COVID-19-induced hypoxaemia: Focus on endothelium-red blood cell interaction
Dear Editor,
The mechanism of severe hypoxaemia during early stages of COVID-19 has
remained a mystery. Although, early studies suggested viral pneumonitis
as the main cause of hypoxemia, recent reports have questioned the
existence of a typical acute respiratory distress syndrome (ARDS) as the
main pathophysiologic feature of severe hypoxemia during SARS-Cov2
infection 1. The main characteristics of atypical ARDS
in COVID-19 are as follows: (a) severe hypoxemia with relatively
well-preserved lung mechanics1, (b) increased chance
of pulmonary thrombosis2, (c) the presence of severe
ventilation/prefusion mismatch. To explain all these features, we should
have a closer look at red blood cell (RBC) and endothelium interaction
in patients with COVID-19. The dynamic crosstalk between RBCs and
endothelium is crucial in maintaining pulmonary perfusion in health and
disease. The following evidence may suggest a role of RBC-endothelium
interaction during COVID-19:
(1) Angiotensin-Converting Enzyme-2 (ACE2) is abundantly expressed in
arterial and venous endothelial cells in the lung 3.
This surface protein appears to be the main binding site of SARS-Cov2 as
well as the main point of entry to the endothelial cells4. Endothelial cells adapt their phenotype (e.g.
procoagulant phenotype) according to the local microenvironment,
particularly during viral infection 5.
(2) SARS-Cov2 can also bind and enter RBCs through CD147 (the same point
of entry of malaria parasite) 6. A recent in silico study has
suggested that the viral protein (i.e. ORF1ab, ORF10, and ORF3a) may
bind to haemoglobin beta-chain and release free haem7. Chloroquine, which has recently been considered for
clinical management of COVID-19, has an apparent ability to inhibit
SARS-Cov2-haemoglobin interaction 7.
(3) Endothelial cells are the main cells involved in haem metabolism
using haem oxygenase, a critical enzyme responsible for production of
the endogenous gaseous transmitter, carbon monoxide (CO). It is well
known that free haem upregulates endothelial haem oxygenase expression8. Increased production of endogenous CO has not yet
been investigated in COVID-19 patients. However, at least in theory,
exaggerated production of CO may further inhibit haemoglobin saturation
and causes vasodilatation in the pulmonary circulation. Local
hypoxia-induced vasoconstriction is a physiological compensatory
mechanism in the lung to prevent formation of shunt and
ventilation/perfusion mismatch. Exaggerated formation of gaseous
transmitters such as CO can attenuate this physiological mechanism and
may enhance ventilation/perfusion mismatch and thus hypoxaemia.
Investigating the complex interaction between RBC and endothelium may
bring together different parts of the jigsaw puzzle on the
pathophysiology of COVID-19 (pulmonary thrombosis, pulmonary shunt and
severe hypoxaemia). If future investigations show that such interaction
is impaired in COVID-19, RBC/endothelium could become a plausible target
for therapy in patients with severe hypoxaemia. Thus, the following
therapies can be suggested in management of COVID-19-induced hypoxaemia:
(a) Blood transfusion in conjunction with iron chelation: Blood
transfusion is not routinely recommended in typical ARDS9. However, the unique pathophysiology of COVID-19 may
make it an exceptional respiratory distress syndrome that respond to
transfusion. At least in theory, RBC transfusion or therapeutic red cell
exchange may increase the pool of RBCs that are able to carry oxygen in
patients with COVID-19-induced hypoxemia. Since SARS-Cov2 binds to RBCs,
new red cells may also act as a decoy receptor and reduce viral load. To
prevent iron overload and exacerbation of tissue injury during blood
transfusion, iron chelators (e.g. deferoxamine) may be given in
conjunction with blood transfusion. This is similar to the treatments
strategy currently used in patients with hemoglobinopathies such as beta
thalassemia.
(b) Hyperbaric oxygen therapy: Our knowledge on optimum characteristics
of mechanical ventilation is evolving during the pandemic. Some critical
care specialists suggest that protocol-driven mechanical ventilation
used for standard ARDS could be doing more harm than good in patients
with COVID-19 1. If studies show that gaseous
transmitters (such as CO and hydrogen sulphide) play an important role
in pathophysiology of COVID-19, hyperbaric oxygen therapy might be a
good way to support patients with severe symptoms.
(c) Inhibition of haem oxygenase: Another strategy could be considering
haem oxygenase as a target for therapy. Understanding the role of
endogenous CO in pathophysiology of ventilation/perfusion mismatch in
COVID-19 may open new insight into finding novel targets for therapy.
(d) Stimulation of foetal haemoglobin expression: If beta chain of
haemoglobin is the main target for SARS-Cov2 related protein inside the
RBCs, it is logical to suggest that stimulation of foetal haemoglobin
(HbF) expression may help COVID-19 patients who are at risk of severe
hypoxemia. Short-chain fatty acids as well as erythropoietin are shown
to stimulate HbF expression 10. This can be considered
within the context of COVID-19.
Ali R. Mania, Keshvad
Hedayatyanfardb, Razieh Mohammad
Jafaric, Parsa Mohammadic, Shahram
Ejtemaei Mehrc, Ahmad R. Dehpourc
a Division of Medicine, UCL, London, UK
(a.r.mani@ucl.ac.uk)