Abstract Number: OC 38.2
Meeting: ISTH 2022 Congress
Background: Thrombosis is a frequent complication during JAK2V617F myeloproliferative neoplasms (MPN) and neutrophils, especially through emission of neutrophil extracellular traps (NETs) were shown to promote thrombosis in MPN mouse models.
Aims: To assess whether JAK2V617F neutrophils alone are prone to NET formation, or whether they need to be activated to promote thrombosis.
Methods: We used two MPN mouse models with JAK2V617F expression in neutrophils: PF4-iCre;JAK2V617/WT mice with JAK2V617F expression in all blood cells compartments and MRP8-iCre;JAK2V617/WT mice with JAK2V617F expression only in neutrophils and monocytes. Thrombosis was analyzed in the lungs. Ex vivo NETosis was studied by immunofluorescence using histone 3 staining. In vivo NETosis was studied measuring plasmatic DNA and citrullinated histone 3 levels.
Results: We observed increased ex vivo NETosis in both models, but in vivo NETosis was only increased in PF4-iCre;JAK2V617/WT mice. Besides, only PF4-iCre;JAK2V617/WT mice had increased thrombosis formation, and NET inhibition reduced it. We hypothesized that increased inflammation or increased platelet activation could explain the differences in NET formation and thrombosis between PF4-iCre;JAK2V617/WT and MRP8-iCre;JAK2V617/WT mice. We could not find any evidence for the role of inflammation as (1) plasmatic TNF-alpha concentration was similar, (2) addition of plasma from PF4-iCre;JAK2V617/WT mice on JAK2V617F neutrophils did not increase ex vivo NETosis, (3) TNF-alpha or LPS treatment of MRP8-iCre;JAK2V617/WT mice did not increase thrombosis. We then focused on platelets and observed increased ex vivo NETosis when JAK2V617F platelets were coincubated with JAK2V617F neutrophils. Finally, treatment of PF4-iCre;JAK2V617/WT mice with aspirin reduced in vivo NETosis and thrombosis formation.
Conclusion(s): We show here that the presence of JAK2V617F neutrophils together with JAK2V617F platelets is necessary to trigger increased NETosis and thrombosis in a mouse model of JAK2V617F MPN. Interestingly, platelet inhibition can inhibit NETosis and subsequent increased thrombosis formation.
To cite this abstract in AMA style:Guy A, Gourdou-Latyszenok V, Wolff-Thrombini L, Favre S, Labrouche-Colomer S, Renault M, James C. Neutrophils and platelets collaborate to induce an increase NET formation during JAK2V617F positive myeloproliferative neoplasms [abstract]. https://abstracts.isth.org/abstract/neutrophils-and-platelets-collaborate-to-induce-an-increase-net-formation-during-jak2v617f-positive-myeloproliferative-neoplasms/. Accessed February 28, 2024.
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