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Neutrophils Prothrombotic Characteristics during Myeloproliferative Neoplasms
ISTH Academy. James C. Jul 10, 2019; 273861; OC 77.3
Chloé James
Chloé James
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OC 77.3

Neutrophils Prothrombotic Characteristics during Myeloproliferative Neoplasms

A. Guy1,2, V. Gourdou-Latyszenok1,2, S. Favre1,2, S. Labrouche-Colomer1,2,3, L. Deloison1,2, M.-A. Renault1,2, T. Couffinhal1,2, C. James1,2,3
1University of Bordeaux, Bordeaux, France, 2University of Bordeaux, INSERM, UMR 1034, Biology of Cardiovascular Diseases, Pessac, France, 3Laboratory of Hematology, University Hospital Center of Bordeaux, Pessac, France

Main Topic: Immunothrombosis and Vascular Biology
Category: Blood Cells & Vessel Wall

Background: Thrombosis is the most frequent complication during evolution of myeloproliferative neoplasms (MPN) but the events causing these clotting abnormalities remain unclear. Neutrophils are now recognized as important actors of thrombosis, especially by their capacity to emit neutrophil extracellular traps (NETs).
Aims: To assess if JAK2V617F neutrophils are more prone to form NETs, thus promoting thrombosis.
Methods: We first studied MPN patients and quantified:
1) NETosis markers,
2) NET formation,
3) reactive oxygen species (ROS) formation.
In a second part, we studied two different mouse models: PF4-iCre;JAK2V617/WT mice with expression of JAK2V617F in hematopoietic cells and MRP8-iCre;JAK2V617/WT mice with expression of JAK2V617F in neutrophils only. In these models, we quantified: 1) NET formation, 2) plasma levels of circulating DNA, 3) pulmonary thrombus formation. In PF4-iCre;JAK2V617/WT mice, we analysed thrombus formation after DNAse administration. Finally, we quantified NET formation from JAK2WT or JAK2V617F neutrophils in presence or absence of JAK2WT or JAK2V617F platelets.
Results: In MPN patients, we found:
1) increased plasma levels of free DNA in all patients and increased plasma levels of MPO-DNA complex in patients with history of thrombosis,
2) increased ex-vivo NETs formation,
3) increased neutrophils ROS production.
In mouse models, we observed an increased NETs formation in the two mouse models analysed. We observed increased plasma levels of free DNA and increased thrombus formation in PF4-iCre;JAK2V617F/WT mice only. Thrombus formation was abrogated in PF4-iCre;JAK2V617F/WT mice after DNAse administration. We observed an increased NET formation in presence of JAK2V617F neutrophils and JAK2V617F platelets, with a decreased NETs formation after platelets inhibition.
Conclusions: Our results show that neutrophils are prone to form NETs during MPN, in a patient cohort, and in two different mouse models. More, our study demonstrates that JAK2V617F neutrophils alone are not sufficient to promote thrombosis and that the cooperation with platelets is important in NETs formation.

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