Stroke mechanisms associated with coronavirus disease (COVID-19)
Authors: Kruchinina M , Gromov A A , Generalov V M , Rabko A V , Kruchinin V N 
Published: October 2021

Abstract

The purpose is to identify the pathophysiological mechanisms of stroke development in patients with COVID-19.

Methods
A total of 92 patients (46.72+1.72 years) with impairments of cerebral circulation due to COVID-19 (confirmed by positive PCR test results) had been examined. Among them, 67 patients had an ischemic stroke, 14–a transient ischaemic attack, 11–an intracerebral hemorrhage, 3– a subarachnoid hemorrhage.
The parameters of hemostasis were measured by standard methods, electrical and viscoelastic parameters of red blood cells (RBC) by the dielectrophoresis method was carried out.

Results
Most of the surveyed persons (60 patients) showed signs of an intravascular coagulation and thrombosis: accelerated platelet-leukocyte aggregation, increased levels of coagulation products, reduced fibrinolysis activity (p=0.002–0.04). The levels of D-dimer, fibrinogen, ESR, platelet count were significantly higher in this group compared to patients in the second one (p&lt;0.01). A moderate increase in summarized rigidity, viscosity of RBC was noted. The level of RBC hemolysis was associated with platelet count (r=0.727, p&lt;0.05), D-dimer level (r=0.422, p=0.04), and fibrinogen level (r=0.318, p&lt;0.05).
In the second group of patients (32 persons with a predominance of men - 25 male subjects), the markers of thrombosis had moderate deviations. A sharply reduced RBC deformability with increased summarized rigidity and viscosity was dominant coupled with the background of high electrical conductivity of cell membranes compared to the indicators in the first group (p&lt;0.01). There was a decrease in membrane capacity, surface charge, electrical dipole moment of the cells and polarizability at all frequencies of the electric field than those in the first group (p=0.0001–0.05). A sharp decrease in RBC deformability creates obstacles to overcoming small-diameter capillaries, leading to violations of microcirculatory blood flow.
The RBC deformability was associated with levels of ferritin (r=0.407, p=0.024), HbA1c (r=0.419, p=0.033), uric acid (r=−0.303, p&lt;0.05), and LDL cholesterol (r=0.426, p=0.029).
Incubation of blood samples in vitro for 10 min with riboflavin, nicotinamide, inosine, which ensures RBC energy metabolism (anaerobic glycolysis and pentose phosphate pathway) restored the reduced the RBC deformability (p&lt;0.01), and decreased the RBC aggregation (p&lt;0.001). Similar changes were obtained when coenzymes were administered to patients in vivo.

Conclusion
Two independent mechanisms of cerebral circulatory disturbances have been identified in COVID-19 stroke patients: both thrombotic and hemorheologic. The thrombotic variant is associated with a procoagulant state and with an activity of inflammation. The hemorheologic variant is caused by a decrease in the activity of the RBC energy metabolism enzymes; it is associated with the presence of metabolic disorders and is to be eliminated by an administration of coenzymes and metabolites.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): This research was done within the framework of the topic “Epidemiological monitoring of the population state of health and studies on molecular genetic and molecular biological mechanisms of the development of common internal diseases in Siberia for improvement of the relevant diagnostic, preventive, and therapeutic methods” in State Assignment No. 0324-2018-0001, registration No. AAAA-A17-117112850280-2