Proposed mechanisms by which NETs/chromatin components activate coagulation in vitro. Intact NETs (1), extracellular chromatin (2), nucleosomes (3), or histone octamers (4) do not directly activate coagulation. (5) Free DNA activates coagulation through the contact pathway. (6) Free histones promote coagulation activation mainly by inducing a procoagulant phenotype on blood and endothelial cells (ECs). FVa, activated factor V; Kal, kallikrein; PolyP, polyphosphate; PS, phosphatidylserine; RBC, red blood cell; TLR, tool-like receptor.