Abstract Number: OC 72.3
Meeting: ISTH 2022 Congress
Background: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. JAK2V617F mutation, the most frequent mutation in myeloproliferative neoplasms (MPNs), has been reported to be associated with CVST. Worse outcome has been observed in MPN-related CVST patients with particularly higher thrombotic recurrence. However, the underlying related pathophysiological mechanisms are still poorly understood.
Aims: To investigate whether JAK2V617F mutation predisposes to specific pathophysiological processes and/or worse prognosis using a mouse model of CVST.
Methods: A new CVST model was achieved by autologous clot injection into the superior sagittal sinus. Clinical, biological and imaging outcomes, were analyzed in mice expressing JAK2V617F mutation only in hematopoietic cells (Jak2V617F) compared to Jak2WT mice. On day 1 (D1) after CVST, parenchymal injury was monitored (magnetic resonnance imaging, immuno-histology, intravital microscopy). Platelet-neutrophil agregates (PNAs) and neutrophil activation were determined by flow cytometry analysis of whole blood samples.
Results: At D1 after CVST, survival rate was decreased in Jak2V617F mice compared to Jak2WT mice (78.5% versus 100%, p=0.04). Two hours after CVST, intravital microscopy demonstrated increased neutrophil and platelet adhesion in cortical cerebral veins in Jak2V617F mice compared to Jak2WT mice. At D1, higher level of circulating PNAs (69±18% vs 23±13%, p < 0.01) and increased expression of CD11b on neutrophils were also observed in Jak2V617F mice. At D1, occurrence of intracranial hemorrhage was higher in Jak2V617F compared to Jak2WT mice (69% vs 36% respectively, p=0.03). Following sacrifice at D1, brain immunohistological analyses showed that neutrophils localized within cortical haemorrhagic area suggesting involvement of neutrophils in the bleeding process.
Conclusion(s): Our study shows that the JAK2V617F mutation leads to a specific CVST pattern with increased intracranial hemorrhage and mortality. Our results suggest that neutrophils could contribute to hemorrhagic complications as part of the thrombo-inflammatory response.
To cite this abstract in AMA style:BOURRIENNE M, Solo-nomenjanahary M, Faille D, GAY J, Loyau S, Villeval J, Edmond V, Plo I, Ho-Tin-Noé B, Mazighi M, Ajzenberg N. JAK2V617F mutation exacerbates the thrombo-inflammatory response to Cerebral Venous Sinus Thrombosis in mice [abstract]. https://abstracts.isth.org/abstract/jak2v617f-mutation-exacerbates-the-thrombo-inflammatory-response-to-cerebral-venous-sinus-thrombosis-in-mice/. Accessed September 26, 2022.
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