Circulating histones play a central role in COVID-19-associated coagulopathy and mortality

Abstract

Circulating histones play a central role in COVID-19-associated coagulopathy and mortality COVID-19 has highlighted the lethal consequences of immunothrombosis; i.e., the cross-talk between coagulation, inflammation and the innate immune system. Patients with immunothrombosis have significant immune cell death, 1 which can release pro-coagulant 2 and cytotoxic 3 histones. Histones are small, positivelycharged proteins that are typically found within the cell nucleus and which bind to negatively-charged DNA. We hypothesize that circulating histones play a central role in critically-ill COVID-19 patients. This translational study demonstrates that admission histone levels are significantly elevated with increasing severity of COVID-19 infection (Mild, median=2.6 g/mL [IQR=0.7-7.6], Moderate, 10.5 g/mL [3.5-27.2], Critical, 20.0 g/mL [6.2-33.0], Non-survivors, 29.6 g/mL [11.2-60.0]; P<0.001). Circulating histones associated with severe coagulopathy, inflammation and organ injury markers, including cardiac troponin. Extracellular histone levels on admission are associated with poor outcomes and independently predict 28-day mortality of hospitalized COVID-19 patients. This is the first report to indicate that circulating histones, released following immune cell death, may play a central pathological role in severe SARS-CoV-2 infection.