New (re)purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm

Severe manifestations of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as acute respiratory distress syndrome (ARDS), are characterized by hyperinflammation, exuberant cytokine release, profound and progressive hypoxia, deranged coagulation, and multiorgan failure (1). COVID-19 also presents not infrequently with a devastating thrombotic diathesis, manifesting as arterial thrombosis, pulmonary embolism, deep vein thrombosis, and thrombotic microangiopathy. Not surprisingly, dysregulation of tonic vascular homeostatic functions of endothelial and hematopoietic lineage cells has been implicated in the pathophysiology of COVID-19. Reminiscent of neutrophil and macrophage hyperactivation syndromes, the COVID-19-associated systemic inflammatory response syndrome is likely driven by the activation and/or death of infected cells and collateral damage triggered by explosive production of cytokines and chemokines. Recruited leukocytes spew a fibrin/platelet-entrapping meshwork of DNA and associated histones, which in a vicious cycle further recruits leukocytes and triggers intravascular coagulation through endothelial, platelet, and leukocyte dysfunction (2). These concepts are supported by autopsy studies that have detected clusters of activated and degenerating myeloid cells in both intravascular and extravascular spaces (3) as well as an endotheliitis that is characterized by viral inclusion bodies and SARS-CoV-2 nucleoprotein in the walls of blood vessels (4, 5).