Exacerbation of thrombo-inflammation by JAK2V617F mutation worsens the prognosis of cerebral venous sinus thrombosis.


Journal

Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425

Informations de publication

Date de publication:
22 Feb 2024
Historique:
accepted: 09 02 2024
received: 21 09 2023
revised: 22 01 2024
medline: 22 2 2024
pubmed: 22 2 2024
entrez: 22 2 2024
Statut: aheadofprint

Résumé

Cerebral venous sinus thrombosis (CVST) is an uncommon venous thromboembolic event accounting for <1% of strokes resulting in brain parenchymal injuries. JAK2V617F mutation, the most frequent driving mutation of myeloproliferative neoplasms has been reported to be associated with worse clinical outcomes in patients with CVST. We investigated whether hematopoietic JAK2V617F expression predisposes to specific pathophysiological processes and/or worse prognosis after CVST. Using an in vivo mouse model of CVST, we analyzed clinical, biological and imaging outcomes in mice with hematopoietic-restricted Jak2V617F expression, compared to Jak2WT mice. In parallel, we studied a human cohort of JAK2V617F-positive or negative CVST. Early after CVST, mice with hematopoietic Jak2V617F expression had increased adhesion of platelets and neutrophils in cerebral veins located in the vicinity of CVST. On day 1, Jak2V617F mice had a worse outcome characterized by significantly more frequent and severe intracranial hemorrhages (ICH) and higher mortality rates. Peripheral neutrophil activation was enhanced, as indicated by higher circulating platelet-neutrophil aggregates, upregulated CD11b expression, and higher myeloperoxydase (MPO) plasma level. Concurrently, immunohistological and brain homogenates analysis showed higher neutrophil infiltration and increased blood-brain-barrier disruption. Similarly, JAK2V617F-positive CVST patients tended to present higher thrombotic burden and had significantly higher SII, a systemic thrombo-inflammatory marker, compared to JAK2V617F-negative patients. In mice with CVST, our study corroborates that Jak2V617F mutation leads to a specific pattern including increased thrombotic burden, ICH and mortality. The exacerbated thrombo-inflammatory response, observed both in mice and JAK2V617F-positive patients, could contribute to hemorrhagic complications.

Identifiants

pubmed: 38386979
pii: 515036
doi: 10.1182/bloodadvances.2023011692
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 American Society of Hematology.

Auteurs

Marie-Charlotte Bourrienne (MC)

INSERM U1148, LVTS, Paris, France.

Véronique Le Cam Duchez (V)

Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit, F 76000 Rouen, France, Rouen, France.

Dorothée Faille (D)

Bichat Hospital, PARIS CEDEX 18, France.

Carine Farkh (C)

INSERM U1148, LVTS, Paris, France.

Mialitiana Solo Nomenjanahary (M)

INSERM U1148, Paris, France.

Juliette Gay (J)

Hôpital Bichat Claude Bernard, Paris, France.

Stéphane Loyau (S)

INSERM U1148, LVTS, Paris, France.

Clément Journé (C)

INSERM U1148, LVTS, Paris, France.

Sébastien Dupont (S)

INSERM U1148, LVTS, Paris, France.

Véronique Ollivier (V)

INSERM, Paris, France.

Jean-Luc J-L Villeval (JJ)

INSERM, U1287, Gustave Roussy, Université Paris Saclay, Villejuif, France.

Isabelle Plo (I)

INSERM UMR 1287, Villejuif, France.

Valérie Edmond (V)

INSERM U1287, Villejuif, France.

Martine Jandrot-Perrus (M)

University Paris Cité, Paris cedex 18, France.

Sylvie Labrouche-Colomer (S)

University Bordeaux, INSERM, Biologie des maladies cardiovasculaires, U1034, F-33600 Pessac, France, PESSAC, France.

Bruno Cassinat (B)

Hopital Saint-Louis, Assistance Publique-Hopitaux de Paris, Paris, France.

Emmanuelle Verger (E)

APHP Hôpital St Louis, Paris, France.

Jean-Philippe Desilles (JP)

Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France.

Aude Triquenot Bagan (A)

Rouen University Hospital, Department of Neurology and INSERM CIC-CRB 1404, F-76000 Rouen , France, Rouen, France.

Mikaël Mazighi (M)

Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, F-75006 Paris, France.

Nadine Ajzenberg (N)

AP-HP, INSERM, PARIS CEDEX 18, France.

Classifications MeSH