The contact activation system as a potential therapeutic target in patients with COVID‐19

Shatzel, Joseph J.; DeLoughery, Emma P.; Lorentz, Christina U.; Tucker, Erik I.; Aslan, Joseph E.; Hinds, Monica T.; Gailani, David; Weitz, Jeffrey I.; McCarty, Owen J. T.; Gruber, Andras

Coronavirus disease 2019 (COVID‐19) is predicted to overwhelm health care capacity in the United States and worldwide, and, as such, interventions that could prevent clinical decompensation and respiratory compromise in infected patients are desperately needed. Excessive cytokine release and activation of coagulation appear to be key drivers of COVID‐19 pneumonia and associated mortality. Contact activation has been linked to pathologic upregulation of both inflammatory mediators and coagulation, and accumulating preclinical and clinical data suggest it to be a rational therapeutic target in patients with COVID‐19. Pharmacologic inhibition of the interaction between coagulation factors XI and XII has been shown to prevent consumptive coagulopathy, pathologic systemic inflammatory response, and mortality in at least 2 types of experimental sepsis. Importantly, inhibition of contact activation also prevented death from Staphylococcus aureus–induced lethal systemic inflammatory response syndrome in nonhuman primates. The contact system is likely dispensable for hemostasis and may not be needed for host immunity, suggesting it to be a reasonably safe target that will not result in immunosuppression or bleeding. As a few drugs targeting contact activation are already in clinical development, immediate clinical trials for their use in patients with COVID‐19 are potentially feasible for the prevention or treatment of respiratory distress.