COVID-19 has highlighted the lethal consequences of immunothrombosis; i.e. the cross-talk between coagulation, inflammation and the innate immune system. These patients have significant immune cell death, which can release pro-coagulant and cytotoxic histones. In this translational study, we showed that circulating histones play a central role in critically ill COVID-19 patients with admission histone levels significantly elevated with increasing severity of COVID-19 infection.