From PurUUpurU to Cytokine Storm to Hyperviscosity, Thrombosis and Other
Complications of Coronavirus Disease 2019
Abstract
Background: Severe coronavirus disease 2019 (COVID-19) is associated
with pathological elevations of tumor necrosis factor-alpha (TNF-ɑ) and
interleukin 6 (IL-6). These cause extreme elevations of the acute phase
reactant fibrinogen and plasma viscosity. Severe COVID-19 is also
associated with poorly understood complications including a high
incidence of arterial and venous thrombosis despite prophylactic
anticoagulation, silent hypoxemia, pulmonary microvascular thrombosis,
excess neutrophil extracellular trap formation, encephalopathy, and
cardiac dysfunction. Aims: To investigate the cause of this pathological
inflammatory response, the authors determined the number of
purine-uridine-uridine-purine-uridine (purUUpurU) motifs in the genomes
of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and
other RNA viruses. This motif is the precursor to the oligonucleotide
which is the minimal motif required to activate inflammation via
toll-like receptor 8 (TLR8). A genome containing the same nucleotides in
SARS-CoV-2 in random order was used as a control. Result: PurUUpurU
occurred 2.8 times more often in the actual SARS-CoV-2 genome than the
randomized genome. The number of purUUpurU motifs correlates with the
severity of the acute illnesses caused by the RNA viruses examined,
except for influenza A. Conclusion: Hyperactivation of TLR8 mediated
inflammation by purUUpurU may cause pathological inflammation in
COVID-19. Marked elevations of TNF-ɑ, IL-6, and fibrinogen will cause
erythrocyte aggregation and increase blood viscosity. This promotes
thrombosis and decreases tissue perfusion. Therapeutic plasmapheresis
reduces blood hyperviscosity and should be used in severe COVID-19. To
date, use of this therapy has only been reported in COVID-19 associated
thrombosis.