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

Abstract

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.