Dysregulation in erythrocyte dynamics caused by SARS-CoV-2 infection: possible role in shuffling the homeostatic puzzle during COVID-19

Abstract

Introduction: The evolving COVID-19 pandemic became a hallmark in human history, not only by changing lifestyles, but also by enriching scientific knowledge on viral infection and its consequences.

Objective: Although the management of cardiorespiratory changes is pivotal to a favorable prognosis during severe clinical findings, dysregulation of other systems caused by SARS-CoV-2 infection may imbalance erythrocyte dynamics, such as a bidirectional positive feedback loop pathophysiology.

Method and results: Recent evidence shows that SARS-CoV-2 is capable of affecting the genetics and dynamics of erythrocytes and this coexists with a non-homeostatic function of cardiovascular, respiratory and renal systems during COVID-19. In hypothesis, SARS-CoV-2-induced systematical alterations of erythrocytes dynamics would constitute a setpoint for COVID-19-related multiple organ failure syndrome and death.

Conclusion: The present review covers the most frequent erythrocyte-related non-homeostatic findings during COVID-19 capable of providing mechanistic clues of SARS-CoV-2-induced infection and inspiring therapeutic-oriented scientific evidence.

Keywords: COVID-19; Erythrocyte; Hemoglobin; Hemorphins; SARS-CoV-2.

Figure 1

Hypothetical feedback loop oxidative mechanism resulting in, and from, erythrocyte death. The SARS-CoV-2 infection would activate metabolic processes inside the host cell and in inflammatory/immune systems that would result in an imbalanced redox status. Oxidative stress affects erythrocytes, thus inducing death of these red blood cells. The release of free iron, as a direct consequence of this erythrocyte destruction, would facilitate the metabolic reactions underlying the oxidative stress. The major structural proteins of SARS-CoV-2 interacting with host cells are spike (S), membrane (M) and envelope (E). Angiotensin-converting enzyme type 2 (ACE-2) and serine protease 2 (TMPRSS2) are the host cell membrane proteins interacting with SARS-CoV-2 proteins. Alpha and Beta are the hemoglobin chains released following erythrocyte death, from which bioactive peptides are derived. ROS: reactive oxygens species.

Figure 2

Slide from a critically ill patient with COVID-19 admitted to an intensive care unit of a hospital. The slide details evidence of morphological alterations in red blood cells by the SARS-CoV-2 infection: red - mushroom red blood cells; green - red blood cells with the presence of Heinz bodies; blue - dacryocytes; purple - spherocytes; yellow - echinocytes (plasmolysis), and; black - acanthocytes; orange - keratocytes (bite cell). Staining method: Leishman. Magnification: 400X. Credits: Dr. Denise da Silva Pinheiro - LACES-ICB UFG.

Figure 3

Hypothetical mechanisms underlying the SARS-CoV-2-induced formation of Heinz Bodies as a clinical sign of hematological alteration that may occur through two possible routes, as represented by black arrows. The SARS-CoV-2 infection may affect the membrane Band-3-anchored multiprotein complex, thus resulting in erythrocyte damages. Furthermore, the SARS-CoV-2 infection may interfere with the early hematopoiesis processes in the bone marrow, resulting in the production and release of immature erythrocytes, the so-called reticulocytes. Therefore, this red blood cell maturation would be impaired by the viral infection, thus reducing the chances of producing a healthy erythrocyte, which may culminate in either reticulocyte death or its bizarre morphophysiological maturation.

Figure 4

Slide highlighting Heinz bodies from a critically ill patient with COVID-19 admitted to an intensive care unit of a hospital. Staining method: Brilliant Cresyl Blue. Magnification: 400X. Credits: Dr. Denise da Silva Pinheiro - LACES-ICB UFG.