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J Thromb Haemost. 2011 Sep;9(9):1795-803. doi: 10.1111/j.1538-7836.2011.04422.x.

Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation.

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  • 1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

Abstract

BACKGROUND:

Histones are basic proteins that contribute to cell injury and tissue damage when released into the extracellular space. They have been attributed a prothrombotic activity, because their injection into mice induces diffuse microvascular thrombosis. The protein C-thrombomodulin (TM) system is a fundamental regulator of coagulation, particularly in the microvasculature, and its activity can be differentially influenced by interaction with several cationic proteins.

OBJECTIVE:

To evaluate the effect of histones on the protein C-TM system in a plasma thrombin generation assay and in purified systems.

METHODS:

The effect of histones on plasma thrombin generation in the presence or absence of TM was analyzed by calibrated automated thrombinography. Protein C activation in purified systems was evaluated by chromogenic substrate cleavage. The binding of TM and protein C to histones was evaluated by solid-phase binding assay.

RESULTS:

Histones dose-dependently increased plasma thrombin generation in the presence of TM, independently of its chondroitin sulfate moiety. This effect was not caused by inhibition of activated protein C activity, but by the impairment of TM-mediated protein C activation. Histones were able to bind to both protein C and TM, but the carboxyglutamic acid domain of protein C was required for their effect. Histones H4 and H3 displayed the highest activity. Importantly, unlike heparin, DNA did not inhibit the potentiating effect of histones on thrombin generation.

CONCLUSIONS:

Histones enhance plasma thrombin generation by reducing TM-dependent protein C activation. This mechanism might contribute to microvascular thrombosis induced by histones in vivo at sites of organ failure or severe inflammation.

© 2011 International Society on Thrombosis and Haemostasis.

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PMID:
21711444
[PubMed - indexed for MEDLINE]
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