Summary
Inflammatory cytokines promote the activation of coagulation through the induction
of tissue factor, downregulation of thrombomodulin and upregulation of plasminogen
activator inhibitor. In addition to these mechanisms, infections can trigger the release
of extracellular traps from leukocytes consisting of DNA and histones. Tissue injury
results in release of nucleosomes. Either of these histone containing structures activate
platelets and form a potent procoagulant surface on polyphosphates secreted from the
platelets, thereby augmenting thrombus formation. In addition, the histones can inhibit
thrombomodulin function. The combination of augmenting the platelet procoagulant activity
and impairing thrombomodulin activity probably explains the microvascular thrombotic
problems observed when histones are infused into mice. Of the histones, H4 is the
most potent in all of these activities. DNAase or blocking histone H4 can decrease
the thrombotic response initiated by either the extracellular traps or nucleosomes.
In addition to the direct prothrombotic activity of histone-DNA complexes, the complexes
trigger activation of the toll-like receptors 2, 4 and 9 thereby increasing inflammatory
cytokine formation and fostering thrombotic responses through the mechanisms mentioned
previously. Furthermore, these cytokines are likely to increase cell necrosis and
apoptosis releasing nucleosomes and further augmenting the activation of leukocytes
with the subsequent release of extracellular traps. Blocking this histone-mediated
cascade has the potential to impact a variety of clinical conditions including sepsis,
trauma, chemical toxicity, transplant injury and reperfusion injury.
Keywords
Neutrophils - histones - infection - inflammation - sepsis