A hypothesis linking the renin-angiotensin, kallikrein-kinin systems, and disseminated coagulation in COVID-19

In this article we present a hypothesis based on the relationship between four physiological systems: the renin-angiotensin system (RAS), the kallikrein-kinin system (KKS), the arachidonic acid (AA) cascade, and platelet aggregation/coagulation − in the context of COVID-19. The central point of our proposition relies on ACE₂ levels, which reduce following SARS-CoV-2 entry in the cell. The following cascade of events. Triggered by this reduction, involves the increase in Ang II levels and its consequent binding to AT1-R, initiating the release of pro-inflammatory cytokines such as TNF-α, IL-1, IL-10, and IL-12. These pro-inflammatory cytokines activate immune cells, including mast cells, which release heparin, thus activating Coagulation factor XII and increasing pre-kallikrein (PK) production. Consequently, there is an increase in bradykinin (BK) levels. BK, via its receptor BKB2-R, induces Ca² + release increasing secreted phospholipase A₂ (sPLA₂) levels. Concomitantly, both the imbalance in Ang II/AT1-R and BK/BKB2-R signaling contribute to sPLA₂ activation, inducing the release of arachidonic acid (AA) from cell membrane phospholipids, by cyclooxygenase-2 (COX-2) cleavage to produce prostaglandin G₂ (PGG₂), and later prostaglandin H₂ (PGH₂). At least, PGH₂ is converted to thromboxane A₂ (TXA₂), which is involved in the platelet aggregation process. Platelet aggregation further increases TXA₂ levels, initiating a positive feedback loop leading to further platelet activation and clot formation. Ultimately, this cascade of events may contribute to the development of a pre-thrombotic state and increase the risk of mortality, in COVID-19. We believe that this integrated approach could provide a deeper understanding of the underlying mechanisms of COVID-19 and guide future therapeutic strategies.