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Neutrophils Are Responsible for Colitis-induced Anemia and Thrombosis in P2X1-deficient Mice
ISTH Academy. Oury C. Jul 10, 2019; 274124; OC 79.1
Dr. Cecile Oury
Dr. Cecile Oury
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OC 79.1

Neutrophils Are Responsible for Colitis-induced Anemia and Thrombosis in P2X1-deficient Mice

C. Oury, O. Wéra, L. Servais, C. Delierneux, A. Hego, C. Lecut, A. Keutgens, P. Delvenne, A. Nchimi, P. Lancellotti
Univ of Liège, Liège, Belgium

Main Topic: Platelets and Megakaryocytes
Category: Platelets & Inflammation

Background: Chronic inflammatory bowel diseases are associated with intestinal bleeding and systemic thrombotic events. However, the mechanisms underlying this hemostatic imbalance remain largely unknown. Particularly, the respective contributions of platelets and neutrophils to intestinal bleeding and extra-intestinal thrombosis have never been investigated.
Aims: To study the mechanisms involved in the maintenance of vascular integrity and thrombosis under intestinal inflammatory conditions.
Methods: We used a mouse model of acute colitis induced by oral administration of dextran sodium sulfate for 7 days. Diarrhea and bleeding scores were determined upon depletion of platelets, neutrophils or glycoprotein VI, treatment with aspirin or clopidogrel or in P2X1-/- mice. Platelet and neutrophil count, red blood cell (RBC) indices and plasma levels of erythropoietin (EPO), IL-6 and G-CSF were analyzed. Extra-intestinal thrombosis was assessed using a laser-induced injury model of thrombosis in cremaster muscle arterioles. Accumulation of platelets, neutrophils and fibrin generation were recorded in real-time.
Results: Thrombocytopenia or P2X1 deficiency led to macrocytic regenerative anemia due to intestinal hemorrhage. Hemoglobin levels and RBC count were severely decreased while mean corpuscular volume (MCV) and red cell distribution width (RDW) were higher as compared to wild-type controls. EPO plasma levels were elevated. Spleens were enlarged and contained higher fraction of immature erythroblasts. Strikingly, P2X1-/- mice exhibited higher neutrophil count due to increased G-CSF levels, while platelet count was unchanged. Neutrophil depletion limited blood loss and fully restored RBC indices P2X1-/- mice. Colitic P2X1-/- mice showed a strong increase of neutrophil accumulation at the site of arteriolar wall injury. Fibrin generation was reinforced despite impaired platelet recruitment in the growing thrombi.
Conclusions: In inflamed intestine, platelets and P2X1 ion channels are mandatory to preserve vascular integrity. Upon P2X1 deficiency, neutrophils are responsible for massive intestinal bleeding associated with extra-intestinal pro-thrombotic tendency due to formation of neutrophil-rich thrombi.

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