Université Paris Cité and Université Sorbonne Paris Nord, INSERM UMRS-1148, Laboratory for Vascular Translational Science, Paris, France.
Laboratoire d'Hématologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France.
Blood Adv. 2024 Jun 25;8(12):3330-3343. doi: 10.1182/bloodadvances.2023011692.
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 with wild-type Jak2 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 (ICHs) and higher mortality rates. Peripheral neutrophil activation was enhanced, as indicated by higher circulating platelet-neutrophil aggregates, upregulated CD11b expression, and higher myeloperoxydase plasma level. Concurrently, immunohistological and brain homogenate analysis showed higher neutrophil infiltration and increased blood-brain barrier disruption. Similarly, patients with JAK2V617F-positive CVST tended to present higher thrombotic burden and had significantly higher systemic immune-inflammation index, a systemic thromboinflammatory marker, than patients who were JAK2V617F-negative. In mice with CVST, our study corroborates that Jak2V617F mutation leads to a specific pattern including increased thrombotic burden, ICH, and mortality. The exacerbated thromboinflammatory response, observed both in mice and patients positive for JAK2V617F, could contribute to hemorrhagic complications.
脑静脉窦血栓形成（CVST）是一种不常见的静脉血栓栓塞事件，占脑实质损伤引起的中风的<1%。JAK2V617F 突变是骨髓增殖性肿瘤最常见的驱动突变，已有报道称其与 CVST 患者的临床结局较差相关。我们研究了造血 JAK2V617F 表达是否易导致 CVST 后特定的病理生理过程和/或较差的预后。我们使用 CVST 的体内小鼠模型，分析了具有造血限制 JAK2V617F 表达的小鼠与野生型 Jak2 小鼠相比的临床、生物学和影像学结局。同时，我们研究了 JAK2V617F 阳性或阴性 CVST 的人类队列。在 CVST 后早期，具有造血 Jak2V617F 表达的小鼠大脑静脉中靠近 CVST 的部位血小板和中性粒细胞的粘附增加。第 1 天，Jak2V617F 小鼠的结果更差，表现为更频繁和更严重的颅内出血（ICH）和更高的死亡率。外周中性粒细胞活化增强，表现为循环血小板-中性粒细胞聚集体增加、CD11b 表达上调和髓过氧化物酶血浆水平升高。同时，免疫组织化学和脑匀浆分析显示中性粒细胞浸润增加和血脑屏障破坏增加。同样，JAK2V617F 阳性 CVST 患者的血栓形成负担较高，全身免疫炎症指数（一种全身性血栓炎症标志物）明显高于 JAK2V617F 阴性患者。在 CVST 小鼠中，我们的研究证实了 Jak2V617F 突变导致了一种特定的模式，包括增加的血栓形成负担、ICH 和死亡率。在 JAK2V617F 阳性的小鼠和患者中观察到的加剧的血栓炎症反应可能导致出血并发症。
