Circulating histones play a central role in COVID-19-associated coagulopathy and mortality
Rebecca Shaw, Simon T. Abrams, James Austin, Joseph M. Taylor, Steven Lane, Tina Dutt, Colin Downey, Min Du, Lance Turtle, J. Kenneth Baillie, Peter Openshaw, Guozheng Wang, Malcolm G. Semple, Cheng‐Hock Toh
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.