P2X1 ion channel deficiency causes massive bleeding in inflamed intestine and increases thrombosis

[en] Background: Intestinal inflammation is associated with bleeding and thrombosis, two processes that may involve both platelets and neutrophils. However, the mechanisms and the respective contribution of these cells to intestinal bleeding and extra-intestinal thrombosis remain largely unknown. Objective: Our study aimed at investigating the mechanisms underlying the maintenance of vascular integrity and thrombosis in intestinal inflammation. Methods: We used a mouse model of acute colitis induced by oral administration of dextran sodium sulfate (DSS) for 7 days. Bleeding was assessed after depletion of platelets, neutrophils, or glycoprotein VI (GPVI); treatment with aspirin or clopidogrel; or in P2X1-deficient mice. Extra-intestinal thrombosis was analyzed using a laser-induced injury model of thrombosis in cremaster muscle arterioles. Results: Platelet depletion or P2X1 deficiency led to macrocytic regenerative anemia due to intestinal hemorrhage. In contrast, GPVI, P2Y12, and thromboxane A2 were dispensable. Platelet P-selectin expression and regulated on activation, normal T-cell expressed and secreted (RANTES) plasma levels were lower in DSS-treated P2X1-deficient mice as compared to wild-type mice, indicative of a platelet secretion defect. Circulating neutrophils had a more activated phenotype, and neutrophil infiltration in the colon was increased. P2X1-deficient mice also had elevated plasma granulocyte-colony stimulating factor (G-CSF) levels. Neutrophil depletion limited blood loss in these mice, whereas exogenous administration of G-CSF in colitic wild-type mice caused macrocytic anemia. Anemic colitic P2X1-deficient mice formed atypical neutrophil- and fibrin-rich, and platelet-poor thrombi upon arteriolar endothelial injury. Conclusions: Platelets and P2X1 ion channels are mandatory to preserve vascular integrity in inflamed intestine. Upon P2X1 deficiency, neutrophils contribute to bleeding and they may also be responsible for enhanced thrombosis. © 2019 International Society on Thrombosis and Haemostasis

Disciplines :

Hematology

Author, co-author :

Wéra, Odile ; Université de Liège - ULiège > Cardiovascular Sciences-Cardiology

LECUT, Christelle ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Unité de laboratoire - thrombose - hémostase

Servais, Laurence ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie analytique inorganique

Hego, Alexandre ; Université de Liège - ULiège > Platform Imaging & Flow cytometry

Delierneux, Céline ; Université de Liège - ULiège > Cardiovascular Sciences-Cardiology

Jiang, Zheshen ; Université de Liège - ULiège > Cardiovascular Sciences-Cardiology

Keutgens, Aurore ; Université de Liège - ULiège > Département des sciences de la santé publique > Département des sciences de la santé publique

Evans, R. J.; Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom

Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques

Lancellotti, Patrizio ; Université de Liège - ULiège > Département des sciences cliniques > Cardiologie - Pathologie spéciale et réhabilitation

Oury, Cécile ; Université de Liège - ULiège > Cardiovascular Sciences-Cardiology

Language :

English

Title :

P2X1 ion channel deficiency causes massive bleeding in inflamed intestine and increases thrombosis

Publication date :

21 August 2019

Journal title :

Journal of Thrombosis and Haemostasis

ISSN :

1538-7933

eISSN :

1538-7836

Publisher :

Blackwell Publishing Ltd

Volume :

Issue :

Pages :

44-56

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

FNRS‐FRSM 3.4611.11; FSRC‐13/12

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
FRSM - Fonds de la Recherche Scientifique Médicale [BE]
FWB - Fédération Wallonie-Bruxelles [BE]
Fondation Léon Fredericq [BE]
FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture [BE]

Available on ORBi :

since 13 October 2020

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