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

Yong, Jun ORCID: 0000-0002-0092-4604, Abrams, Simon T, Wang, Guozheng ORCID: 0000-0001-5525-3548 and Toh, Cheng-Hock (2023) Cell-free histones and the cell-based model of coagulation. Journal of thrombosis and haemostasis : JTH, 21 (7). S1538-7836(23)00340-9-S1538-7836(23)00340-9.

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Abstract

The cell-based model of coagulation remains the basis of our current understanding in clinical haemostasis and thrombosis. Its advancement on the coagulation cascade model has enabled new pro-haemostatic 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 CFH released following extensive cell death in acute critical illnesses, e.g. 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 (TF) exposure, either by destruction of the endovascular barrier or induction of endoluminal TF expression on endothelia and monocytes. CFH can also bind prothrombin directly, generating thrombin via the alternative prothrombinase pathway. In amplifying and augmenting the procoagulant signal, CFHs activate and aggregate platelets, increases procoagulant material bioavailability through platelet degranulation and Weibel-Palade body exocytosis, activates intrinsic coagulation via platelet polyphosphate release, and induces 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.

Item Type:	Article
Uncontrolled Keywords:	coagulation, extracellular histones, neutrophil extracellular traps (NETs), thrombin, thrombosis
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	05 May 2023 09:30
Last Modified:	21 Sep 2023 03:54
DOI:	10.1016/j.jtha.2023.04.018
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3170217