Cell-free histones and the cell-based model of coagulation

Abstract

The cell-based model of coagulation remains the basis of our current understanding of clinical hemostasis and thrombosis. Its advancement on the coagulation cascade model has enabled new prohemostatic and anticoagulant treatments to be developed. In the past decade, there has been increasing evidence of the procoagulant properties of extracellular, cell-free histones (CFHs). Although high levels of circulating CFHs released following extensive cell death in acute critical illnesses, such as sepsis and trauma, have been associated with adverse coagulation outcomes, including disseminated intravascular coagulation, new information has also emerged on how its local effects contribute to physiological clot formation. CFHs initiate coagulation by tissue factor exposure, either by destruction of the endovascular barrier or induction of endoluminal tissue factor expression on endothelia and monocytes. CFHs can also bind prothrombin directly, generating thrombin via the alternative prothrombinase pathway. In amplifying and augmenting the procoagulant signal, CFHs activate and aggregate platelets, increase procoagulant material bioavailability through platelet degranulation and Weibel-Palade body exocytosis, activate intrinsic coagulation via platelet polyphosphate release, and induce phosphatidylserine exposure. CFHs also inhibit protein C activation and downregulate thrombomodulin expression to reduce anti-inflammatory and anticoagulant effects. In consolidating clot formation, CFHs augment the fibrin polymer to confer fibrinolytic resistance and integrate neutrophil extracellular traps into the clot structure. Such new information holds the promise of new therapeutic developments, including improved targeting of immunothrombotic pathologies in acute critical illnesses.

Keywords: coagulation; extracellular histones; neutrophil extracellular traps (NETs); thrombin; thrombosis.