Exacerbation of thromboinflammation by JAK2 V617F mutation worsens the prognosis of cerebral venous sinus thrombosis

Abstract

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.