OC 72.3 - JAK2V617F mutation exacerbates the thrombo-inflammatory response to Cerebral Venous Sinus Thrombosis in mice

Wednesday, July 13, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, ICC Capital Suite Room 7&12

Presentation Format: In-Person

Presenting Author(s)

Marie-Charlotte BOURRIENNE, PharmD

Assistant
Laboratoire d'Hématologie, AP-HP, Hôpital Bichat Claude-Bernard, Paris, France.
PARIS, Ile-de-France, France

Co-Author(s)

MS

Mialitiana Solo-nomenjanahary

Engineer
INSERM U1148, Laboratory for Vascular Translational Science
PARIS, Ile-de-France, France
Dorothée FAILLE, PharmD PhD

Associate professor
Laboratoire d'Hématologie, AP-HP, Hôpital Bichat Claude-Bernard, Paris, France.
PARIS CEDEX 18, Ile-de-France, France
JG

Juliette GAY

Assistant
Bichat Hospital, Paris, France
PARIS, Ile-de-France, France
SL

Stéphane Loyau

IE
INSERM UMRS-1148
PARIS, Ile-de-France, France
JV

Jean-Luc Villeval

Director of research
INSERM UMR1287, Université Paris Saclay, Gustave Roussy
Villejuif, Ile-de-France, France
VE

Valérie Edmond

Engineer
INSERM UMR1287, Université Paris Saclay, Gustave Roussy
Villejuif, Ile-de-France, France
IP

Isabelle Plo

Director of research
INSERM UMR1287, Université Paris Saclay, Gustave Roussy
Villejuif, Ile-de-France, France
Benoît Ho-Tin-Noé, PhD

Research Director
Université de Paris Descartes, INSERM, Hôpital Bichat, UMR-S1148, F-75000 Paris, France
Paris, Ile-de-France, France
MM

Mikaël Mazighi

Head of the department of neurology
Département de neurologie, Hôpital Lariboisière (APHP), FHU NeuroVasc, INSERM U1148, Laboratory for Vascular Translational Science
PARIS, Ile-de-France, France
NA

Nadine Ajzenberg

MD, PhD
Laboratoire d'Hématologie, AP-HP, Hôpital Bichat Claude-Bernard, Paris, France.
Paris, Ile-de-France, France

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.