, like flaviviruses, which can invade RBCs. The activation of specific immune responses, notably the cGAS-STING-interferon-IDO1-kynurenine pathway, further complicates the interaction between COVID-19 and RBCs. These immune responses, while generally triggered by infectious pathogens, particularly in the context of chronic inflammation associated with aging, may exacerbate the detrimental effects on RBCs.

An intriguing aspect of the COVID-19-RBC dynamic involves the potential inhibition of pyruvate kinase, a key enzyme in glucose metabolism, by the SARS-CoV-2 nucleocapsid protein. Given the shared genetic encoding between liver pyruvate kinase (PKL) and the RBC variant (PKLR), there’s speculation about a similar inhibitory effect on RBC PKLR activity, which could contribute to reduced RBC lifespan in COVID-19 patients. However, direct evidence supporting this mechanism remains elusive.

TABLE 2 – The potential inhibition of pyruvate kinase (PK)

The potential inhibition of pyruvate kinase (PK), a critical enzyme in glucose metabolism, by the SARS-CoV-2 nucleocapsid protein presents a multifaceted interaction between viral components and host cellular processes. Let’s delve into the detailed reasons, encompassing chemical, physical, and biological aspects, along with their consequences:

  • Viral Protein Interaction: The SARS-CoV-2 nucleocapsid protein may interact with pyruvate kinase, potentially inhibiting its activity. This interaction could occur through various mechanisms, including direct binding or modification of the enzyme’s active site.
  • Glucose Metabolism Perturbation: Pyruvate kinase catalyzes the final step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate, generating ATP and pyruvate for further metabolic processes. Inhibition of this enzyme could disrupt cellular energy production and metabolic homeostasis.
  • Genetic Encoding Similarity: Both liver pyruvate kinase (PKL) and the RBC variant (PKLR) share genetic encoding, implying a potential similarity in their susceptibility to inhibition by viral proteins. This shared genetic background raises speculation about the impact of viral interactions on RBC PKLR activity.
  • RBC Lifespan Reduction: If the SARS-CoV-2 nucleocapsid protein inhibits RBC pyruvate kinase activity, it could lead to impaired glucose metabolism within RBCs. This metabolic dysfunction might result in reduced RBC lifespan, as proper glucose metabolism is crucial for maintaining cellular integrity and function.
  • Hypoxia and Oxidative Stress: Reduced RBC lifespan due to impaired glucose metabolism could exacerbate hypoxia, leading to tissue damage and organ dysfunction. Additionally, the metabolic imbalance resulting from pyruvate kinase inhibition may contribute to oxidative stress, further compromising RBC viability and function.
  • Clinical Manifestations: The speculated inhibition of RBC pyruvate kinase activity by SARS-CoV-2 could have clinical consequences, such as exacerbating anemia and thrombotic events in COVID-19 patients. Reduced RBC lifespan may contribute to the development of complications associated with tissue hypoxia and impaired oxygen delivery.
  • Research Challenges: Despite the speculative link between SARS-CoV-2 nucleocapsid protein and pyruvate kinase inhibition, direct evidence supporting this mechanism is currently lacking. Investigating this interaction requires rigorous experimental validation, including biochemical assays, structural studies, and in vivo models.

The potential inhibition of pyruvate kinase by the SARS-CoV-2 nucleocapsid protein represents a complex interplay between viral factors and host cellular metabolism. While speculation exists regarding its impact on RBC lifespan and clinical outcomes in COVID-19 patients, further research is necessary to elucidate the molecular mechanisms and physiological consequences of this interaction.

Clinical and Prognostic Implications

The occurrence of anemia in COVID-19 patients, significantly more prevalent than in non-infected individuals, points to a direct impact of the infection on RBC health. This relationship, however, is complex, as it intertwines with factors related to iron metabolism and inflammatory conditions. The present study aims to dissect these interactions by examining the effects of COVID-19 on RBC hemoglobin levels, enzyme activities, and deformability, thereby shedding light on how SARS-CoV-2 RNA might precipitate RBC dysfunction and anemia.

As the scientific community advances in its understanding of COVID-19’s implications for RBC dynamics, the exploration of proteomic biomarkers emerges as a promising avenue for enhancing disease outcome predictions. This approach not only facilitates a deeper comprehension of the viral mechanisms at play but also opens pathways to more effective treatment strategies, ultimately aiming to mitigate the infection’s impact on patient health.

COVID-19’s reach extends far beyond the respiratory symptoms it is primarily known for, affecting the body’s fundamental processes, including those governing RBC function and integrity. The alterations in RBC properties observed in COVID-19 patients underscore the virus’s capacity to inflict systemic damage, leading to complications such as anemia. Understanding these effects is crucial for developing targeted therapies and improving patient care, marking an important step in the ongoing battle against this pervasive infection.

DISCUSSION – Exploring the Intricacies of Anemia in COVID-19 Patients: Insights into Red Blood Cell Dynamics and Metabolic Alterations

The multifaceted etiology and prognosis of numerous clinical conditions, including those associated with respiratory complications such as COVID-19 infection, are significantly influenced by anemia. Iron deficiency anemia (IDA) has been identified as a predisposing factor for lower respiratory tract infections in the pediatric demographic . In adults, its presence upon hospital admission has been implicated as a potential determinant for adverse COVID-19 outcomes .

Recent investigations have linked anemia, particularly in the context of COVID-19, to increased mortality rates attributed to immune-mediated disruptions in iron homeostasis [28]. Furthermore, a reduction in hemoglobin levels has been observed in critically ill patients , underscoring the complex relationship between anemia and severe COVID-19 illness, which remains insufficiently elucidated.

The pathogenesis of multifactorial anemia in SARS-CoV-2-infected individuals encompasses several mechanisms, including potential hemolysis induced by viral entry through erythrocyte membrane receptors, impaired erythropoiesis due to hematopoietic precursor invasion, and altered iron metabolism driven by pro-inflammatory cytokine-mediated upregulation of hepcidin. However, since clinical and omics characterization of RBCs and plasma from COVID-19+ patients failed to document the increase in hemolysis, it can be assumed that the association of decreased iron availability, elevated levels of acute phase reactants, and a hindered erythropoiesis may explain the anemia of most COVID-19-infected patients.

This study introduces additional factors contributing to anemia in COVID-19 patients, emphasizing the comparative analysis of patients with other viral infections to enhance the understanding of this condition. Significantly, this research found elevated levels of d-dimer, procalcitonin (PCT), and markers of chronic kidney disease (CKD) in COVID-19 patients with anemia, suggesting a link between CKD and anemia in these patients. This association was further supported by a recent meta-analysis indicating a direct influence of aging and concurrent CKD on anemia in COVID-19 patients in like fashion to patients suffering from CKD. The study also highlights the role of elevated comorbidities, including renal dysfunction and alterations in erythrocyte structural membrane proteins, in the pathogenesis of anemia.

Despite these findings, erythrocyte deformability was generally normal across the cohort, suggesting the complexity of anemia’s impact on patient outcomes. Increased serum ferritin levels in anemic COVID-19 patients were noted, indicating inflammation. However, similar observations in patients with other viral infections suggest a broader context of anemia beyond COVID-19. Altogether, these observations may contribute to explaining the role of anemia and hypoxia.

The study underscores the importance of timely anemia management in hospitalized COVID-19 patients, suggesting that oxygen supplementation or steroids, in addition to standard care, may mitigate deterioration. In this view, it is worth highlighting the reassuring evidence on the potential impact of COVID-19 on RBC oxygen kineticsdespite evidence of a potential disruption in the so-called oxygen-dependent metabolic modulation revolving around band 3 stability.

Furthermore, the analysis of hemoglobin stability and erythrocyte enzyme activities, including pyruvate kinase (PK) and adenylate kinase (AK), offers insights into the metabolic alterations associated with COVID-19 and anemia and its probable contribution to the prognostic role of anemia in COVID-19 Patients. Concerning hemoglobin, the coronavirus, similar to other viruses, is able to interact with protoporphyrin IX through the spike protein involving beta chains of Hb, causing eventual Hb denaturation and the inhibition of viral replication by blocking the SARS-CoV-2-cell fusion mediated by the spike protein.

Using the isopropanol test, we have analyzed the stability of the hemoglobin molecule in all the patients included in this study, and with the exception of five cases, all the patients exhibited a normal hemoglobin stability. Probably, in mature RBCs, the interaction between SARS-CoV-2 and hemoglobin can take place, but since the virus replication is prevented by the absence of a nucleus, the final effect on hemoglobin stability is not significant. The same may happen at the bone marrow level, where the virus enters the nascent erythroblasts through CD147 and CD26. Here, even though the virus can replicate, there may be no significant effect on hemoglobin stability.

Concerning RBC enzyme activities, their measurement was performed in all the patients included in this study and showed normal values, with the exception of pyruvate kinase (PK) and adenylate kinase (AK), which exhibited a significant (p < 0.05) increase in activity in both COVID-19+ and virally infected patients with anemia. Previous studies on RBCs from COVID-19 patients have highlighted an increase in the glycolytic pathway manifested by a characteristic increase in glucose consumption accompanied by an accumulation of intermediates of glycolysis and higher levels of phosphofructokinase (PFK), the rate-limiting enzyme of glycolysis. Mammals have two pyruvate kinase genes, PK-LR and PK-M. PK-LR encodes for two PK isozymes: PKL (liver) and PKR (RBCs).

The PK-M gene encodes for pyruvate kinase isozyme M1 (muscle and brain) and M2 (leukocytes and early fetal tissues). Only PKLR encodes for the RBC isozyme, which is affected in PK deficiency. However, it has been shown that patients with severe COVID-19 disease exhibit a higher expression of leukocyte PKM2, suggesting that increased PKM2 is involved in the metabolic reprogramming process participating in the immune response induced by COVID-19. Adenylate kinase (AK) is the key enzyme of nucleotide metabolism and belongs to the nucleoside monophosphate kinase (NMPK) family.

The mechanism/s of the increased AK (AK1) activity in COVID-19+ patients with anemia is unknown, but increased AK, together with other biomarkers, can be helpful in assessing the risk of diseases where oxidative/inflammatory stress plays a crucial role in pathogenesis. Of note, here, AK1 levels positively correlated with increases in RDW, a marker of disease severity and prognosis in COVID-19 patients [6,51].

This research sheds light on the direct effects of SARS-CoV-2 on erythrocyte structural proteins and metabolic pathways, potentially contributing to thromboembolic and coagulopathic complications. Finally, the minimal changes observed through ektacytometry, despite proteomic evidence, pose a conundrum. It is plausible that, within our cohort, the protein modifications induced by viral interaction were not substantial enough to significantly alter red blood cell deformability.

In conclusion, this study highlights the complexity of RBC dynamics in the context of viral infections and enhances the understanding of anemia as a significant factor in the severity of outcomes in SARS-CoV-infected patients. Unfortunately, although these compelling findings are encouraging, the study’s limitations, including a modest cohort size and geographical restrictions, suggest caution in generalizing the results, and we advocate for a deeper exploration of erythrocyte dynamics in viral infections.

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