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erYtHroCYtes as a tarGet
oF sars CoV-2 in PatHoGenesis
oF CoVid-19
abstraCt — e paper considers the possible mechanism
of the pathogenesis of COVID-19 caused by SARS-
COV-2, associated with damage to red blood cells, which
the authors attribute to the main key target that triggers a
cascade of reactions leading to multiple organ failure. e
paper presents morphological evidence for the presence
of pathological forms of erythrocytes characteristic of
various anemias in the blood vessels and parenchyma of
damaged lungs of patients with COVID-19. e death
of red blood cells leads to cell ischemia and anemia. e
defeat of brain neurons, blood vessels and hematotissue
barriers in organ systems is a consequence of ischemia
due to the impossibility of transferring hemoglobin by
damaged erythrocytes and ends at the terminal stages of
the development of the disease with their dysfunction.
Adaptive erythropoiesis with an increase in erythropoietin
secretion is especially dangerous for patients suering from
hypertension, and then it is impossible, since all organs
involved in the synthesis of erythropoietin are damaged. In
this case, the synthesis of hemoglobin is also disrupted due
to a deciency of iron and cyancobolamin, whereas toxic
iron and hemosiderin are deposited in the tissues.
KEywords — COVID-19, SARS-COV-2, erythrocytes,
hemoglobin, erythropoiesis, viruses, pathogenesis of
COVID-19.
Ivan Reva1 , Tatsuo Yamamoto1 ,
Mariya Rasskazova2, Tatyana Lemeshko3,
Victor Usov2 , Yuriy Krasnikov2, Anna Fisenko3,
Evgeniy Kotsyurbiy3, Vladislav Tudakov3,
Ekaterina Tsegolnik3, Olesya Oleksenko3,
Anatoly Korobkin2, Ellada Slabenko2,
Anastasiya Shindina2, Kseniya Gordzievskaya2,
Anna Furgal2, Galina Reva1,2 ,
1 International Medical Research Center, Niigata, Japan,
2 Far Eastern federal university, Vladivostok;
3 Pacic State Medical University, Vladivostok, Russia
avers2@yandex.ru
r e l e V a n C e
In the world, the number of cases of COVID-19
has reached 16.4 million. e number of coronavirus
victims worldwide exceeds 600 thousand, including
children [1, 5, 16]. Madabhavi I., Sarkar M., Kadakol
N. (2020) identied the pandemic as a catastrophe
Received 01 July 2020;
Received in revised form 05 August 2020;
Accepted 07 August 2020
Editor’s ChoiCE
http://dx.doi.org/10.35630/2199-885X/2020/10/3.1
of global signicance [6], which indicates the high
urgency of the problem under study [9, 12, 21]. It is
generally accepted that viruses multiply in the cell,
specializing in certain cell types: HIV infects -
lymphocytes, the inuenza virus infects the epithe-
lium of the larynx and lungs, coronavirus destroys
the epithelium of the upper respiratory tract, lungs
and gastrointestinal tract, herpes aects the nerves
and causes neuroinfections, hepatitis viruses infect
liver cells, etc. [17, 20]. With COVID-19 caused by
SARS-COV-2, multiple organ disorders occur in
various structures, including nerve structures [3, 14].
Burness A. T. and Pardoe I. U. (1981) established the
possibility of attachment of the inuenza virus to
human erythrocytes, followed by hemagglutination of
the cells [4]. Allaway G.P., Burness A.T. (1986) showed
that the main type of glycophorins, glycophorin A, is a
receptor for the attachment of inuenza and encepha-
lomyocarditis (EMS) viruses to human erythrocytes
[2, 4]. e attachment of the EMS virus to glycoph-
orin A includes a region containing amino acids 35 to
about 70 (numbered from the end of NH2), four of
which (amino acids 37, 44, 47 and 50) are glycosylated.
In addition, there is evidence that segments contain-
ing amino acids 35 to 39 with an oligosaccharide side
chain on threonine-37 are particularly important for
the attachment of EMS virus. However, in the avail-
able scientic literature against the background of the
available pathomorphological data on the destruction
of lung tissue, death of alveolocytes, brotic changes
in the lungs, there is no assessment of erythrocytes
located both in the lumen of blood vessels and released
into the parenchyma of aected organs [5, 19, 24].
Given the multiple organ failure that develops in
COVID-19 [7, 18], the absence of a key morphologi-
cal target for SARS-COV-2 [8], as well as controver-
sial data on the nature of the virus itself, we directed
our research to study changes in the red blood cell
pool against the background of COVID-19. Accord-
ing to Rodríguez-Nóvoa S., Morello J., González M.,
et al (2008), the use of antiviral drugs causes hemolysis
and increases hyperbilirubinemia [13]. According to
them, treatment of HIV/hepatitis-C infected patients
led to an increase in hyperbilirubinemia from 9% to
45% aer starting treatment for hepatitis C. Anemia
has a multifactorial nature [10, 15], which explains the
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cases of unsuccessful attempts to empirically use eryth-
ropoietin in the treatment of patients with hepatitis C
and HIV-infected [11]. All this dictates an expansion
of the range of measures aimed at studying the etiology
and pathogenesis of COVID-19 for the development
of pathogenetically justied prevention and treatment
that is absent at the present stage [22, 23].
Purpose of the study:
To study the role of red blood cells in the patho-
genesis of COVID-19.
m at e r ia l an d m et H o d s
e paper analyzes and discusses the results of
our own studies of lung biopsies of 11 patients who
died from COVID-19 caused by SARS-CoV-2, with
PCR conrmation, obtained in accordance with the
order of the Ministry of Healthcare of the Russian
Federation dated 04.29.94 N 82 On the procedure for
conducting pathological autopsies, which regulates the
procedure for autopsies in medical institutions. e
control group consisted of 14 patients who died as a
result of injuries incompatible with life, presumably
without somatic pathology at the age of 24 to 76
years. e biopsy specimens were xed immediately
aer collection in accordance with the preparation
protocol for histological examination. e exclusion
of possible artifacts is based on data obtained during
a special study on dogs, indicating that when corpses
are stored at a temperature of 4–7° C for 4–6 hours,
microscopically visible changes in the morphology
of various organ systems are not observed, except for
a slight decrease in the intensity of specic reactions
on enzymatic activity. We used classical histological
research methods with hematoxylin-eosin staining to
obtain a general morphological picture.
e material was analyzed using an Olympus-
Bx82 microscope and a CDx82 digital camera with
proprietary soware. e morphological method of
the study consisted in the preparation of sections from
paran blocks of lung biopsies from SARS-CoV-2
victims, followed by staining with hematoxylin and
eosin in accordance with the classical protocol. Analy-
sis of preparations and production of illustrations were
carried out using an Olympus Bx52 microscope and a
DP25 digital camera.
r e s ult s o F ou r o wn r e se a r C H
We have found that erythrocytes are one of the
targets damaged by SARS-COV-2. Anisocytosis and
poikilocytosis of erythrocytes are noted, macrophages
with hemosiderin, hypochromic and hyperchromic
erythrocytes are identied. Erythrocytes in the form
of a sickle are identied (in Fig. 1 it is indicated by an
arrow), as well as spherocytes, macro and microcytes.
e appearance of sickle erythrocytes may be as-
sociated with disturbances in the B-chains of globin
and the replacement of glutamine with valine. e
solubility of such globin decreases 25 times, depending
on the partial pressure of oxygen in the blood and the
concentration of HbS in the erythrocyte. e distribu-
tion of hemoglobin in the cytoplasm of erythrocytes is
uneven, bright oxyphilia is observed both in the center
of erythrocytes and in the periphery. ickening of
the erythrocyte membrane, chromophobic courtyard
around the red blood cells. Kebot's rings are identied,
staining red. Kebot's rings are characteristic and are
found mainly in megaloblastic anemia and metal in-
toxication (Pb). Under COVI-19 conditions, this toxic
eect is exerted by the hemoglobin of dying erythro-
cytes, transferrin and iron, as well as hemosiderin. We
have established that Howell-Jolly bodies are identied
on lung preparations, which are small round violet-red
inclusions 1–2 microns in size, less oen found in 2–3
in one erythrocyte. It is known that Howell-Jolly bod-
ies are the remainder of the erythrocyte nucleus aer
removal of its RES. Revealed more oen with intense
hemolysis and with megaloblastic anemia (Fig. 1).
Some of the erythrocytes have a swollen mem-
brane at one of the poles with the formation of a vacu-
ole (Figure 1, indicated by blue arrows). In addition, all
degenerative forms of erythrocytes with a characteris-
tic location of hemoglobin are observed: hypochromic
with a hole, ring, and also in the form of shadows,
indicating iron deciency and B12 anemia; hyperchro-
mic with an arrangement of hemoglobin in the form of
a ring with and without enlightenment (Fig. 2).
is explains the severity of clinical manifesta-
tions when the gastrointestinal tract is involved in
the pathological process, since the participation of
cyancobolamine in the normalization of erythropoi-
esis is inhibited. e presence of spherocytes in the
lung parenchyma and in the lumen of blood vessels
indicates hyperhydration of the erythrocyte, increased
permeability of the erythrocyte membrane for Na+
and Ca2+ ions, followed by the acquisition of spheri-
cal erythrocytes with the inability to plasticity and
deformation in the microvasculature, with a decrease
in life expectancy. It is known that with such changes,
the developing membranopathy is mainly due to a
signicant change in the content of the spectrin pro-
tein, a violation of its binding to other proteins of the
erythrocyte membrane. Since glycolysis is the leading
pathway for ATP resynthesis in erythrocytes, a lack of
ATP energy causes a violation of the transmembrane
transfer of ions, a decrease in the activity of enzymes
of the pentose phosphate cycle. eir imbalance
develops, leading to overhydration and swelling of
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Editor’s ChoiCE
erythrocytes. In addition, we noted the distribution
of hemoglobin at opposite poles of cells or at one of
the poles, typical for erythrocytes located both in the
lumen of blood vessels and in the parenchyma of the
lung. Also, cell nuclei are identied, the morphology
of which is characteristic of those damaged by viruses,
has a ring-shaped shape, or inclusions (Fig. 3).
Damage to erythrocytes does not have the
character of artifacts resulting from non-technological
implementation of methods in violation of the recom-
mended protocol, as evidenced by the presence of nor-
mocytes, as well as a clear morphology of macrophages
and other cells containing hemosiderin, a product of
erythrocyte destruction (Fig. 4).
In addition, hemosiderin is contained not only in
the cytolasm of macrophages, but also in the lumen of
blood vessels (Fig. 5, 6).
e presence of macrophages with hemosiderin
in the cytoplasm, as well as free hemosiderin in the
lumen of blood vessels, indicate that the death of
erythrocytes begins not in the lung parenchyma, but
at the stage of circulation and oxygen delivery to the
tissues. e consequence of this is the generalization
of the pathological process, leading to multiple organ
failure. us, for the causative agent of COVID-19
SARS COV-2 in starting the cascade of pathogenesis,
one of the main targets is the erythrocyte, in which
membranopathy, fermentopathy and hemoglobinopa-
thy are clearly manifested. Adaptive erythrocytosis,
an increase in the number of reticulocytes and arterial
hypertension are accompanied by a decrease in blood
plasma volume when the body loses uid as a result of
diarrhea, vomiting, and plasmorrhage. In our observa-
tions, 3 out of 11 patients developed anemia with a
Fig. 1. Lung parenchyma of patients a) 53 years old; b) 74 years old with COVID-19. Staining with hematoxylin and eosin. Microphoto, ×400.
Howell-Jolly bodies are identied (indicated by black arrows)
Fig. 2. Lung parenchyma of patients a) 56 years old; b) 64 years old with COVID-19. Staining with hematoxylin and eosin. Microphoto, ×400. Sphero-
cytes, microcytes, hypo- and hyperchromic erythrocytes are identied
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Fig. 3. Lung parenchyma of patients a) 39 years old; b) 56 years old; c) 64 years old; d) 71 years old with COVID-19. Staining with hematoxylin and eosin.
Microphoto, ×400. Spherocytes, microcytes, hypo- and hyperchromic erythrocytes are identied. The uneven distribution of hemoglobin at the poles of
eryrocytes is indicated by blue arrows, and the nuclei of cells aected by viral RNA are indicated by green arrows
Fig. 4. Lung parenchyma of patients a) 51 years old; b) 56 years old with COVID-19. Staining with hematoxylin and eosin. Microphoto
Editor’s ChoiCE
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Fig. 5. Lung parenchyma of patients a) 51 years old; b) 56 years old; c)
64 years old; d, e) 74 years old with COVID-19. Staining with hematoxylin
and eosin. Microphoto, ×400. Macrophages with hemosiderin granules
in cytolasm are identied against the background of degenerative forms
of erythrocytes
decrease in Hb and erythrocyte count to 2.12 1012/L.
It is these facts that explain the multiple organ struc-
tural disorders in the human body, as well as the death
of the air-blood barrier structures, which results in the
uselessness of resuscitation measures with the help of
mechanical ventilation devices (IVL) against the back-
ground of defective, with a shortened life cycle, dying
or missing oxygen carriers.
C o n C l u s i o n
Hemolytic anemia in COVID-19, which devel-
ops at the rst stage as a reaction to the SARS COV-2
viral microorganisms, causes cascading reactions to
toxic erythropoietin and hemoglobin released from
erythrocytes in the bloodstream, and then to hemosi-
derin released due to the death of erythrocytes in the
tissue. e process ends with a decrease in the synthe-
sis of erythropoietin in the decaying liver and kidneys,
in the absence of the necessary vitamin B12 due to the
pathology of its secretion in the gastrointestinal tract.
e characteristic signs of damage to red blood cells
in conditions of infection with COVID-19 indicate
Editor’s ChoiCE
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Fig. 6. Lung parenchyma of patients a) 64 years old; b) 71 years old with COVID-19. Staining with hematoxylin and eosin. Microphoto, ×400. (Green
arrow indicates sickle-shaped erythrocyte. Orange arrows indicate viral inclusions in cell nuclei)
disruption of erythropoiesis, with developing iron
deciency and B12 anemia. e synthesis of hemo-
globin lags behind the dierentiation of erythrocytes,
which in the initial period of the disease induces an
increase in the secretion of erythropoietin, which has a
hypertensive eect; increases blood viscosity and leads
to impaired blood microcirculation, which is why
patients with essential hypertension are the main risk
group. is underlies the inability to use erythropoi-
etin-based drugs to treat patients with anemia in the
context of COVID-19 infection. Pathological changes
in erythrocytes infected with viruses are caused by
specic and non-specic processes. Reactions caused
by the conguration of the permeability of the plasma
membrane of erythrocytes, margination of chromatin
in the form of Howell-Jolly bodies, and vacuolization
of the cytoplasm are nonspecic. SARS COV-2, like
SV40, can be attributed to vacuolizing viruses, but only
erythrocytes, since the virus has a particularly peculiar
and pronounced character of inducing vacuolization.
Specic changes are oxyphilic viral inclusions in cell
nuclei, leading to cell destruction through a rapid and
deep eect on the synthesis of cellular proteins.
C o n C l u s i o n s
1. e key target for SARS COV-2 is erythrocytes.
2. Multiorgan failure is the result and consequence
of SARS COV-2 virus damage to erythrocytes,
which develops against this background of
ischemia and anemia with cell death of various
organ systems.
3. e use of erythrocyte mass for the treatment of
COVID-19 is pathogenetically substantiated.
e study was carried out within the amework of
the state assignment 17.5740.2017 / 6.7, the international
Russian-Japanese grant of the FEFU (agreement No. 13-
09-0602-m_a dated 06.11.2013) and the execution of the
grant om the Russian Science Foundation 19-14-00260
(2019).
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